Celiac Disease

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Classifications

Harrison's Part

👪

Inheritance

1

Polygenic inheritance HP:0010982

Strong HLA association (HLA-DQ2/DQ8) plus non-HLA polygenic risk factors and environmental triggers

Polygenic inheritance

Show evidence (1 reference)

PMID:31331324 SUPPORT Human clinical

"A genetic background (HLA-DQ2/DQ8 positivity and non-HLA genes) is a mandatory determinant of the development of the disease, which occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota)"

Celiac disease requires multiple genetic risk loci plus environmental triggers, characteristic of polygenic inheritance.

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Subtypes

9

Classical (symptomatic malabsorptive)

Presents with the malabsorptive syndrome - diarrhea, steatorrhea, weight loss and nutrient deficiency - on a background of villous atrophy.

Non-classical (extraintestinal or minor GI presentation)

Presents without the malabsorptive syndrome, through extraintestinal features such as anemia, reduced bone mineral density, transaminase elevation or neurological manifestations, or with non-specific bowel symptoms including constipation.

Subclinical / silent (screen-detected)

Positive serology and villous atrophy on biopsy with no attributable symptoms, usually found by screening a risk group. "Subclinical" is the Oslo term; "silent" is the older usage and is sometimes restricted to asymptomatic villous atrophy specifically.

Show evidence (1 reference)

PMID:33179621 SUPPORT Human clinical

"In 2011, the Oslo Classification ranked the clinical presentation of CD in classical, non classical, subclinical and refractory"

The naming authority for the clinical forms recorded in this block, and the source of "subclinical" as the preferred term for this one.

Latent

A historically ambiguous label, used both for disease that was previously abnormal and has normalized on diet, and for currently normal mucosa that later becomes abnormal. Recorded because it appears in older literature; because the two senses are opposites, a report using it has to say which is meant.

Nonresponsive celiac disease

Persistent or recurrent symptoms, laboratory abnormalities or enteropathy after six to twelve months of prescribed gluten withdrawal. This is not a synonym for refractory disease and is the more common situation: most cases turn out to be continued gluten exposure, a second diagnosis, or a complication, and evaluation for those comes before a refractory label.

Potential

Positive celiac serology and a compatible HLA genotype with normal duodenal architecture. Some, but not all, progress to enteropathy. This form and the seronegative form are defined by the absence of one of the two components the standard diagnosis requires - positive serology on a gluten-containing diet and characteristic small-bowel histology - which is what makes each of them a named exception rather than simply an incomplete workup.

Show evidence (1 reference)

PMID:20301720 SUPPORT REVIEW SYNTHESIS Human clinical

"The diagnosis of celiac disease is established in an individual with positive celiac serologic testing results while on a gluten-containing diet"

The GeneReviews chapter's statement of the diagnostic standard. The same sentence continues by requiring "characteristic histologic findings on small bowel biopsy", so the standard has two components; it is quoted here only to its first component because the intervening parenthetical lists the antibodies in brackets, which snippet normalization strips. That two-component baseline is what makes the potential form (serology without histology) and the seronegative form (histology without serology) named exceptions rather than incomplete workups.

Seronegative

Villous atrophy with HLA-DQ2/DQ8 positivity that responds to a gluten-free diet, in a patient with no detectable celiac antibodies. Roughly 1.7% of cases, and the boundary condition on the entry's autoantibody node.

Refractory celiac disease type I

Persistent or recurrent malabsorptive symptoms with villous atrophy after more than twelve months of strict gluten withdrawal, with a normal (polyclonal) intraepithelial lymphocyte phenotype. Reported five-year survival reaches about 95%, with five-year progression to enteropathy-associated T-cell lymphoma below 14%.

Refractory celiac disease type II (RCDII)

Refractory disease carrying a clonal population of phenotypically aberrant intraepithelial lymphocytes, commonly with JAK1 or STAT3 gain-of-function mutations. This is the premalignant form, and the clinical counterpart of the Aberrant Clonal Intraepithelial Lymphocyte Expansion node; it precedes most enteropathy-associated T-cell lymphoma. Reported five-year survival is about 58%, substantially below type I.

Show evidence (1 reference)

PMID:33579790 SUPPORT Human clinical

"often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII)"

Defines this subtype as the clonal intraepithelial lymphoproliferation that commonly precedes lymphoma, which is what distinguishes it from type I.

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Mechanistic Hypotheses

1

Canonical Gluten / HLA-DQ2-DQ8 / tTG Enteropathy Model

canonical_gluten_hladq_ttg_enteropathy_model CANONICAL

Evidence balance 4 support

Celiac disease arises in HLA-DQ2 / HLA-DQ8 positive individuals from a CD4 T-cell-mediated immune response to dietary gluten/gliadin peptides that have been deamidated by tissue transglutaminase 2 (TG2/tTG). Deamidation converts neutral glutamine residues to negatively charged glutamate, dramatically increasing peptide affinity for HLA-DQ2/DQ8 and licensing presentation to gluten-reactive CD4 T cells in the lamina propria. The resulting mixed Th1/Th17/IL-21 cytokine response, together with IL-15-driven innate epithelial activation (proposed as a co-required signal in the three-signal model, so far demonstrated as a strict co-requirement only in an engineered mouse), drives intraepithelial lymphocyte cytotoxicity, B-cell expansion with anti-TG2 autoantibody production, crypt hyperplasia, and villous atrophy. Gluten-free diet remission, HLA-DQ2/DQ8 restriction, and the ZED1227 randomized TG2-inhibitor trial (attenuated the gluten-induced fall in villus-height/crypt-depth ratio) all corroborate the gluten / HLA / TG2 axis as the canonical pathogenic mechanism.

Retained as CANONICAL. The 2026 openscientist hypothesis-search report (kb/hypotheses/Celiac_Disease/canonical_gluten_hladq_ttg_enteropathy_model) finds STRONGLY SUPPORTED with five required mechanistic expansions. Core gluten → TG2-deamidation → HLA-DQ2/DQ8 presentation → CD4 T-cell activation → mucosal injury cascade is validated by ZED1227 Phase 2a (TG2 inhibition attenuated gluten-induced mucosal injury — the first causal human perturbation of the axis), HLA-DQ2 tetramer and direct-cloning studies (0.5–1.8% of intestinal CD4 T cells gluten-reactive by cloning and 0.1–1.2% tetramer-positive, correlating with Marsh grade and serum IgA anti-TG2), and gluten-free-diet remission. The report's five proposed expansions are recorded here with the dispositions from the 2026 assessment sidecar (assessments/openscientist-assessment-by-codex.yaml), which are weaker than the report's own wording: (1) IL-15 / innate immunity co-required for villous atrophy — three-signal model (IL-15 + HLA-DQ + gluten) — QUALIFIED: demonstrated in an engineered HLA-DQ8 mouse overexpressing IL-15, not established as a universal human co-requirement (see the HUMAN_MODEL_MISMATCH discussion); (2) the cytokine response is mixed Th1/Th17/IL-21 rather than pure Th1/IFN-γ — QUALIFIED: IL-17A and IL-21 production is documented in active human mucosa, largely in cells that also make IFN-γ, which is cytokine complexity rather than a coequal independent Th17 driver; (3) three nested positive feedback loops (IgA-CD71 retrotranscytosis, IFN-γ / thioredoxin/TG2 activation, B-cell APC amplification) drive chronicity — QUALIFIED: each loop has separate experimental support, but they have never been tested as an integrated system and the histologic follow-up cohorts do not attribute incomplete healing to them; (4) wheat amylase-trypsin inhibitors (ATIs) provide parallel TLR4-mediated innate signaling as adjuvant — QUALIFIED: TLR4 activation and low-grade murine intestinal inflammation are shown, contribution to human celiac initiation is not; (5) transcellular IgA-CD71 retrotranscytosis is the dominant gluten transport route — REJECTED: the cited work demonstrates a transport mechanism in epithelial monolayers, not its quantitative dominance over the paracellular route in patients, so no route ranking is asserted here. The tolerance-breaking trigger — what converts ~97% of HLA-DQ2/DQ8 carriers (oral-tolerant) into the ~1–3% who develop disease — remains unresolved. Boundary conditions where the model is insufficient: seronegative CeD (~1.7%), refractory CeD type II (gluten-independent clonal T-cell expansion), and DQ8-specific mechanistic differences.

Deep research

OpenScientist citations 46 citations 2026-05-23T22:39:43.397866

Show evidence (4 references)

PMID:38914866 SUPPORT Human clinical

"Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of"

Canonical mechanism reference used as the seed for the hypothesis-search deep-research run.

PMID:34192430 SUPPORT Human clinical

"Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury."

ZED1227 Phase 2a randomized trial (CEC-3) provides the strongest interventional evidence for the canonical gluten/HLA/TG2 axis: pharmacological TG2 inhibition attenuated the loss of villus-height/crypt-depth ratio during gluten challenge. The primary-endpoint differences from placebo were 0.44 (10 mg), 0.49 (50 mg) and 0.48 (100 mg), so the trial establishes a causal contribution of TG2 and its therapeutic tractability rather than a monotonic dose response or strict necessity of TG2 in every genotype and disease context.

PMID:23775608 SUPPORT Human clinical

"the frequency of gluten-specific T cells correlated with the degree of histological damage in the gut mucosa as scored by Marsh-grading, and also with serum IgA anti-transglutaminase 2 antibody levels"

Direct measurement of the HLA-DQ2-restricted, gluten-reactive CD4 T-cell compartment in intestinal biopsies ties the frequency of the cells the canonical model makes central to both the histological severity and the anti-TG2 humoral output the model predicts.

+ 1 more reference

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Discussions and Knowledge Gaps

8

Is dual epithelial and lamina propria IL-15 overexpression a genuine co-requirement for villous atrophy in human celiac disease, as it is in the engineered HLA-DQ8 mouse, or is IL-15 an amplifier whose removal does not by itself prevent gluten-induced mucosal injury?

HUMAN MODEL MISMATCH OPEN mismatch_three_signal_villous_atrophy_requirement

Attached to

mechanistic_hypotheses#canonical_gluten_hladq_ttg_enteropathy_model pathophysiology#Intestinal Epithelial Damage phenotypes#Villous Atrophy

The three-signal model (gluten + HLA-DQ + IL-15) is the single most consequential expansion the 2026 openscientist report proposed, and the canonical hypothesis description leans on it. Its direct demonstration is a mouse engineered to overexpress IL-15 in two gut compartments while expressing HLA-DQ8; that construction shows the three signals are jointly sufficient in the model, not that each is separately necessary in patients. Human biopsy work supports IL-15 involvement and shows epithelial stress and adaptive antigluten immunity acting in synergy, but it does not establish the engineered configuration as a universal human rule. The published anti-IL-15 trial cuts the other way: AMG 714 did not prevent mucosal injury during gluten challenge, which is what removing one of three strictly required signals should have done. Curate the three-signal model as strong model-organism support plus a human mechanistic hypothesis, and do not assert a proven human co-requirement.

Proposed experiments

IL-15 blockade in gluten-exposed celiac disease, powered for histology and stratified by HLA-DQ

exp_celiac_il15_blockade_active_disease

Building on the AMG 714 phase 2a result, run an adequately powered randomized trial of IL-15 or IL-15Ralpha blockade during a standardized gluten challenge, stratified by HLA-DQ2 homozygosity, DQ2 heterozygosity and DQ8, with predefined co-primary histologic and intraepithelial lymphocyte endpoints and mucosal transcriptomics. Include an arm combining IL-15 blockade with TG2 inhibition to separate additive from synergistic action of the innate and adaptive arms.

Would support

pathophysiology#Intestinal Epithelial Damage

Would refute

mechanistic_hypotheses#canonical_gluten_hladq_ttg_enteropathy_model

Supporting outcome

IL-15 blockade alone prevents the gluten-induced fall in villus height-to-crypt depth ratio, establishing IL-15 as a required signal in humans rather than an amplifier.

Refuting outcome

Adequately powered IL-15 blockade again fails to protect mucosal architecture while TG2 inhibition in the same trial does, indicating that the human requirement is carried by the adaptive arm and that the engineered mouse configuration does not transfer.

Show evidence (3 references)

PMID:32051586 SUPPORT Model organism

"Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease."

The primary source of the three-signal claim. The requirement is established inside an engineered mouse that expresses HLA-DQ8 and overexpresses IL-15 in two compartments, which is why the claim is curated as model-organism evidence.

PMID:26001928 SUPPORT Human clinical

"The adaptive immune response to gluten appears to act in synergy with epithelial stress to allow intraepithelial cytotoxic T cells to kill epithelial cells and induce villous atrophy in patients with active celiac disease."

Human tissue evidence that epithelial stress and antigluten adaptive immunity are both involved and synergistic. It supports two contributing arms without demonstrating that a specific two-compartment IL-15 configuration is necessary in every patient.

PMID:31494096 REFUTE Human clinical

"AMG 714 did not prevent mucosal injury due to gluten challenge."

The strong reading of the three-signal model predicts that removing IL-15 should block villous atrophy. A randomized anti-IL-15 antibody trial in gluten-challenged patients missed that endpoint, which is the central reason this is recorded as an open human-model mismatch rather than as an established human co-requirement. Note the trial was in treated patients undergoing short gluten challenge and did show a smaller intraepithelial lymphocyte rise at 300 mg, so it constrains the necessity claim without excluding an IL-15 contribution.

What event converts an HLA-DQ2/DQ8 carrier who is orally tolerant to gluten into one who mounts the pathogenic gluten-specific CD4 T-cell response?

KNOWLEDGE GAP OPEN gap_celiac_tolerance_breaking_trigger

Attached to

pathophysiology#Gluten-Triggered Immune Response mechanistic_hypotheses#canonical_gluten_hladq_ttg_enteropathy_model environmental#Gastrointestinal Infections

The canonical model starts at gluten presentation and is silent on what licenses that presentation to break tolerance. HLA-DQ2 or DQ8 is carried by a large minority of the general population and only about 1 percent develop disease, so the haplotype fixes susceptibility rather than timing or penetrance. The candidate triggers this entry already records as environmental factors are individually inconclusive: enteric infection is supported by reovirus work in mice without human replication, dysbiosis is correlative and bidirectional, and randomized trials found that the timing of infant gluten introduction does not alter risk. Because this gap sits upstream of every node in the entry, it is the step whose resolution would do most for primary prevention.

Proposed experiments

Serial virome, microbiome and mucosal immune phenotyping in at-risk infants through seroconversion

exp_celiac_prospective_virome_before_seroconversion

Extend an existing HLA-DQ2/DQ8 at-risk birth cohort with serial stool virome and microbiome sequencing, interferon-signature profiling and, where ethically possible, mucosal sampling, anchored on the date of anti-TG2 seroconversion rather than on diagnosis, so that candidate triggers can be ordered before and after the loss of tolerance instead of being sampled after disease is established.

Would support

environmental#Gastrointestinal Infections

Supporting outcome

A specific exposure window, viral taxon or interferon signature reproducibly precedes anti-TG2 seroconversion in at-risk carriers and is absent in matched carriers who remain tolerant.

Refuting outcome

No exposure or immune signature separates carriers who seroconvert from those who do not, which would move the trigger to host-intrinsic or stochastic explanations rather than an environmental event.

What sustains the clonal intraepithelial lymphocyte expansion of refractory celiac disease type II once it no longer depends on gluten stimulation, and at what point does the canonical model stop applying?

KNOWLEDGE GAP OPEN gap_celiac_rcd2_gluten_independent_clonal_expansion

Attached to

mechanistic_hypotheses#canonical_gluten_hladq_ttg_enteropathy_model pathophysiology#Intestinal Epithelial Damage treatments#Corticosteroids

Refractory celiac disease type II is the clearest boundary condition on the canonical model in this entry. Dominant T-cell receptor beta clonotypes recovered from these patients are patient-specific and bear no homology to known gliadin-specific sequences, and the clones persist stably for years on a strict gluten-free diet, so the driving stimulus is no longer the antigen the rest of the entry is built around. Genetic susceptibility to the progression also appears to be separate from susceptibility to celiac disease itself. What the entry cannot yet say is what does drive the expansion, which matters because this is the pre-lymphomatous state that the gluten-free diet does not treat.

Show evidence (2 references)

PMID:28188172 SUPPORT Human clinical

"Dominant TCRβ sequences identified in patients with RCD type II are unique and not homologous to known gliadin-specific TCR sequences, supporting the assumption that these clonal T-cells expand independent of gluten stimulation."

High-throughput sequencing of the duodenal T-cell repertoire is the direct evidence that the expanded clones are not the gluten-specific cells the canonical model describes. The authors themselves frame this as supporting an assumption rather than proving stimulus independence.

PMID:29787419 SUPPORT Human clinical

"SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10, odds ratio=2.36) but not with CeD susceptibility."

A susceptibility variant specific to the progression and absent from celiac susceptibility indicates the refractory state has partly separate genetic determinants, reinforcing it as a boundary rather than a late stage of the same mechanism.

Do the proposed amplification loops of celiac disease operate as one integrated system, and would disrupting a single loop collapse the cascade?

KNOWLEDGE GAP OPEN gap_celiac_integrated_feedback_loops

Attached to

mechanistic_hypotheses#canonical_gluten_hladq_ttg_enteropathy_model pathophysiology#Autoantibody Production pathophysiology#Barrier Dysfunction

Three amplification loops are commonly invoked to explain why celiac disease escalates quickly and heals slowly: secretory IgA delivering gliadin peptides back across the epithelium through CD71, IFN-gamma driving thioredoxin release that reactivates extracellular TG2, and TG2-reactive B cells presenting gluten peptides to gluten-specific T cells. Each has separate experimental support, but they were characterized in different reductionist systems and have never been perturbed together in one system, so their joint contribution is an inference rather than a measurement. The follow-up cohorts that document delayed or incomplete mucosal recovery on a gluten-free diet describe the outcome without attributing it to these loops.

Proposed experiments

Combinatorial loop perturbation in patient-derived intestinal organoid immune co-cultures

exp_celiac_combinatorial_loop_perturbation

In duodenal organoid or air-liquid-interface cultures retaining tissue-resident immune cells from celiac patients, block CD71-mediated retrotranscytosis, extracellular TG2 activity and B-cell antigen presentation singly and in combination during gliadin exposure, reading out gluten-specific T-cell activation, epithelial injury and anti-TG2 output.

Would support

pathophysiology#Autoantibody Production

Supporting outcome

Blocking any single loop produces a disproportionate reduction in gluten-specific T-cell activation and epithelial injury, which is the signature of a coupled amplifying system.

Refuting outcome

Single blockades produce only additive, proportionate reductions, indicating three parallel contributors rather than one nested self-amplifying circuit.

Show evidence (2 references)

PMID:22750506 SUPPORT In vitro / ex vivo

"In the presence of celiac IgA or SIgA against p31-49, transport of intact 3H-p31-49 increased significantly across Caco-2 monolayers; this transport was inhibited by soluble CD71 or Tgase2 inhibitors."

Demonstrates the retrotranscytosis loop as a transport mechanism in epithelial cell monolayers. It establishes that the route exists and is CD71 and TG2 dependent, and deliberately does not establish that it is the dominant route to the lamina propria in patients.

PMID:31285344 SUPPORT Human clinical

"Production of antibodies against N-terminal epitopes coincided with clinical onset of disease, suggesting that TG2-reactive B cells with certain epitope specificities could be the main antigen-presenting cells for pathogenic, gluten-specific T cells."

Supports the B-cell antigen-presenting loop from patient-derived plasma cells, with the authors' own hedge that these B cells could be the main presenting cells, which is the level of claim curated here.

Do wheat amylase-trypsin inhibitors contribute to human celiac disease as a TLR4-dependent innate adjuvant, or is the evidence confined to cell lines, mice and non-celiac inflammatory settings?

HUMAN MODEL MISMATCH OPEN mismatch_celiac_ati_tlr4_adjuvant

Attached to

environmental#Wheat Food Products pathophysiology#Gluten-Triggered Immune Response

Amylase-trypsin inhibitors are a non-gluten wheat component proposed as a parallel innate signal that lowers the threshold for the adaptive gluten response, and they are one reason wheat is singled out among cereals. The supporting work is TLR4 reporter activation in mouse and human cell lines plus modest intestinal inflammation in healthy mice fed dietary concentrations of ATIs. The most frequently paired second citation concerns ATIs as adjuvants of allergic inflammation in PBMC-humanized mice, which is a different disease context. No cited experiment shows an ATI contribution to initiation or enteropathy in celiac patients, and the gluten-free diet that treats the disease removes ATIs and gluten together, so the clinical observation cannot separate them. Recorded here rather than as a pathophysiology node, because adding a node would assert a human celiac mechanism the evidence does not reach.

Show evidence (1 reference)

PMID:27993525 SUPPORT Model organism

"Concentrations of ATIs found in a normal daily gluten-containing diet increased low-level intestinal inflammation."

Establishes that dietary-level ATI intake produces measurable intestinal inflammation, in healthy mice and via TLR4-responsive cell lines. This is the strongest form of the claim the primary literature supports, and it is not a celiac-specific or human result.

Are the developmental enamel defects of celiac disease produced by calcium/vitamin-D/micronutrient deficiency during amelogenesis, by ameloblast-directed IgA autoimmunity arising from broken peripheral tolerance to shared dietary/enamel antigens, or by both?

KNOWLEDGE GAP OPEN gap_celiac_enamel_defect_mechanism

Attached to

phenotypes#Dental Enamel Defects pathophysiology#Autoantibody Production

Two live mechanistic hypotheses have never been separated in patients. The nutrient-deficiency hypothesis rests on cross-sectional nutrient measurements usually taken after the developmental window, and defect burden does not track Marsh grade. The autoimmunity hypothesis gained antigen-level human evidence in 2023 (IgA against ameloblast-specific proteins in celiac cohorts, with kappa-casein cross-reactivity), but the decisive serum-transfer experiments were performed in animals modeling APS-1 rather than ordinary celiac disease. Even the association is heterogeneous - one matched case-control study found no significant excess of enamel hypoplasia. Because enamel records injury only while a crown is mineralizing, established defects are irreversible and diet-response designs cannot arbitrate; no causal edge is recorded in the pathograph for this phenotype until the mechanism is resolved.

Proposed experiments

Pediatric inception cohort spanning permanent-tooth mineralization

exp_celiac_enamel_inception_cohort

Prospective cohort of genetically at-risk children enrolled before permanent-tooth mineralization, with serial ameloblast-protein autoantibody titers, calcium/phosphate/vitamin-D status, verified gluten exposure, and blinded standardized dental imaging as permanent teeth erupt, comparing promptly treated, delayed-diagnosis and nutrient-matched non-celiac children.

Would support

pathophysiology#Autoantibody Production

Supporting outcome

Ameloblast-directed autoantibody titers during mineralization predict enamel defects independently of calcium and vitamin-D status.

Refuting outcome

Enamel defects track nutrient status during the mineralization window with no independent contribution from ameloblast-directed antibodies.

Show evidence (2 references)

PMID:37993717 SUPPORT Human clinical

"the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins"

The human-serology observation behind the autoimmune hypothesis: enamel defects in celiac disease are accompanied by IgA against ameloblast-specific proteins. The paper's causal transfer experiments are animal work in an APS-1 model, so the human claim here is the antibody observation, not established causation.

PMID:17537244 SUPPORT Human clinical

"The prevalence of enamel hypoplasia was not higher in the study population than in the control group."

A matched case-control study in which even the association was absent (26% vs 16%, not significant), supporting this discussion's framing that both the strength of the association and its mechanism remain unsettled across cohorts.

By what mechanism does gluten exposure produce recurrent aphthous stomatitis, sterile inflammatory arthropathy, constipation-predominant bowel dysfunction, fatigue, and peripheral neuropathy in celiac disease, when each improves on a gluten-free diet but no intermediate step has been demonstrated in patients?

KNOWLEDGE GAP OPEN gap_celiac_gfd_responsive_extraintestinal_mechanisms

Attached to

phenotypes#Recurrent Aphthous Stomatitis phenotypes#Arthritis phenotypes#Constipation phenotypes#Fatigue phenotypes#Peripheral Neuropathy

For each of these five phenotypes the association and a gluten-free-diet response are documented, but the mechanism is not, so no causal edge is recorded in the pathograph. Recurrent aphthous stomatitis: candidate routes are hematinic (iron/folate/B12) deficiency from malabsorption versus gluten-driven mucosal immune inflammation; the diet-response evidence is four adherent responders in an uncontrolled series, and nutrient correction has never been factorially separated from gluten withdrawal. Arthritis: a rigorously investigated case of sterile non-erosive polyarthritis remitted within three weeks of gluten withdrawal, and ultrasound series report more subclinical synovitis with gluten exposure, but synovial tissue has rarely been profiled and shared immune susceptibility to coincident rheumatic disease is a live alternative. Constipation: four weeks of gluten-free diet shortened small-bowel and colonic transit and increased contractility in newly diagnosed patients, yet the treatment diet itself - low in fiber and rich in refined substitutes - can cause constipation, so the phenotype can arise from the disease and from its treatment in the same patient. Fatigue: a prospective controlled study found it substantially reduced after twelve months of gluten-free diet yet still higher than in matched controls, and associated with depression and pain rather than with disease activity or nutritional deficiency - so neither the hematinic nor the inflammatory route is established and a psychosocial contribution cannot be separated out. Peripheral neuropathy: nerve biopsies show axonopathy, loss of myelinated fibers and perivascular inflammatory infiltration, which points to immune injury without settling whether the effector is humoral (anti-TG6 or antiganglioside antibodies) or cell-mediated; B12 or copper deficiency, diabetes and coincident autoimmune neuropathy also have to be excluded.

Proposed experiments

Blinded gluten challenge with phenotype-specific endpoints

exp_celiac_blinded_gluten_challenge_extraintestinal

In patients in remission on a gluten-free diet with a history of one of these manifestations, a randomized blinded gluten challenge with phenotype-specific endpoints (blinded ulcer counts, ultrasound synovitis scoring, wireless motility capsule transit), stratified by corrected versus uncorrected hematinic deficiency and with quantified fiber intake, to separate gluten-driven from nutritional and diet-composition routes.

Would support

pathophysiology#Gluten-Triggered Immune Response

Supporting outcome

The manifestation recurs or objectively worsens during blinded gluten challenge and not on placebo, independent of nutrient status and fiber intake.

Refuting outcome

No difference between gluten and placebo challenge, indicating the manifestation tracks nutrient status, diet composition, or a coincident disease rather than gluten-driven immunity.

Show evidence (7 references)

PMID:17537244 SUPPORT Human clinical

"RAS was significantly more frequent in patients with CD."

Matched case-control association for recurrent aphthous stomatitis (36% vs 12%), documenting the association whose mechanism this gap records.

PMID:19534771 SUPPORT Human clinical

"Four patients who adhered to a strict gluten-free diet showed noticeable improvement in their aphthous lesions over a period of 6 months."

The gluten-withdrawal response for aphthous stomatitis - supportive of a gluten-dependent process but uncontrolled and based on four responders, which is why it grounds a knowledge gap rather than a causal edge.

PMID:37434897 SUPPORT Human clinical

"Her joint symptoms resolved in 3 weeks."

Dechallenge observation in a case of sterile, seronegative, non-erosive polyarthritis with an otherwise negative etiological workup: joint disease remitted on gluten withdrawal alone. A single case supports gluten dependence without establishing the immune mechanism.

+ 4 more references

Cerebellar ataxia, abdominal pain and bloating each have a coherent proposed chain from celiac disease and no demonstrated intermediate step in patients. What evidence would place any of them in the pathograph?

KNOWLEDGE GAP OPEN gap_celiac_proposed_but_unplaced_chains

Attached to

phenotypes#Cerebellar Ataxia phenotypes#Abdominal Pain phenotypes#Bloating

These three differ from the wholly unexplained manifestations: each has a specific proposed route, and each route stops one step short of what a causal edge would assert. Cerebellar ataxia is the closest to placement and the most instructive. Its proposed chain mirrors the dermatitis herpetiformis chain that is wired in this entry - a transglutaminase isoform outside the gut, here TG6, with antibodies plus tissue pathology - and cerebellar neuropathology is documented: Purkinje cell loss, gliosis, and lymphocytic infiltration with perivascular cuffing. What is missing is the step that makes the dermatitis herpetiformis edge assertable: there, the antigen was demonstrated inside the lesion-defining deposit, whereas TG6 remains a candidate antigen and antibody sufficiency has not been shown. Neurologic gluten sensitivity also occurs without enteropathy, and genetic, paraneoplastic, nutritional and other autoimmune ataxias compete. Abdominal pain and bloating have physiologically coherent chains - mucosal nociception and luminal distension for the former, brush-border enzyme loss to carbohydrate maldigestion, microbial fermentation and gas for the latter - but neither has been demonstrated end to end in celiac patients, and irritable bowel syndrome, lactose or FODMAP intolerance and bacterial overgrowth produce both.

Proposed experiments

TG6 antibody sufficiency and cerebellar target engagement in gluten ataxia

exp_celiac_tg6_antibody_sufficiency

Establish for TG6 what is already established for TG3 in dermatitis herpetiformis: demonstrate the antigen within the cerebellar lesion, then test sufficiency by passive transfer or by an ex vivo cerebellar preparation exposed to patient IgA, with titer tracked against imaging and ataxia severity before and during gluten withdrawal in antibody-positive and antibody-negative patients.

Would support

pathophysiology#Autoantibody Production

Supporting outcome

TG6 is demonstrated in cerebellar tissue lesions and patient antibody produces Purkinje cell injury in a preparation free of other celiac factors, with titer tracking ataxia severity.

Refuting outcome

Anti-TG6 titer is unrelated to cerebellar injury and ataxia severity, or cerebellar pathology occurs as often in antibody-negative patients, indicating the antibodies are a marker of gluten exposure rather than the effector.

Show evidence (1 reference)

PMID:32244870 SUPPORT Human clinical

"In gluten ataxia, loss of Purkinje cells, atrophy, gliosis and astrocytosis were apparent, as well as diffuse lymphocytic infiltration and perivascular cuffing with lymphocytes."

The human cerebellar pathology of gluten ataxia, which establishes that a lesion exists and is inflammatory. It does not identify the effector, which is the step this gap records as missing.

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Pathophysiology

9

Gluten-Triggered Immune Response

Gluten peptides (gliadin) cross the intestinal epithelium and are deamidated by tissue transglutaminase (tTG). Deamidated peptides bind HLA-DQ2/DQ8 and activate CD4+ T cells.

T Helper Cell CL:0000492

Antigen Processing GO:0019882

Downstream

Mixed Th1/Th17/IL-21 Mucosal Cytokine Response Gliadin challenge of duodenal biopsies from patients in remission raises IL-17A output from mucosal CD4+ and CD4+CD8+ cells, so the gluten-driven T-cell activation node feeds the mucosal cytokine node directly.

Show evidence (3 references)

PMID:10684852 SUPPORT In vitro / ex vivo

"tissue transglutaminase (tTG)-mediated deamidation of gliadin plays an important role in recognition of this food antigen by intestinal T cells"

Demonstrates the critical role of tTG deamidation in converting gluten peptides into immunogenic epitopes recognized by T cells in celiac disease. Evidence derives from patient-derived intestinal T-cell lines and antigen-recognition assays (ex vivo/in vitro).

PMID:10684852 SUPPORT In vitro / ex vivo

"the deamidated peptides displayed an increased affinity for DQ2, a molecule known to preferentially bind peptides containing negatively charged residues"

Shows how tTG deamidation increases HLA-DQ2 binding affinity by introducing negatively charged glutamate residues, enhancing antigen presentation. Based on HLA-DQ2 peptide-binding assays (in vitro).

PMID:38914866 SUPPORT

"Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response."

Confirms TG2 deamidation as the pivotal mechanism enabling gluten peptide presentation and T cell activation in celiac disease pathogenesis.

Mixed Th1/Th17/IL-21 Mucosal Cytokine Response

The effector cytokine milieu of active celiac mucosa is not purely Th1/IFN-gamma. IL-17A and IL-21 are overproduced alongside IFN-gamma, and the IL-17A-producing CD4+ and CD4+CD8+ cells largely co-express IFN-gamma rather than forming a separate stable Th17 lineage. IL-15, the innate arm cytokine, positively regulates mucosal IL-21 production, providing a mechanistic junction between the innate and adaptive arms. Curated as cytokine complexity within the canonical response, not as an independent coequal Th17 driver.

Mucosal CD4+ T cell CL:0000492

T-helper 1 cell cytokine production GO:0035744 ↑ INCREASED Mucosal interleukin-17A production GO:0032620 ↑ INCREASED

Downstream

Intestinal Epithelial Damage The mixed effector cytokine response is the proximal output of gluten-specific T-cell activation that precedes intraepithelial lymphocyte cytotoxicity and villous atrophy. The intermediate steps between individual cytokines and enterocyte killing are not resolved in human tissue, so the edge is recorded as indirect.

Show evidence (4 references)

PMID:20061410 SUPPORT Human clinical

"expression of IL-17A RNA and protein is more pronounced in active CD biopsy specimens in comparison with inactive CD and normal mucosal biopsy specimens"

Establishes that IL-17A is elevated specifically in active disease mucosa, which is the observation that qualifies the pure Th1 description.

PMID:20061410 SUPPORT Human clinical

"The majority of IL-17A-producing CD4(+) and CD4(+)CD8(+) cells coexpressed IFN-gamma but not CD161."

The co-expression is why this node is curated as a mixed response rather than as a separate Th17 lineage acting in parallel to Th1.

PMID:22785229 SUPPORT Human clinical

"IL-21 was highly produced by CD4+ and CD4+/CD8+ IELs and LPLs in active CD."

Documents the IL-21 component of the mixed response in both intraepithelial and lamina propria compartments of active disease.

+ 1 more reference

Intestinal Epithelial Damage

Activated T cells release IFN-gamma and other cytokines causing villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes. Leads to malabsorption.

Intestinal Epithelial Cell CL:0002563

Apoptosis GO:0006915

Animal models

IL-15 overexpressing HLA-DQ8 transgenic mouse Mouse recapitulates The first model to reproduce gluten-dependent villous atrophy, and the experimental basis of the three-signal model (gluten plus HLA-DQ plus IL-15). "First" rather than "only" is what the source supports: it reports that no such model existed before this one, which is not a claim that none has been produced since.

Downstream

Villous Atrophy Villous atrophy is the histologic expression of this node: cytotoxic killing of enterocytes with crypt hyperplasia shortens the villi, which is what the biopsy reports as a reduced villus-height to crypt-depth ratio.

Generalized Nutrient Malabsorption Enterocyte loss and villous shortening reduce the absorptive surface area and the brush-border transport capacity of the proximal small intestine, which is the proximate cause of malabsorption.

Aberrant Clonal Intraepithelial Lymphocyte Expansion Sustained IL-15-rich mucosal signaling in a chronically injured epithelium selects for intraepithelial lymphocyte clones that lose normal dependence on their activating signals. The selection pressure is inferred from the clinical sequence (uncomplicated disease preceding refractory disease type II) rather than demonstrated prospectively, so the edge is indirect.

Show evidence (6 references)

PMID:38914866 SUPPORT

"Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response."

Demonstrates that IFN-gamma signaling drives a major portion of the transcriptional changes underlying epithelial damage in celiac disease.

PMID:15357947 SUPPORT

"under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR..."

Shows how IL-15 converts intraepithelial CD8+ T cells into cytotoxic lymphokine-activated killer cells via NKG2D signaling, mediating epithelial damage.

PMID:24942692 SUPPORT

"the upregulation of IL-15 expression in the intestinal mucosa has become a hallmark of the disease"

Identifies IL-15 upregulation as a defining feature of celiac disease that drives intraepithelial lymphocyte expansion and epithelial injury.

+ 3 more references

Generalized Nutrient Malabsorption

Loss of absorptive surface area and brush-border transport capacity in the proximal small intestine produces defective mucosal absorption of macronutrients, iron, folate, vitamin B12, zinc and the fat-soluble vitamins. This is the convergence point through which most of the non-gastrointestinal manifestations of celiac disease are produced: it is the node the nutrient-deficiency, growth, bone and anemia branches all pass through. Deficiencies are not proportional to histologic grade - one newly-diagnosed adult cohort found vitamin and mineral deficiencies were not associated with the degree of intestinal damage - so the magnitude of this node is not read off the biopsy.

enterocyte CL:0000584

intestinal absorption GO:0050892 ↓ DECREASED

Downstream

Chronic Diarrhea Unabsorbed solute raises the luminal osmotic load, fat and bile salts reaching the colon are converted by bacteria into cathartic hydroxy-fatty acids, and electrolyte secretion increases; together these raise stool water. The individual contributions of the osmotic, fatty-acid, bile-acid and secretory routes have not been partitioned in celiac cohorts, so the edge is recorded as indirect.

Weight Loss Macronutrient malabsorption and steatorrhea create a negative energy balance. Reduced intake and inflammatory anorexia contribute in parallel and have not been separated from the absorptive loss, and a normal or raised body mass index does not exclude active disease.

Iron Deficiency Anemia Iron is absorbed principally in the proximal duodenum, which is the segment celiac disease destroys, so iron malabsorption and store depletion follow directly from the lesion's location. Menstrual or occult blood loss and inflammatory hepcidin-mediated restriction can coexist.

Vitamin D Deficiency Fat malabsorption and reduced absorptive area impair uptake of the fat-soluble vitamins, vitamin D among them. Low dietary intake and limited sunlight exposure contribute independently, and deficiency can persist on a gluten-free diet.

Growth Failure in Children Chronic energy, protein and micronutrient malabsorption in a growing child produces malnutrition and impaired weight gain, and malnutrition with chronic inflammation suppresses the growth-hormone/IGF-1 axis. The endocrine step is inferred rather than demonstrated in celiac cohorts, and socioeconomic nutrition and diagnostic delay modify the outcome, so the edge is indirect.

Short stature Short stature is the accumulated outcome of the same growth-failure branch once reduced linear growth velocity has persisted. Familial short stature, endocrine disease and failure of catch-up growth after treatment are separate explanations that this edge does not displace.

Hypoproteinemia Serum protein falls in active disease. Two routes are available and the cited evidence does not separate them: failure to absorb dietary protein across a reduced absorptive surface, and protein loss across the damaged mucosa (protein-losing enteropathy). The edge is recorded as indirect for that reason rather than because the association is weak.

Secondary Hyperparathyroidism Calcium and vitamin D malabsorption lowers serum calcium and 25-hydroxy vitamin D, which raises parathyroid hormone secretion - the compensatory response that then drives skeletal resorption.

Show evidence (2 references)

PMID:24084055 SUPPORT Human clinical

"Almost all CD-patients (87%) had at least one value below the lower limit of reference."

Establishes the node quantitatively in 80 newly diagnosed untreated adults: zinc deficiency in 67%, decreased iron stores in 46%, anemia in 32%, folate 20%, B12 19%.

PMID:24084055 SUPPORT Human clinical

"Vitamin/mineral deficiencies were counter-intuitively not associated with a (higher) grade of histological intestinal damage or (impaired) nutritional status."

Bounds the node: the deficiency burden does not track histologic severity, so this node's magnitude cannot be inferred from the biopsy grade of the epithelial-damage node upstream of it.

Secondary Hyperparathyroidism

Calcium and vitamin D malabsorption lowers serum calcium, and the compensatory rise in parathyroid hormone increases osteoclast-mediated bone resorption to defend the serum calcium concentration at the expense of the skeleton. This is the nutrient branch of celiac bone disease; the inflammatory RANKL/OPG branch acts on the same skeletal endpoint in parallel.

bone resorption GO:0045453 ↑ INCREASED

Downstream

Reduced Bone Mineral Density Parathyroid-hormone-driven osteoclastic resorption, together with impaired mineralization from the calcium and vitamin D deficit itself, lowers bone mineral density.

Osteoporosis Sustained remodeling imbalance carries low bone mineral density through to osteoporosis and fragility. Age, sex hormones, low body mass index and primary osteoporosis modify the threshold, and bone density does not always normalize on a gluten-free diet, so the edge is indirect.

Show evidence (2 references)

PMID:36904090 SUPPORT Human clinical

"As blood Ca2+ concentration decreases, a rapid increase in PTH release promotes bone turnover and cortical bone loss."

States this node's mechanism in full: falling serum calcium drives parathyroid hormone release, and the hormone accelerates bone turnover and cortical loss. This is the sentence the node rests on.

PMID:24290593 SUPPORT Human clinical

"The etiology of pathologic bone alterations in CD is multifactorial; however, two main mechanisms are involved: intestinal malabsorption and chronic inflammation."

Establishes the two-branch structure of celiac bone disease, of which this node is the malabsorption branch. The review also presents the roles of calcium and its transport mechanisms.

Aberrant Clonal Intraepithelial Lymphocyte Expansion

Chronic IL-15-rich signaling in the damaged epithelium selects intraepithelial lymphocyte clones that acquire JAK1 and STAT3 gain-of-function mutations, giving them cytokine-independent survival and proliferative fitness. The clinical counterpart is refractory celiac disease type II, a low-grade clonal intraepithelial lymphoproliferation that commonly precedes enteropathy-associated T-cell lymphoma. This is the mechanism through which the neoplastic risk of celiac disease is realized, and it is also why the risk is concentrated in patients whose mucosa does not heal.

intraepithelial lymphocyte CL:0002496

cell surface receptor signaling pathway via JAK-STAT GO:0007259 ⇑ GAIN OF FUNCTION cell population proliferation GO:0008283 ↑ INCREASED

Downstream

Small intestinal lymphoma Clones carrying JAK1/STAT3 gain-of-function lesions, with cooperating NF-kB and epigenetic changes, expand to overt enteropathy-associated T-cell lymphoma. JAK1 inhibition blocked survival and proliferation of malignant refractory-disease cells in vitro, which is direct functional support for the driver role of this step. Some lymphomas arise without a recognized refractory-disease stage, and other small-intestinal lymphomas have different causal wiring.

Show evidence (1 reference)

PMID:33579790 SUPPORT Human clinical

"often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII)"

Establishes refractory celiac disease type II as the clonal intraepithelial-lymphocyte stage standing between celiac enteropathy and lymphoma.

Autoantibody Production

B cells produce antibodies against tTG (anti-tTG IgA) and deamidated gliadin peptides (anti-DGP). These serve as diagnostic markers and may contribute to pathology.

Plasma Cell CL:0000786

Downstream

Dermatitis Herpetiformis The humoral response spreads from TG2 to the related epidermal enzyme transglutaminase 3 (TG3), and patients with dermatitis herpetiformis carry an antibody population specific for TG3 with markedly higher avidity for it than for TG2. The granular IgA precipitates that define the skin lesion contain TG3, so the antigen and the deposit are established. The terminal sequence - immune-complex deposition in dermal papillae, complement and endothelial activation, neutrophil recruitment and protease-mediated injury at the dermal-epidermal junction - is the part not fully demonstrated, and dermal IgA deposits can occur without clinical disease, so the edge is recorded as indirect.

Female infertility Anti-TG2 antibodies from untreated patients bind TG2 on the maternal-facing syncytiotrophoblast and inhibit its local activity, and in primary human trophoblasts they reduce invasiveness and matrix metalloprotease activity and increase apoptosis — the proposed route from the humoral arm to impaired implantation and placentation. Epidemiologically, the excess of adverse reproductive outcomes is confined to undiagnosed disease and attenuates after diagnosis and gluten-free diet, tying the phenotype to disease activity. Mechanism attribution remains contested: malabsorption-related nutrient deficiency and systemic inflammation are credible parallel contributors, and the antibody evidence is from human tissue and cell systems with no in vivo perturbation in women, so the edge is recorded as indirect. How much weight that tissue-level and cell-level work can carry is itself unsettled in the literature, which is why the chain is placed no more strongly than indirect.

Show evidence (2 references)

PMID:18803427 SUPPORT Human clinical

"The serum levels of immunoglobulin (Ig)A anti-tissue transglutaminase (or TG2) are the first choice in screening for celiac disease, displaying the highest levels of sensitivity (up to 98%) and specificity (around 96%)."

Documents IgA anti-tissue transglutaminase (anti-tTG/TG2) autoantibodies as the primary celiac serological marker, supporting B-cell/plasma-cell autoantibody production against tTG; the same review reports deamidated gliadin peptide (DGP) antibodies as an additional marker.

PMID:27352981 SUPPORT Human clinical

"fourteen fulfilled the diagnostic criteria for seronegative celiac disease based on antibody negativity, villous atrophy, HLA-DQ2/-DQ8 positivity and clinical/histological improvement after gluten free diet"

Bounds the autoantibody node. A small minority of patients develop villous atrophy that remits on a gluten-free diet with no detectable serum antibodies, so the humoral arm is a near-universal accompaniment and diagnostic handle rather than a required step for enteropathy. The study used HLA typing and diet response as inclusion criteria and did not measure gluten-specific T cells, so it does not itself demonstrate that the T-cell pathway is intact in these patients.

Barrier Dysfunction

Increased intestinal permeability allows greater gluten peptide translocation. Zonulin upregulation disrupts tight junctions.

Downstream

Elevated Hepatic Transaminases Reversible hepatocellular injury ("celiac hepatitis") is present in roughly a third to two-fifths of untreated patients and normalizes on a gluten-free diet in the large majority, so the hepatic injury tracks gluten-driven intestinal disease activity. The leading proposed route is the gut-liver axis: increased intestinal permeability delivering microbial products, antigens and cytokines to the liver through the portal circulation. The responsible portal mediator has not been identified in patients, and anti-TG2 deposition and systemic cytokines remain alternative contributors, so the edge is recorded as indirect.

Show evidence (1 reference)

PMID:38914866 SUPPORT

"ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group."

TG2 inhibition preserves mucosal-morphology, differentiation and nutrient-absorption transcriptomic signatures — indirect support that mucosal/barrier integrity is downstream of gluten-driven immune activation. The specific zonulin/tight-junction mechanism in the node description is mechanistic context and is not directly established by this transcriptomic citation.

Microbiome Dysbiosis

Alterations in gut microbial composition and metabolic activity contribute to disease initiation and progression. Dysbiosis occurs in genetically at-risk individuals prior to disease onset, persists in active disease, and may not be fully restored by gluten-free diet. Dysbiosis impairs microbial-mediated gluten degradation, reduces production of short-chain fatty acids, and compromises intestinal barrier integrity and immune homeostasis.

Intestinal Epithelial Cell CL:0002563

Response to Bacterium GO:0009617 ↕ DYSREGULATED

Show evidence (3 references)

PMID:42386020 SUPPORT Human clinical

"The gut microbiome has emerged as a key modulator of immune homeostasis, intestinal barrier integrity, and gluten metabolism, implicating microbial dysbiosis in both the initiation and progression of CD"

The microbiome plays a key mechanistic role in disease pathogenesis through immune regulation, barrier function, and gluten degradation.

PMID:42386020 SUPPORT Human clinical

"Alterations in microbial composition and metabolic activity have been documented in genetically at-risk individuals prior to disease onset, in patients with active disease, and in treated patients on a GFD"

Dysbiosis signatures appear early in disease development and persist despite treatment, suggesting dysbiosis as both an initiating and maintaining mechanism.

PMID:42386020 SUPPORT Human clinical

"accumulating evidence indicates that it does not consistently restore gut microbiome composition or function, and many patients experience persistent symptoms despite good dietary adherence"

Gluten-free diet does not reliably restore dysbiotic microbiota, suggesting dysbiosis as a mechanism underlying persistent symptoms in diet-adherent patients.

✶

Histopathology

2

Marsh Classification of Duodenal Mucosal Injury VERY_FREQUENT

The histological grading scheme for celiac enteropathy, applied to duodenal biopsy and reported in ascending order of injury: infiltrative change with raised intraepithelial lymphocyte counts and preserved architecture (Marsh 1), the addition of crypt hyperplasia (Marsh 2), and villous atrophy graded partial, subtotal and total (Marsh 3a to 3c). The Oberhuber revision is the form in routine diagnostic use. Grade is not a proxy for clinical severity: an entry-level caveat worth keeping in view is that vitamin and mineral deficiencies in newly diagnosed patients do not track the histological grade.

Show evidence (1 reference)

PMID:10524652 SUPPORT Human clinical

"we review the histological features of coeliac disease and propose a standardized report scheme based on the Marsh classification"

The source of the revised reporting scheme built on Marsh's grades, which is the classification named here.

Corazza-Villanacci Grading of Duodenal Mucosal Injury VERY_FREQUENT

A simplified alternative to Marsh grading, collapsing the scheme to three categories - grade A, non-atrophic, with raised intraepithelial lymphocytes and normal villous architecture; grade B1, atrophic, with villi shortened but still identifiable; and grade B2, atrophic-flat, with complete villous flattening. Its purpose is reproducibility: the larger Marsh-Oberhuber category set carries substantial interobserver disagreement, and collapsing the atrophic grades removes the boundary judgements that drive most of it.

Show evidence (1 reference)

PMID:33179621 SUPPORT Human clinical

"Biopsy of duodenal mucosa remains the gold standard in the diagnosis of celiac disease with the recognition of the spectrum of histological changes and classification of mucosa damage based on updated Corazza-Villanacci system."

A diagnostic-pathology review naming this system as the basis for grading mucosal damage, which is what this record captures alongside the older Marsh scheme.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

24

Blood 2

Iron Deficiency Anemia FREQUENT HP:0001891

From malabsorption of iron in proximal small bowel

Show evidence (2 references)

PMID:28722929 SUPPORT Human clinical

"malabsorption of essential nutrients, including micronutrients, fat-soluble vitamins, iron, vitamin B12, and folate"

Iron malabsorption in the damaged proximal small intestine leads to iron deficiency anemia.

PMID:30759885 SUPPORT Human clinical

"iron-deficiency anemia, osteoporosis, dermatitis herpetiformis, and neurologic disorders"

Iron deficiency anemia is listed among the common extra-intestinal manifestations of celiac disease.

Small intestinal lymphoma HP:0002665

Show evidence (1 reference)

PMID:31331324 SUPPORT Human clinical

"preventing the occurrence of refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma"

This review notes a gluten-free diet prevents occurrence of small intestinal lymphoma in celiac disease.

Digestive 4

Chronic Diarrhea FREQUENT HP:0002028

Show evidence (1 reference)

PMID:28722929 SUPPORT Human clinical

"Typical gastrointestinal symptoms include diarrhea, abdominal discomfort, bloating, and constipation."

Diarrhea is listed as a typical gastrointestinal symptom of celiac disease.

Bloating FREQUENT Abdominal distention HP:0003270

Show evidence (1 reference)

PMID:28722929 SUPPORT Human clinical

"Typical gastrointestinal symptoms include diarrhea, abdominal discomfort, bloating, and constipation."

Bloating is a typical gastrointestinal symptom of celiac disease.

Constipation OCCASIONAL HP:0002019

Show evidence (1 reference)

PMID:28722929 SUPPORT Human clinical

"Typical gastrointestinal symptoms include diarrhea, abdominal discomfort, bloating, and constipation."

Constipation is listed as a typical GI symptom, though less common than diarrhea.

Villous Atrophy VERY_FREQUENT HP:0011473

Histological hallmark of celiac disease on small bowel biopsy

Show evidence (1 reference)

PMID:28722929 SUPPORT Human clinical

"villous atrophy, crypt hyperplasia, and infiltration of the lamina propria by immune cells"

Villous atrophy is the defining histopathological finding in celiac disease.

Genitourinary 1

Female infertility HP:0008222

Show evidence (1 reference)

PMID:24395055 SUPPORT Human clinical

"such as dermatitis herpetiformis, anemia, dental enamel hypoplasia, recurrent oral aphthae, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminase levels, and female infertility"

This review lists female infertility among extraintestinal manifestations of celiac disease.

Head and Neck 2

Dental Enamel Defects FREQUENT Abnormal dental enamel morphology HP:0000682

Bilaterally symmetrical enamel defects, particularly in permanent dentition

Show evidence (2 references)

PMID:37373569 SUPPORT Human clinical

"enamel defects (42.47%), delayed dental eruption (47.34%)"

Systematic review finds dental enamel defects in over 42% of celiac disease patients.

PMID:34244963 SUPPORT Human clinical

"Overall higher number of patients with CeD (66.9%), both treatment naïve (69.4%) and those on GFD (65.8%) had DED in comparison to controls (20%)"

Two-thirds of celiac patients have dental enamel defects regardless of treatment status.

Recurrent Aphthous Stomatitis FREQUENT HP:0011107

Show evidence (2 references)

PMID:37373569 SUPPORT Human clinical

"Recurrent aphthous stomatitis (34.6%), atrophic glossitis and geographic tongue (15.26%)"

Systematic review reports aphthous stomatitis in ~35% of celiac patients.

PMID:34244963 SUPPORT Human clinical

"Recurrent aphthous ulcers were also significantly higher in patients with CeD"

Controlled study confirms significantly elevated aphthous ulcers in celiac disease.

Integument 1

Dermatitis Herpetiformis OCCASIONAL Subepidermal blistering HP:0033804

Specific cutaneous manifestation with granular IgA deposits at dermal papillae

Show evidence (2 references)

PMID:29757210 SUPPORT Human clinical

"Dermatitis herpetiformis (DH) is a common extraintestinal manifestation of coeliac disease presenting with itchy papules and vesicles on the elbows, knees, and buttocks."

Dermatitis herpetiformis is the specific cutaneous manifestation of celiac disease.

PMID:29757210 SUPPORT Human clinical

"The DH to coeliac disease prevalence ratio is 1:8 in Finland and the United Kingdom (U.K.)"

DH occurs in approximately 1 in 8 celiac patients, supporting OCCASIONAL frequency.

Metabolism 3

Elevated Hepatic Transaminases FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910

Celiac hepatitis; typically resolves with gluten-free diet

Show evidence (2 references)

PMID:23434875 SUPPORT Human clinical

"CD is associated with elevated transaminase levels in about one-third of newly diagnosed children"

Meta-analysis shows ~36% of newly diagnosed celiac patients have elevated transaminases.

PMID:23434875 SUPPORT Human clinical

"A gluten-free diet normalized transaminase levels in 77% to 100% of patients with CD within 4 to 8 months"

Elevated transaminases in celiac disease are typically reversible with gluten-free diet.

Vitamin D Deficiency FREQUENT Decreased circulating vitamin D concentration HP:0100512

From fat-soluble vitamin malabsorption

Show evidence (2 references)

PMID:10071918 SUPPORT Human clinical

"A low 25-(OH)D vitamin concentration was a typical biochemical abnormality in our patients (64% of men and 71% of women)"

Vitamin D deficiency is found in the majority of celiac patients due to fat-soluble vitamin malabsorption.

PMID:28722929 SUPPORT Human clinical

"malabsorption of essential nutrients, including micronutrients, fat-soluble vitamins, iron, vitamin B12, and folate"

Fat-soluble vitamin malabsorption including vitamin D is a direct consequence of mucosal damage.

Hypoproteinemia FREQUENT HP:0003075

Show evidence (1 reference)

PMID:39234463 SUPPORT Human clinical

"Iron deficiency anemia was the most common extra-digestive manifestation, affecting 20.37% of patients, followed by hypoproteinemia (18.52%) and Hashimoto's thyroiditis (14.81%)."

Establishes hypoproteinemia as a frequent finding in an adult celiac cohort, second only to iron deficiency anemia. Single tertiary-centre series of 108 patients, so the figure is a cohort prevalence rather than a population estimate.

Musculoskeletal 3

Reduced Bone Mineral Density FREQUENT HP:0004349

Includes both osteopenia and osteoporosis from calcium/vitamin D malabsorption

Show evidence (2 references)

PMID:10071918 SUPPORT Human clinical

"26% of all celiac patients, but only 5% of control subjects, were classified as having osteoporosis"

Osteoporosis is significantly more prevalent in celiac disease patients.

PMID:10071918 SUPPORT Human clinical

"celiac disease constitutes a risk factor for osteoporosis. This finding applies particularly to untreated and poorly treated patients"

Untreated celiac disease is a particular risk factor for reduced bone density.

Osteoporosis HP:0000939

Show evidence (1 reference)

PMID:24395055 SUPPORT Human clinical

"such as dermatitis herpetiformis, anemia, dental enamel hypoplasia, recurrent oral aphthae, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminase levels, and female infertility"

This review lists osteoporosis among extraintestinal manifestations of celiac disease.

Arthritis HP:0001369

Show evidence (1 reference)

PMID:24395055 SUPPORT Human clinical

"such as dermatitis herpetiformis, anemia, dental enamel hypoplasia, recurrent oral aphthae, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminase levels, and female infertility"

This review lists arthritis among extraintestinal manifestations of celiac disease.

Nervous System 2

Peripheral Neuropathy OCCASIONAL HP:0009830

Predominantly sensory, may precede GI symptoms

Show evidence (3 references)

PMID:30759885 SUPPORT Human clinical

"Gluten neuropathy was a neurological manifestation in CD (up to 39%) in 13 studies"

Systematic review reports gluten neuropathy prevalence up to 39% across studies.

PMID:12771245 SUPPORT Human clinical

"Neurologic complications are estimated to occur in 10% of affected patients, with ataxia and peripheral neuropathy being the most common problems"

Peripheral neuropathy is one of the most common neurological complications of celiac disease.

PMID:12771245 SUPPORT Human clinical

"CD is commonly associated with sensory neuropathy and should be considered even in the absence of gastrointestinal symptoms"

Celiac-associated neuropathy is predominantly sensory and can occur without GI symptoms.

Cerebellar Ataxia OCCASIONAL HP:0001251

Gluten ataxia; may improve with strict gluten-free diet

Show evidence (2 references)

PMID:36555205 SUPPORT Human clinical

"Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression"

Cerebellar ataxia is listed among the key neurological manifestations of celiac disease.

PMID:30759885 SUPPORT Human clinical

"Nine studies reported a lower risk and/or prevalence of gluten ataxia with a range of 0%⁻6%"

Systematic review reports gluten ataxia prevalence of 0-6% in celiac patients.

Constitutional 3

Abdominal Pain FREQUENT HP:0002027

Show evidence (1 reference)

PMID:28722929 SUPPORT Human clinical

"Typical gastrointestinal symptoms include diarrhea, abdominal discomfort, bloating, and constipation."

Abdominal pain/discomfort is a typical gastrointestinal symptom of celiac disease.

Fatigue FREQUENT HP:0012378

Show evidence (2 references)

PMID:28722929 SUPPORT Human clinical

"celiac disease can also present with extraintestinal manifestations such as fatigue, weight loss, skin rashes, anemia, and osteoporosis."

Fatigue is a common extraintestinal manifestation of celiac disease.

PMID:30400298 SUPPORT Human clinical

"Celiac disease may present with a range of different symptoms, including abdominal problems in a broader sense, iron deficiency and "constant tiredness""

Systematic review confirming fatigue/tiredness as a recognized extra-intestinal manifestation.

Arthralgia FREQUENT HP:0002829

Not merged into Arthritis, because the distinction is the substance of the disagreement about celiac joint disease - whether there is an inflammatory arthropathy at all, or predominantly pain without synovitis. Its mechanism is unresolved for the same reasons recorded in the gap_celiac_gfd_responsive_extraintestinal_mechanisms discussion, and studies of gluten withdrawal on joint pain conflict.

Show evidence (2 references)

PMID:38931169 SUPPORT REVIEW SYNTHESIS Human clinical

"Joint pain is a frequent musculoskeletal manifestation occurring in 20–30% of patients at CeD diagnosis."

Gives the frequency and establishes joint pain as a recognized musculoskeletal manifestation at diagnosis.

PMID:38931169 SUPPORT REVIEW SYNTHESIS Human clinical

"Symptoms are usually described in a general way as arthralgia rather than objective synovitis"

The sentence that justifies recording this separately from Arthritis rather than treating the two as one phenotype.

Growth 3

Weight Loss FREQUENT HP:0001824

Show evidence (1 reference)

PMID:28722929 SUPPORT Human clinical

"celiac disease can also present with extraintestinal manifestations such as fatigue, weight loss, skin rashes, anemia, and osteoporosis."

Weight loss is a common extraintestinal manifestation of celiac disease due to malabsorption.

Growth Failure in Children FREQUENT Failure to thrive HP:0001508

Primarily seen in pediatric celiac disease; childhood onset

Show evidence (1 reference)

PMID:28722929 SUPPORT Human clinical

"Growth failure is a frequent additional symptom in children with celiac disease"

Growth failure is explicitly described as frequent in pediatric celiac disease.

Short stature HP:0004322

Show evidence (1 reference)

PMID:24395055 SUPPORT Human clinical

"such as dermatitis herpetiformis, anemia, dental enamel hypoplasia, recurrent oral aphthae, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminase levels, and female infertility"

This review lists short stature among extraintestinal manifestations of celiac disease.

🧬

Genetic Associations

12

HLA-DQ2 (Risk Factor)

relationship_type: RISK_FACTOR

Show evidence (1 reference)

PMID:31331324 SUPPORT Human clinical

"A genetic background (HLA-DQ2/DQ8 positivity and non-HLA genes) is a mandatory determinant of the development of the disease"

HLA-DQ2/DQ8 positivity is a mandatory genetic determinant for celiac disease development.

HLA-DQ8 (Risk Factor)

relationship_type: RISK_FACTOR

IL2 (Risk Factor)

Gene: IL2 hgnc:6001 relationship_type: SUSCEPTIBILITY

IL21 (Risk Factor)

Gene: IL21 hgnc:6005 gene page relationship_type: SUSCEPTIBILITY

BACH2 (GWAS)

Gene: BACH2 hgnc:14078 gene page relationship_type: SUSCEPTIBILITY

TNFAIP3 (GWAS)

Gene: TNFAIP3 hgnc:11896 gene page relationship_type: SUSCEPTIBILITY

CD28 (GWAS)

Gene: CD28 hgnc:1653 gene page relationship_type: SUSCEPTIBILITY

EGR2 (GWAS)

Gene: EGR2 hgnc:3239 gene page relationship_type: SUSCEPTIBILITY

ETS1 (GWAS)

Gene: ETS1 hgnc:3488 gene page relationship_type: SUSCEPTIBILITY

IRF4 (GWAS)

Gene: IRF4 hgnc:6119 gene page relationship_type: SUSCEPTIBILITY

SMAD3 (GWAS)

Gene: SMAD3 hgnc:6769 gene page relationship_type: SUSCEPTIBILITY

PTPN22 (GWAS)

Gene: PTPN22 hgnc:9652 gene page relationship_type: SUSCEPTIBILITY

💊

Medical Actions

6

Gluten-Free Diet

Action: Gluten-free diet Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Diet: avoid wheat food product FOODON:00001141 avoid barley FOODON:00003108 avoid rye FOODON:00003734

Lifelong strict gluten avoidance is the only effective treatment.

Mechanism Target:

INHIBITS Gluten-Triggered Immune Response — Removing dietary gluten withdraws the antigen the entire cascade depends on, shutting off TG2-deamidated peptide presentation and gluten-reactive CD4 T-cell activation upstream of mucosal injury.

Show evidence (1 reference)

PMID:31331324 SUPPORT Human clinical

"the only treatment for celiac disease is a life-long, strict gluten-free diet leading to improvement in quality of life, ameliorating symptoms, and preventing the occurrence of refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma"

Gluten withdrawal reverses symptoms and prevents complications, which is the clinical demonstration that the treatment acts by removing the trigger of the gluten-driven immune response.

Show evidence (2 references)

PMID:39273359 SUPPORT Human clinical

"The only available treatment strategy is lifelong adherence to a gluten-free diet."

Gluten-free diet is established as the only effective treatment for celiac disease.

PMID:31331324 SUPPORT Human clinical

"the only treatment for celiac disease is a life-long, strict gluten-free diet leading to improvement in quality of life, ameliorating symptoms, and preventing the occurrence of refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma"

Comprehensive review confirms GFD as the sole treatment with benefits for symptom relief and complication prevention.

Nutritional Supplementation

Action: Nutritional supplementation Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Iron, calcium, vitamin D, B12, folate as needed.

Monitoring

Regular serology and bone density monitoring.

Corticosteroids

Action: Corticosteroid therapy Ontology label: Systemic Corticosteroid Therapy NCIT:C122080

For refractory celiac disease.

Dietitian Counseling

Essential for dietary compliance.

Show evidence (1 reference)

PMID:39273359 SUPPORT Human clinical

"The only available treatment strategy is lifelong adherence to a gluten-free diet."

Dietitian counseling is essential to ensure proper adherence to the gluten-free diet.

Probiotics and Prebiotics

Action: Probiotics and Prebiotics Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Emerging microbiome-modulating strategies to restore dysbiotic microbiota and improve gluten metabolism and immune regulation. May serve as adjunctive therapeutic approaches to complement gluten-free diet.

Show evidence (1 reference)

PMID:42386020 SUPPORT Human clinical

"We further discuss emerging strategies aimed at modulating the gut microbiome, including probiotics, prebiotics, postbiotics and precision probiotics, as potential adjunctive therapeutic approaches"

Recent review identifies probiotics, prebiotics, and postbiotics as emerging microbiome-modulating strategies that may improve outcomes when combined with gluten-free diet.

🌍

Environmental Factors

7

Gluten Exposure

Required trigger

Show evidence (1 reference)

PMID:37332011 SUPPORT Human clinical

"requiring genetic susceptibility and gluten exposure to trigger immune-mediated enteropathy"

States gluten exposure as a necessary condition alongside genetic susceptibility, which is what "required trigger" asserts.

Mechanism Target:

TRIGGERS Gluten-Triggered Immune Response — Gluten ingestion is the necessary environmental trigger for the immune response against deamidated gliadin peptides in HLA-DQ2/DQ8 carriers.

Show evidence (1 reference)

PMID:37332011 SUPPORT DIRECT Human clinical

"requiring genetic susceptibility and gluten exposure to trigger immune-mediated enteropathy"

States gluten exposure as a condition required to trigger the immune-mediated enteropathy, which is the claim this edge makes.

Wheat Food Products

Common gluten-containing dietary source

Show evidence (1 reference)

PMID:29941778 SUPPORT Other

"triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye"

Names this grain among the three whose gluten storage proteins trigger and maintain the enteropathy.

Mechanism Target:

TRIGGERS Gluten-Triggered Immune Response — Wheat is one of the three grains whose gluten storage proteins trigger and maintain the enteropathy.

Show evidence (1 reference)

PMID:29941778 SUPPORT DIRECT Other

"triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye"

Names wheat among the grains whose ingested storage proteins trigger and maintain the immune response this node represents.

Barley

Common gluten-containing dietary source

Show evidence (1 reference)

PMID:29941778 SUPPORT Other

"triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye"

Names this grain among the three whose gluten storage proteins trigger and maintain the enteropathy.

Mechanism Target:

TRIGGERS Gluten-Triggered Immune Response — Barley is one of the three grains whose gluten storage proteins trigger and maintain the enteropathy.

Show evidence (1 reference)

PMID:29941778 SUPPORT DIRECT Other

"triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye"

Names barley among the grains whose ingested storage proteins trigger and maintain the immune response this node represents.

Rye

Common gluten-containing dietary source

Show evidence (1 reference)

PMID:29941778 SUPPORT Other

"triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye"

Names this grain among the three whose gluten storage proteins trigger and maintain the enteropathy.

Mechanism Target:

TRIGGERS Gluten-Triggered Immune Response — Rye is one of the three grains whose gluten storage proteins trigger and maintain the enteropathy.

Show evidence (1 reference)

PMID:29941778 SUPPORT DIRECT Other

"triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye"

Names rye among the grains whose ingested storage proteins trigger and maintain the immune response this node represents.

Early Gluten Introduction

Randomized trials found the timing of gluten introduction does not alter celiac disease risk in genetically at-risk infants

Show evidence (1 reference)

PMID:25271603 REFUTE Human clinical

"the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age"

The PreventCD randomized trial (944 HLA-DQ2/DQ8-positive infants with an affected first-degree relative) refutes the earlier observational "window of opportunity" hypothesis that this exposure had recorded as "timing may affect risk".

Gastrointestinal Infections

May trigger onset

Show evidence (1 reference)

PMID:31331324 SUPPORT Human clinical

"occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota)"

Viral infections are recognized environmental cofactors in celiac disease onset.

Mechanism Target:

PREDISPOSES Gluten-Triggered Immune Response — Gluten remains the necessary trigger; enteric infection is proposed to raise the chance that a genetically susceptible person loses tolerance to it. It contributes rather than causes, which is why this is predisposing.

Show evidence (1 reference)

PMID:31331324 SUPPORT Human clinical

"occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota)"

Names viral infections among the environmental factors contributing to disease development, alongside the necessary gluten trigger.

Gut Microbiome

Dysbiosis modulates disease initiation, progression, and symptom burden

Show evidence (3 references)

PMID:31331324 SUPPORT Human clinical

"occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota)"

Gut microbiota dysbiosis is recognized as an environmental factor contributing to celiac disease.

PMID:42386020 SUPPORT Human clinical

"The gut microbiome has emerged as a key modulator of immune homeostasis, intestinal barrier integrity, and gluten metabolism, implicating microbial dysbiosis in both the initiation and progression of CD"

Dysbiosis is mechanistically implicated in both disease initiation and progression through impaired immune homeostasis, barrier function, and gluten degradation.

PMID:42386020 SUPPORT Human clinical

"Alterations in microbial composition and metabolic activity have been documented in genetically at-risk individuals prior to disease onset"

Dysbiosis occurs in pre-disease individuals with genetic risk, supporting dysbiosis as an initiating environmental factor.

Mechanism Target:

MODULATES Microbiome Dysbiosis — Targets the entry's own dysbiosis node rather than the gluten trigger. MODULATES rather than PREDISPOSES because the direction of causation here is genuinely unsettled: dysbiosis is both a proposed contributor to loss of tolerance and a consequence of established disease, and the cited source describes the microbiome as a modulator rather than a risk factor.

Show evidence (1 reference)

PMID:42386020 SUPPORT Human clinical

"The gut microbiome has emerged as a key modulator of immune homeostasis, intestinal barrier integrity, and gluten metabolism, implicating microbial dysbiosis in both the initiation and progression of CD"

Describes the gut microbiome as a key modulator of immune homeostasis, barrier integrity and gluten handling, a modulating role rather than an initiating one.

🔬

Biochemical Markers

4

Anti-tTG IgA (Elevated)

Context: Primary diagnostic marker

Anti-Endomysial Antibodies (Elevated)

Context: Highly specific

Anti-DGP Antibodies (Elevated)

Context: Useful when IgA deficient

Total IgA (Variable)

Context: IgA deficiency common in celiac

🔬

Diagnosis

1

HLA-DQ2/DQ8 genetic testing

HLA-DQ2/DQ8 typing is used for diagnostic clarification in selected cases rather than as a primary diagnostic test.

genetic testing NCIT:C15709

Results: Presence or absence of the HLA-DQ2 and HLA-DQ8 haplotypes.

The test's clinical utility rests on its negative predictive value - absence of both haplotypes makes coeliac disease very unlikely - but that rationale is not stated in the cited guideline abstract and is recorded here rather than asserted against it.

Show evidence (1 reference)

PMID:40999951 SUPPORT Other

"HLA-DQ2/DQ8 typing is recommended for diagnostic clarification in select cases."

The 2025 ESsCD updated guidelines recommend HLA-DQ2/DQ8 typing for diagnostic clarification in selected cases of suspected coeliac disease.

📊

Prevalence

1

General

Point prevalence 1000.0 per 100,000 >1 in 1,000

Show evidence (2 references)

PMID:31331324 SUPPORT Human clinical

"Its prevalence in the general population is of approximately 1%, with female predominance"

Large comprehensive review establishing ~1% general population prevalence.

ORPHA:555 SUPPORT

"NON RARE IN EUROPE: Celiac disease"

Orphanet classifies celiac disease as non-rare in Europe, consistent with ~1% prevalence.

📊

Related Datasets

9

Therapeutic TG2 Inhibition Reverses Systemic Multiomic Dysregulation in Celiac Disease geo:GSE319777

Background and Aims: Celiac disease (CeD) is an autoimmune disease triggered by dietary gluten in genetically predisposed individuals. Deamidation of gluten peptides by the CeD autoantigen and enzyme transglutaminase 2 (TG2) is central to the pathogenesis of CeD. Inhibition of TG2 with the specific inhibitor ZED1227 effectively prevents gluten-induced histological damage in CeD patients. Here we aimed to explore the blood DNA methylomic changes in ZED1227-treated CeD patients undergoing a gluten challenge. Results: Drug treatment revealed consistent patterns suggesting normalization of the DNA methylome indicating that ZED1227 attenuated the systemic responses to gluten challenge.

human METHYLATION n=72

PMID:42032651

Identified by GEO DataSets index search for Celiac Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.

A human autoimmune organoid model reveals IL-7 function in celiac disease geo:GSE200075

In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Celiac disease (CeD) is an autoimmune disease where dietary gluten-derived peptides bind the MHC- II molecules HLA-DQ2 or -DQ8 to initiate immune-mediated duodenal mucosal injury. Here, we generated air-liquid interface (ALI) duodenal organoids from endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The ALI organoid immune diversity spanned T, B, plasma, NK and myeloid cells with extensive T and B cell receptor repertoires.

human BULK RNA SEQ n=30

PMID:39048815

Identified by GEO DataSets index search for Celiac Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.

Single Cell RNA Sequencing Unveils Distinct Cellular Dynamics in Celiac Disease Duodenal Biopsies geo:GSE315138

Celiac disease (CeD) is the most common autoimmune disorder in the U.S., affecting at least 1% of the population. The ingestion of gluten-containing proteins triggers an adaptive immune response, causing intestinal damage and leading to both gastrointestinal and systemic symptoms. Despite a strong genetic predisposition, the mechanistic understanding of CeD remains limited. The lack of approved therapy, other than dietary avoidance of gluten which is difficult and often unsuccessful, underscores the need to identify new mechanisms that can provide insights for developing therapeutics.

human SINGLE CELL RNA SEQ n=8

PMID:41642982

Identified by GEO DataSets index search for Celiac Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.

Celiac disease case-control North Indian Immunochip dataset ega:EGAS00001000849

Illumina Immunochip genotype data for coeliac disease and control samples of North Indian samples origin. Data is in PLINK binary format. Calling algorithm for genotypes is based on GenomeStudio (GenTrain), with manual clustering of selected variants.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Celiac Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Celiac disease-specific intestinal T cells analyzed with HLA-class II tetramers, RNA-seq and mass cytometry have a narrow, autoimmune-associated phenotype ega:EGAS00001003017

Celiac disease (CD) is an HLA-DQ2/8-associated autoimmune enteropathy driven by activation of gluten-specific CD4+ T lymphocytes upon gluten consumption. Much less is known about the phenotype and function of these cells or their correlation, if any, to disease-relevant cells in other autoimmune disorders. Here we use mass cytometry and RNA seq to show that gluten-specific blood and gut T cells occupy a small and phenotypically distinct T-cell subset.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Celiac Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Epitope-linked Ig-seq of self-reactive plasma cells in celiac disease ega:EGAS00001003658

human BULK RNA SEQ

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Celiac Disease"); description-level mentions were not accepted. EGA study_type: Transcriptome Analysis. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Different Binding Motifs of the Celiac Disease Associated HLA Molecules DQ2.5, DQ2.2 and DQ7.5 Revealed by Relative Quantitative Proteomics of Endogenous Peptide Repertoires massive:MSV000080859

In this study relative quantitative analysis of endogenous peptides by mass spectrometry combined with neural network analysis have been used to address why the alpha- or beta-chain sharing human leukocyte antigen (HLA)-DQ molecules DQ2.5, DQ2.2 and DQ7.5 display different risks for celiac disease. Celiac disease is caused by intolerance to cereal gluten proteins, and HLA-DQ molecules are involved in the disease pathogenesis by presentation of gluten peptides to CD4+ T cells.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Celiac Disease"). Retrieved 2026-08-02.

Gluten-specific antibodies of celiac disease gut plasma cells recognize long proteolytic fragments that typically harbor T-cell epitopes massive:MSV000080779

This study aimed to identify proteolytic fragments of gluten proteins recognized by recombinant IgG1 monoclonal antibodies generated from single IgA plasma cells of celiac disease lesions. Peptides bound by monoclonal antibodies in complex gut-enzyme digests of gluten treated with the deamidating enzyme transglutaminase 2, were identified by mass spectrometry after antibody pull-down with protein G beads. The antibody bound peptides were long deamidated peptide fragments that contained the substrate recognition sequence of transglutaminase 2.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Celiac Disease"). Retrieved 2026-08-02.

Genome-Wide Association Study of Celiac Disease dbgap:phs000274

Celiac disease (gluten-sensitive enteropathy, celiac sprue) is a common disease with significant morbidity and mortality. It is caused by sensitivity to the dietary protein gluten, resulting in a chronic enteropathy in the small intestine. Celiac disease is now recognized to be a common disease, with reports that the disease frequency is 1:133 in the United States, similar to European estimates. There is recent evidence to suggest that the incidence of the disease is rising. Occult disease is frequently present with minimal classic symptoms or signs.

Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Celiac Disease"). Retrieved 2026-08-02.

🔬

Clinical Trials

2

EUCTR2017-002241-30-DE PHASE_II COMPLETED

CEC-3: phase IIa randomized, double-blind, placebo-controlled dose-finding trial of the transglutaminase 2 inhibitor ZED1227 over six weeks of gluten challenge in patients with well-controlled celiac disease. Registered on EUCTR rather than ClinicalTrials.gov. The first causal human perturbation of the TG2 node: all three doses attenuated the gluten-induced fall in the villus-height to crypt-depth ratio.

Target Phenotypes: Villous atrophy HP:0011473

Show evidence (2 references)

ICTRP:EUCTR2017-002241-30-DE SUPPORT Other

"| Primary sponsor | Dr. Falk Pharma GmbH |"

WHO ICTRP registration record establishing the trial's identity and design; a registration document rather than study evidence, hence OTHER.

PMID:34192430 SUPPORT Human clinical

"Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury."

The trial's primary result.

NCT02637141 PHASE_II COMPLETED

Phase 2a randomized, double-blind, placebo-controlled trial of the anti-IL-15 monoclonal antibody AMG 714 during gluten challenge. It missed its mucosal-injury endpoint, which is the human result that bounds the three-signal model derived from the IL-15 transgenic mouse.

Target Phenotypes: Villous atrophy HP:0011473

Show evidence (2 references)

clinicaltrials:NCT02637141 SUPPORT Other

"This study is designed to evaluate the efficacy and safety of AMG 714 for the attenuation of the effects of gluten exposure in adult patients with celiac disease during a gluten challenge."

ClinicalTrials.gov record establishing the trial's identity and design.

PMID:31494096 SUPPORT Human clinical

"AMG 714 did not prevent mucosal injury due to gluten challenge."

The trial's primary result, which was negative: anti-IL-15 antibody did not protect mucosal architecture during gluten challenge. Graded SUPPORT because on a trial record the evidence bears on the trial - it reports what this trial found - and a negative finding is still a faithful report of it. The same quote carries REFUTE in the mismatch_three_signal_villous_atrophy_requirement discussion, where the claim at issue is IL-15 as a strictly required signal and the result does cut against it.

🐁

Animal Models

1

IL-15 overexpressing HLA-DQ8 transgenic mouse

Species

Mouse

Genotype

HLA-DQ8 transgenic with IL-15 overexpression in both the intestinal epithelium and the lamina propria, gluten-sensitized

Publication

PMID:32051586

Pathograph links

Intestinal Epithelial Damage recapitulates fidelity: moderate observes: tissue The first model to reproduce gluten-dependent villous atrophy, and the experimental basis of the three-signal model (gluten plus HLA-DQ plus IL-15). "First" rather than "only" is what the source supports: it reports that no such model existed before this one, which is not a claim that none has been produced since.

Limitations: Villous atrophy here requires engineered IL-15 overexpression in two compartments simultaneously, which is a construction of the model rather than a demonstrated configuration in patients. The strong reading of it is contradicted in humans by the AMG 714 trial, where anti-IL-15 antibody did not prevent gluten-induced mucosal injury. Treat the model as establishing joint sufficiency, not the separate necessity of each signal.

Show evidence (1 reference)

PMID:32051586 SUPPORT Model organism

"Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease."

States what the model shows and the compartmental requirement that makes it a constructed configuration.

The open question this model raises is tracked in the mismatch_three_signal_villous_atrophy_requirement discussion; this record is the model itself rather than a restatement of that argument.

{ }

Source YAML

click to show

name: Celiac Disease
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Celiac disease is a chronic immune-mediated enteropathy of the small intestine
  triggered by dietary gluten in genetically susceptible individuals carrying
  HLA-DQ2 or HLA-DQ8 haplotypes. Deamidated gluten peptides presented to gluten-reactive
  CD4+ T cells drive a mucosal immune response that produces villous atrophy,
  crypt hyperplasia, intraepithelial lymphocytosis, and characteristic
  anti-tissue-transglutaminase autoantibodies. The resulting malabsorption causes
  chronic diarrhea, weight loss, iron deficiency anemia, and other nutritional
  deficiencies, and the disease typically remits on a strict gluten-free diet.
category: Complex
parents:
- Gastrointestinal Disease
- Autoimmune Disease
disease_term:
  preferred_term: celiac disease
  term:
    id: MONDO:0005130
    label: celiac disease
prevalence:
- population: General
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1000.0
  percentage: 1.0
  evidence:
  - reference: PMID:31331324
    reference_title: "Celiac disease: a comprehensive current review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Its prevalence in the general population is of approximately 1%, with female predominance"
    explanation: Large comprehensive review establishing ~1% general population prevalence.
  - reference: ORPHA:555
    reference_title: "NON RARE IN EUROPE: Celiac disease"
    supports: SUPPORT
    snippet: "NON RARE IN EUROPE: Celiac disease"
    explanation: Orphanet classifies celiac disease as non-rare in Europe, consistent with ~1% prevalence.
inheritance:
- name: Polygenic inheritance
  description: Strong HLA association (HLA-DQ2/DQ8) plus non-HLA polygenic risk factors and environmental triggers
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  evidence:
  - reference: PMID:31331324
    reference_title: "Celiac disease: a comprehensive current review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A genetic background (HLA-DQ2/DQ8 positivity and non-HLA genes) is a mandatory determinant of the development of the disease, which occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota)"
    explanation: Celiac disease requires multiple genetic risk loci plus environmental triggers, characteristic of polygenic inheritance.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_gluten_hladq_ttg_enteropathy_model
  hypothesis_label: Canonical Gluten / HLA-DQ2-DQ8 / tTG Enteropathy Model
  status: CANONICAL
  description: >-
    Celiac disease arises in HLA-DQ2 / HLA-DQ8 positive individuals from a CD4 T-cell-mediated immune
    response to dietary gluten/gliadin peptides that have been deamidated by tissue transglutaminase 2
    (TG2/tTG). Deamidation converts neutral glutamine residues to negatively charged glutamate,
    dramatically increasing peptide affinity for HLA-DQ2/DQ8 and licensing presentation to gluten-reactive
    CD4 T cells in the lamina propria. The resulting mixed Th1/Th17/IL-21 cytokine response,
    together with IL-15-driven innate epithelial activation (proposed as a co-required signal in the
    three-signal model, so far demonstrated as a strict co-requirement only in an engineered mouse),
    drives intraepithelial lymphocyte cytotoxicity, B-cell expansion with anti-TG2 autoantibody
    production, crypt hyperplasia, and villous atrophy. Gluten-free diet remission, HLA-DQ2/DQ8
    restriction, and the ZED1227 randomized TG2-inhibitor trial (attenuated the gluten-induced fall in
    villus-height/crypt-depth ratio) all corroborate the gluten / HLA / TG2 axis as the canonical
    pathogenic mechanism.
  notes: >-
    Retained as CANONICAL. The 2026 openscientist
    hypothesis-search report
    (kb/hypotheses/Celiac_Disease/canonical_gluten_hladq_ttg_enteropathy_model)
    finds STRONGLY SUPPORTED with five required mechanistic
    expansions. Core gluten → TG2-deamidation → HLA-DQ2/DQ8
    presentation → CD4 T-cell activation → mucosal injury cascade
    is validated by ZED1227 Phase 2a (TG2 inhibition attenuated
    gluten-induced mucosal injury — the first causal human
    perturbation of the axis), HLA-DQ2 tetramer and direct-cloning
    studies (0.5–1.8% of intestinal CD4 T cells gluten-reactive by
    cloning and 0.1–1.2% tetramer-positive, correlating with Marsh
    grade and serum IgA anti-TG2), and gluten-free-diet remission.
    The report's five proposed expansions are recorded here with the
    dispositions from the 2026 assessment sidecar
    (assessments/openscientist-assessment-by-codex.yaml), which are
    weaker than the report's own wording: (1) IL-15 / innate immunity
    co-required for villous atrophy — three-signal model (IL-15 +
    HLA-DQ + gluten) — QUALIFIED: demonstrated in an engineered
    HLA-DQ8 mouse overexpressing IL-15, not established as a
    universal human co-requirement (see the HUMAN_MODEL_MISMATCH
    discussion); (2) the cytokine response is mixed Th1/Th17/IL-21
    rather than pure Th1/IFN-γ — QUALIFIED: IL-17A and IL-21
    production is documented in active human mucosa, largely in cells
    that also make IFN-γ, which is cytokine complexity rather than a
    coequal independent Th17 driver; (3) three nested positive
    feedback loops (IgA-CD71 retrotranscytosis, IFN-γ /
    thioredoxin/TG2 activation, B-cell APC amplification) drive
    chronicity — QUALIFIED: each loop has separate experimental
    support, but they have never been tested as an integrated system
    and the histologic follow-up cohorts do not attribute incomplete
    healing to them; (4) wheat amylase-trypsin inhibitors (ATIs)
    provide parallel TLR4-mediated innate signaling as adjuvant —
    QUALIFIED: TLR4 activation and low-grade murine intestinal
    inflammation are shown, contribution to human celiac initiation
    is not; (5) transcellular IgA-CD71 retrotranscytosis is the
    dominant gluten transport route — REJECTED: the cited work
    demonstrates a transport mechanism in epithelial monolayers, not
    its quantitative dominance over the paracellular route in
    patients, so no route ranking is asserted here. The
    tolerance-breaking trigger —
    what converts ~97% of HLA-DQ2/DQ8 carriers (oral-tolerant)
    into the ~1–3% who develop disease — remains unresolved.
    Boundary conditions where the model is insufficient:
    seronegative CeD (~1.7%), refractory CeD type II
    (gluten-independent clonal T-cell expansion), and DQ8-specific
    mechanistic differences.
  evidence:
  - reference: PMID:38914866
    reference_title: "Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of"
    explanation: >
      Canonical mechanism reference used as the seed for the
      hypothesis-search deep-research run.
  - reference: PMID:34192430
    reference_title: "A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury."
    explanation: >
      ZED1227 Phase 2a randomized trial (CEC-3) provides the strongest
      interventional evidence for the canonical gluten/HLA/TG2 axis:
      pharmacological TG2 inhibition attenuated the loss of
      villus-height/crypt-depth ratio during gluten challenge. The
      primary-endpoint differences from placebo were 0.44 (10 mg),
      0.49 (50 mg) and 0.48 (100 mg), so the trial establishes a causal
      contribution of TG2 and its therapeutic tractability rather than
      a monotonic dose response or strict necessity of TG2 in every
      genotype and disease context.
  - reference: PMID:23775608
    reference_title: "Direct cloning and tetramer staining to measure the frequency of intestinal gluten-reactive T cells in celiac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the frequency of gluten-specific T cells correlated with the degree of histological damage in the gut mucosa as scored by Marsh-grading, and also with serum IgA anti-transglutaminase 2 antibody levels"
    explanation: >
      Direct measurement of the HLA-DQ2-restricted, gluten-reactive CD4
      T-cell compartment in intestinal biopsies ties the frequency of the
      cells the canonical model makes central to both the histological
      severity and the anti-TG2 humoral output the model predicts.
  - reference: PMID:37445994
    reference_title: "The Oral Transglutaminase 2 Inhibitor ZED1227 Accumulates in the Villous Enterocytes in Celiac Disease Patients during Gluten Challenge and Drug Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest that active TG2 is present at the luminal side of the villous epithelium and that inhibition of TG2 activity by ZED1227 occurs already there before gliadin peptides enter the lamina propria."
    explanation: >
      Immunodetection of the drug-enzyme complex in post-treatment
      biopsies from the same phase 2a trial localizes the inhibited step
      to the villous brush border, refining where in the canonical
      cascade the deamidation node acts.
pathophysiology:
- name: Gluten-Triggered Immune Response
  description: >
    Gluten peptides (gliadin) cross the intestinal epithelium and are
    deamidated by tissue transglutaminase (tTG). Deamidated peptides
    bind HLA-DQ2/DQ8 and activate CD4+ T cells.
  cell_types:
  - preferred_term: T Helper Cell
    term:
      id: CL:0000492
      label: CD4-positive helper T cell
  biological_processes:
  - preferred_term: Antigen Processing
    term:
      id: GO:0019882
      label: antigen processing and presentation
  evidence:
  - reference: PMID:10684852
    reference_title: "The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "tissue transglutaminase (tTG)-mediated deamidation of gliadin plays an important role in recognition of this food antigen by intestinal T cells"
    explanation: Demonstrates the critical role of tTG deamidation in converting gluten peptides into immunogenic epitopes recognized by T cells in celiac disease. Evidence derives from patient-derived intestinal T-cell lines and antigen-recognition assays (ex vivo/in vitro).
  - reference: PMID:10684852
    reference_title: "The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the deamidated peptides displayed an increased affinity for DQ2, a molecule known to preferentially bind peptides containing negatively charged residues"
    explanation: Shows how tTG deamidation increases HLA-DQ2 binding affinity by introducing negatively charged glutamate residues, enhancing antigen presentation. Based on HLA-DQ2 peptide-binding assays (in vitro).
  - reference: PMID:38914866
    reference_title: "Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease."
    supports: SUPPORT
    snippet: "Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response."
    explanation: Confirms TG2 deamidation as the pivotal mechanism enabling gluten peptide presentation and T cell activation in celiac disease pathogenesis.
  downstream:
  - target: Mixed Th1/Th17/IL-21 Mucosal Cytokine Response
    causal_link_type: DIRECT
    description: >-
      Gliadin challenge of duodenal biopsies from patients in remission raises
      IL-17A output from mucosal CD4+ and CD4+CD8+ cells, so the gluten-driven
      T-cell activation node feeds the mucosal cytokine node directly.
    evidence:
    - reference: PMID:20061410
      reference_title: "Characterization of IL-17A-producing cells in celiac disease mucosa."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The addition of a peptic-tryptic digest of gliadin to ex vivo organ cultures of duodenal biopsy specimens taken from inactive CD patients enhanced IL-17A production by both CD4(+) and CD4(+)CD8(+) cells."
      explanation: >-
        Ex vivo gliadin challenge of patient biopsies is a direct perturbation
        linking gluten exposure to the mucosal IL-17A response.
- name: Mixed Th1/Th17/IL-21 Mucosal Cytokine Response
  biological_scale: TISSUE
  description: >-
    The effector cytokine milieu of active celiac mucosa is not purely
    Th1/IFN-gamma. IL-17A and IL-21 are overproduced alongside IFN-gamma, and
    the IL-17A-producing CD4+ and CD4+CD8+ cells largely co-express IFN-gamma
    rather than forming a separate stable Th17 lineage. IL-15, the innate arm
    cytokine, positively regulates mucosal IL-21 production, providing a
    mechanistic junction between the innate and adaptive arms. Curated as
    cytokine complexity within the canonical response, not as an independent
    coequal Th17 driver.
  cell_types:
  - preferred_term: Mucosal CD4+ T cell
    term:
      id: CL:0000492
      label: CD4-positive helper T cell
  biological_processes:
  - preferred_term: T-helper 1 cell cytokine production
    term:
      id: GO:0035744
      label: T-helper 1 cell cytokine production
    modifier: INCREASED
  - preferred_term: Mucosal interleukin-17A production
    term:
      id: GO:0032620
      label: interleukin-17 production
    modifier: INCREASED
  downstream:
  - target: Intestinal Epithelial Damage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The mixed effector cytokine response is the proximal output of gluten-specific
      T-cell activation that precedes intraepithelial lymphocyte cytotoxicity and
      villous atrophy. The intermediate steps between individual cytokines and
      enterocyte killing are not resolved in human tissue, so the edge is recorded
      as indirect.
  evidence:
  - reference: PMID:20061410
    reference_title: "Characterization of IL-17A-producing cells in celiac disease mucosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "expression of IL-17A RNA and protein is more pronounced in active CD biopsy specimens in comparison with inactive CD and normal mucosal biopsy specimens"
    explanation: >-
      Establishes that IL-17A is elevated specifically in active disease mucosa,
      which is the observation that qualifies the pure Th1 description.
  - reference: PMID:20061410
    reference_title: "Characterization of IL-17A-producing cells in celiac disease mucosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of IL-17A-producing CD4(+) and CD4(+)CD8(+) cells coexpressed IFN-gamma but not CD161."
    explanation: >-
      The co-expression is why this node is curated as a mixed response rather
      than as a separate Th17 lineage acting in parallel to Th1.
  - reference: PMID:22785229
    reference_title: "IL-15 positively regulates IL-21 production in celiac disease mucosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IL-21 was highly produced by CD4+ and CD4+/CD8+ IELs and LPLs in active CD."
    explanation: >-
      Documents the IL-21 component of the mixed response in both intraepithelial
      and lamina propria compartments of active disease.
  - reference: PMID:22785229
    reference_title: "IL-15 positively regulates IL-21 production in celiac disease mucosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of control LPLs with IL-15, a cytokine overproduced in CD, activated Akt and STAT3 (signal transducer and activator of transcription 3), thus enhancing IL-21 synthesis."
    explanation: >-
      Supplies the mechanistic junction between the IL-15-driven innate arm and
      the adaptive IL-21 output, rather than leaving the two arms unconnected.
- name: Intestinal Epithelial Damage
  description: >
    Activated T cells release IFN-gamma and other cytokines causing
    villous atrophy, crypt hyperplasia, and increased intraepithelial
    lymphocytes. Leads to malabsorption.
  cell_types:
  - preferred_term: Intestinal Epithelial Cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: Apoptosis
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:38914866
    reference_title: "Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease."
    supports: SUPPORT
    snippet: "Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response."
    explanation: Demonstrates that IFN-gamma signaling drives a major portion of the transcriptional changes underlying epithelial damage in celiac disease.
  - reference: PMID:15357947
    reference_title: "Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease."
    supports: SUPPORT
    snippet: "under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR specificity in effector CD8 T cells"
    explanation: Shows how IL-15 converts intraepithelial CD8+ T cells into cytotoxic lymphokine-activated killer cells via NKG2D signaling, mediating epithelial damage.
  - reference: PMID:24942692
    reference_title: "IL-15: a central regulator of celiac disease immunopathology."
    supports: SUPPORT
    snippet: "the upregulation of IL-15 expression in the intestinal mucosa has become a hallmark of the disease"
    explanation: Identifies IL-15 upregulation as a defining feature of celiac disease that drives intraepithelial lymphocyte expansion and epithelial injury.
  - reference: PMID:15357948
    reference_title: "A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MICA is strongly expressed at epithelial cell surface in patients with active disease and is induced by gliadin or its p31-49 derived peptide upon in vitro challenge, an effect relayed by IL-15"
    explanation: >-
      Supplies the missing step between IL-15 and enterocyte killing: gliadin
      induces the NKG2D ligand MICA on the epithelium through IL-15, which is
      what licenses intraepithelial lymphocyte cytotoxicity against enterocytes.
      Graded IN_VITRO because MICA induction was shown by in vitro challenge of
      patient tissue.
  - reference: PMID:33920345
    reference_title: "Small and Large Intestine (I): Malabsorption of Nutrients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "persistent villous atrophy despite a strict GFD longer than one year that leads to concomitant symptoms such as diarrhea, steatorrhea, abdominal pain, weight loss, and/or nutritional deficiencies"
    explanation: >-
      Ties persistent villous atrophy to the malabsorptive clinical
      consequences, which is the step from this node to the nutrient
      malabsorption node downstream of it.
  - reference: PMID:38914866
    reference_title: "Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease."
    supports: SUPPORT
    snippet: "ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group."
    explanation: Provides interventional evidence that blocking TG2-mediated T cell activation prevents the downstream epithelial damage, villous atrophy, and malabsorption.
  downstream:
  - target: Villous Atrophy
    causal_link_type: DIRECT
    description: >-
      Villous atrophy is the histologic expression of this node: cytotoxic
      killing of enterocytes with crypt hyperplasia shortens the villi, which is
      what the biopsy reports as a reduced villus-height to crypt-depth ratio.
    evidence:
    - reference: PMID:34192430
      reference_title: "A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury."
      explanation: >-
        Interventional human evidence that blocking the upstream cascade
        attenuates the loss of villus-height/crypt-depth ratio - the causal link
        between the epithelial-damage mechanism and the histologic phenotype.
  - target: Generalized Nutrient Malabsorption
    causal_link_type: DIRECT
    description: >-
      Enterocyte loss and villous shortening reduce the absorptive surface area
      and the brush-border transport capacity of the proximal small intestine,
      which is the proximate cause of malabsorption.
    evidence:
    - reference: PMID:33920345
      reference_title: "Small and Large Intestine (I): Malabsorption of Nutrients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "celiac disease is the most common example of a malabsorptive condition"
      explanation: >-
        Places celiac enteropathy as the prototypical malabsorptive condition in
        a review of malabsorption mechanisms, which is what makes the
        malabsorption node the direct consequence of this one rather than a
        generic downstream state.
  - target: Aberrant Clonal Intraepithelial Lymphocyte Expansion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Sustained IL-15-rich mucosal signaling in a chronically injured epithelium
      selects for intraepithelial lymphocyte clones that lose normal dependence
      on their activating signals. The selection pressure is inferred from the
      clinical sequence (uncomplicated disease preceding refractory disease type
      II) rather than demonstrated prospectively, so the edge is indirect.
    evidence:
    - reference: PMID:33579790
      reference_title: "Oncogenetic landscape of lymphomagenesis in coeliac disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII)"
      explanation: >-
        Establishes the clonal intraepithelial lymphocyte expansion as the
        intermediate step between celiac enteropathy and lymphoma, which is what
        this edge places downstream of the epithelial-damage node.
- name: Generalized Nutrient Malabsorption
  biological_scale: ORGANISM
  description: >-
    Loss of absorptive surface area and brush-border transport capacity in the
    proximal small intestine produces defective mucosal absorption of
    macronutrients, iron, folate, vitamin B12, zinc and the fat-soluble
    vitamins. This is the convergence point through which most of the
    non-gastrointestinal manifestations of celiac disease are produced: it is
    the node the nutrient-deficiency, growth, bone and anemia branches all pass
    through. Deficiencies are not proportional to histologic grade - one
    newly-diagnosed adult cohort found vitamin and mineral deficiencies were
    not associated with the degree of intestinal damage - so the magnitude of
    this node is not read off the biopsy.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: intestinal absorption
    term:
      id: GO:0050892
      label: intestinal absorption
    modifier: DECREASED
  evidence:
  - reference: PMID:24084055
    reference_title: "Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Almost all CD-patients (87%) had at least one value below the lower limit of reference."
    explanation: >-
      Establishes the node quantitatively in 80 newly diagnosed untreated adults:
      zinc deficiency in 67%, decreased iron stores in 46%, anemia in 32%, folate
      20%, B12 19%.
  - reference: PMID:24084055
    reference_title: "Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vitamin/mineral deficiencies were counter-intuitively not associated with a (higher) grade of histological intestinal damage or (impaired) nutritional status."
    explanation: >-
      Bounds the node: the deficiency burden does not track histologic severity,
      so this node's magnitude cannot be inferred from the biopsy grade of the
      epithelial-damage node upstream of it.
  downstream:
  - target: Chronic Diarrhea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Unabsorbed solute raises the luminal osmotic load, fat and bile salts
      reaching the colon are converted by bacteria into cathartic hydroxy-fatty
      acids, and electrolyte secretion increases; together these raise stool
      water. The individual contributions of the osmotic, fatty-acid, bile-acid
      and secretory routes have not been partitioned in celiac cohorts, so the
      edge is recorded as indirect.
    evidence:
    - reference: PMID:33920345
      reference_title: "Small and Large Intestine (I): Malabsorption of Nutrients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "persistent villous atrophy despite a strict GFD longer than one year that leads to concomitant symptoms such as diarrhea, steatorrhea, abdominal pain, weight loss, and/or nutritional deficiencies"
      explanation: >-
        Links the malabsorptive state to diarrhea and steatorrhea in celiac
        disease specifically, in the review that also describes the osmotic and
        cathartic mechanisms behind it.
  - target: Weight Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Macronutrient malabsorption and steatorrhea create a negative energy
      balance. Reduced intake and inflammatory anorexia contribute in parallel
      and have not been separated from the absorptive loss, and a normal or
      raised body mass index does not exclude active disease.
    evidence:
    - reference: PMID:24084055
      reference_title: "Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall, 17% were malnourished (>10% undesired weight loss)"
      explanation: >-
        Quantifies the weight-loss outcome in untreated newly diagnosed adults,
        in the same cohort that documents the malabsorptive deficiencies
        upstream of it.
  - target: Iron Deficiency Anemia
    causal_link_type: DIRECT
    description: >-
      Iron is absorbed principally in the proximal duodenum, which is the
      segment celiac disease destroys, so iron malabsorption and store depletion
      follow directly from the lesion's location. Menstrual or occult blood loss
      and inflammatory hepcidin-mediated restriction can coexist.
    evidence:
    - reference: PMID:34067622
      reference_title: "Iron Deficiency Anemia in Celiac Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This portion of the intestine is typically destroyed in celiac disease (CD), resulting in a reduction in absorption of iron and subsequent iron deficiency anemia (IDA)."
      explanation: >-
        States the anatomical coincidence that makes this edge direct - the
        principal site of iron absorption is the site of the lesion - and reports
        iron deficiency anemia as the most frequent extraintestinal
        manifestation, at 12-82% at diagnosis.
  - target: Vitamin D Deficiency
    causal_link_type: DIRECT
    description: >-
      Fat malabsorption and reduced absorptive area impair uptake of the
      fat-soluble vitamins, vitamin D among them. Low dietary intake and limited
      sunlight exposure contribute independently, and deficiency can persist on
      a gluten-free diet.
    evidence:
    - reference: PMID:28722929
      reference_title: "Celiac Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "malabsorption of essential nutrients, including micronutrients, fat-soluble vitamins, iron, vitamin B12, and folate"
      explanation: >-
        Names fat-soluble vitamin malabsorption as a consequence of the mucosal
        damage, which is the absorptive route this edge asserts.
    - reference: PMID:10071918
      reference_title: "Osteoporosis in adult patients with celiac disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A low 25-(OH)D vitamin concentration was a typical biochemical abnormality in our patients (64% of men and 71% of women)"
      explanation: >-
        Measures the resulting deficiency in an adult celiac cohort, which is the
        endpoint of this edge: low 25-hydroxyvitamin D in roughly two thirds of
        patients.
  - target: Growth Failure in Children
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic energy, protein and micronutrient malabsorption in a growing child
      produces malnutrition and impaired weight gain, and malnutrition with
      chronic inflammation suppresses the growth-hormone/IGF-1 axis. The
      endocrine step is inferred rather than demonstrated in celiac cohorts, and
      socioeconomic nutrition and diagnostic delay modify the outcome, so the
      edge is indirect.
    evidence:
    - reference: PMID:39334575
      reference_title: "Growth Stunting and Nutritional Deficiencies among Children and Adolescents with Celiac Disease in Kuwait: A Case-Control Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Approximately one-third (31%) of children with CD had stunted growth, 20.8% had a low body mass index for their age, and 5.2% had both growth stunting and wasting."
      explanation: >-
        Case-control evidence pairing the growth outcome with the nutritional
        deficits in the same pediatric celiac population, which is the
        association this edge asserts a route for. The same study found growth
        stunting predicted by serum ferritin alongside maternal education and
        family income, which is why the edge records socioeconomic nutrition as
        a parallel contributor rather than asserting a purely absorptive route.
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Short stature is the accumulated outcome of the same growth-failure branch
      once reduced linear growth velocity has persisted. Familial short stature,
      endocrine disease and failure of catch-up growth after treatment are
      separate explanations that this edge does not displace.
    evidence:
    - reference: PMID:39334575
      reference_title: "Growth Stunting and Nutritional Deficiencies among Children and Adolescents with Celiac Disease in Kuwait: A Case-Control Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A significant proportion of children and adolescents with CD had malnutrition, overt deficiencies, and impaired growth despite coherence with a gluten-free diet."
      explanation: >-
        The linear-growth endpoint in the same case-control cohort. Note the
        impairment persisted on a gluten-free diet, which is why this edge does
        not assert that catch-up growth follows treatment.
  - target: Hypoproteinemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Serum protein falls in active disease. Two routes are available and the
      cited evidence does not separate them: failure to absorb dietary protein
      across a reduced absorptive surface, and protein loss across the damaged
      mucosa (protein-losing enteropathy). The edge is recorded as indirect for
      that reason rather than because the association is weak.
    evidence:
    - reference: PMID:39234463
      reference_title: "Extra-digestive manifestations of celiac disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Iron deficiency anemia was the most common extra-digestive manifestation, affecting 20.37% of patients, followed by hypoproteinemia (18.52%) and Hashimoto's thyroiditis (14.81%)."
      explanation: >-
        Establishes that hypoproteinemia is common in active celiac disease and
        sits alongside iron deficiency anemia, which is already wired to this
        node. The source gives cohort prevalence, not the absorptive mechanism,
        so it supports the edge's existence without choosing between the two
        candidate routes named in the description.
  - target: Secondary Hyperparathyroidism
    causal_link_type: DIRECT
    description: >-
      Calcium and vitamin D malabsorption lowers serum calcium and 25-hydroxy
      vitamin D, which raises parathyroid hormone secretion - the compensatory
      response that then drives skeletal resorption.
    evidence:
    - reference: PMID:36904090
      reference_title: "Osteoporosis and Celiac Disease: Updates and Hidden Pitfalls."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hyperparathyroidism is frequent and should be sought in newly diagnosed patients as it is responsible for accelerating bone turnover"
      explanation: >-
        States the parathyroid step directly and reports it as frequent at
        diagnosis, which is what places this node downstream of the malabsorptive
        calcium and vitamin D deficit.
    - reference: PMID:24290593
      reference_title: "Pathologic bone alterations in celiac disease: etiology, epidemiology, and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "two main mechanisms are involved: intestinal malabsorption and chronic inflammation"
      explanation: >-
        Names intestinal malabsorption as one of the two mechanisms of celiac
        bone disease, which is the branch this edge represents. The review does
        not itself mention parathyroid hormone, so the parathyroid step rests on
        the companion citation rather than on this one.
- name: Secondary Hyperparathyroidism
  biological_scale: ORGANISM
  description: >-
    Calcium and vitamin D malabsorption lowers serum calcium, and the
    compensatory rise in parathyroid hormone increases osteoclast-mediated bone
    resorption to defend the serum calcium concentration at the expense of the
    skeleton. This is the nutrient branch of celiac bone disease; the
    inflammatory RANKL/OPG branch acts on the same skeletal endpoint in
    parallel.
  biological_processes:
  - preferred_term: bone resorption
    term:
      id: GO:0045453
      label: bone resorption
    modifier: INCREASED
  evidence:
  - reference: PMID:36904090
    reference_title: "Osteoporosis and Celiac Disease: Updates and Hidden Pitfalls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As blood Ca2+ concentration decreases, a rapid increase in PTH release promotes bone turnover and cortical bone loss."
    explanation: >-
      States this node's mechanism in full: falling serum calcium drives
      parathyroid hormone release, and the hormone accelerates bone turnover and
      cortical loss. This is the sentence the node rests on.
  - reference: PMID:24290593
    reference_title: "Pathologic bone alterations in celiac disease: etiology, epidemiology, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The etiology of pathologic bone alterations in CD is multifactorial; however, two main mechanisms are involved: intestinal malabsorption and chronic inflammation."
    explanation: >-
      Establishes the two-branch structure of celiac bone disease, of which this
      node is the malabsorption branch. The review also presents the roles of
      calcium and its transport mechanisms.
  downstream:
  - target: Reduced Bone Mineral Density
    causal_link_type: DIRECT
    description: >-
      Parathyroid-hormone-driven osteoclastic resorption, together with impaired
      mineralization from the calcium and vitamin D deficit itself, lowers bone
      mineral density.
    evidence:
    - reference: PMID:36904090
      reference_title: "Osteoporosis and Celiac Disease: Updates and Hidden Pitfalls."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As blood Ca2+ concentration decreases, a rapid increase in PTH release promotes bone turnover and cortical bone loss."
      explanation: >-
        States this edge's claim: the parathyroid response accelerates bone
        turnover and produces cortical bone loss, which is the reduction in bone
        mineral density this edge targets.
    - reference: PMID:36904090
      reference_title: "Osteoporosis and Celiac Disease: Updates and Hidden Pitfalls."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The etiopathology of bone lesions in CD is multifactorial and other conditions, rather than mineral and vitamin D malabsorption, may affect skeletal health"
      explanation: >-
        Cited as the bound on this edge rather than as its mechanism: the same
        review records that contributors beyond mineral and vitamin D
        malabsorption affect skeletal health, which is why the edge does not
        claim the parathyroid route is the only one.
  - target: Osteoporosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Sustained remodeling imbalance carries low bone mineral density through to
      osteoporosis and fragility. Age, sex hormones, low body mass index and
      primary osteoporosis modify the threshold, and bone density does not
      always normalize on a gluten-free diet, so the edge is indirect.
    evidence:
    - reference: PMID:24290593
      reference_title: "Pathologic bone alterations in celiac disease: etiology, epidemiology, and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Low bone mineral density (BMD), osteopenia, and osteoporosis are frequent complications of celiac disease (CD)."
      explanation: >-
        Places osteoporosis at the end of the same continuum as low bone mineral
        density in celiac disease, which is the progression this edge records.
- name: Aberrant Clonal Intraepithelial Lymphocyte Expansion
  biological_scale: CELLULAR
  description: >-
    Chronic IL-15-rich signaling in the damaged epithelium selects intraepithelial
    lymphocyte clones that acquire JAK1 and STAT3 gain-of-function mutations,
    giving them cytokine-independent survival and proliferative fitness. The
    clinical counterpart is refractory celiac disease type II, a low-grade clonal
    intraepithelial lymphoproliferation that commonly precedes
    enteropathy-associated T-cell lymphoma. This is the mechanism through which
    the neoplastic risk of celiac disease is realized, and it is also why the
    risk is concentrated in patients whose mucosa does not heal.
  cell_types:
  - preferred_term: intraepithelial lymphocyte
    term:
      id: CL:0002496
      label: intraepithelial lymphocyte
  biological_processes:
  - preferred_term: cell surface receptor signaling pathway via JAK-STAT
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: GAIN_OF_FUNCTION
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:33579790
    reference_title: "Oncogenetic landscape of lymphomagenesis in coeliac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII)"
    explanation: >-
      Establishes refractory celiac disease type II as the clonal
      intraepithelial-lymphocyte stage standing between celiac enteropathy and
      lymphoma.
  downstream:
  - target: Small intestinal lymphoma
    causal_link_type: DIRECT
    description: >-
      Clones carrying JAK1/STAT3 gain-of-function lesions, with cooperating
      NF-kB and epigenetic changes, expand to overt enteropathy-associated
      T-cell lymphoma. JAK1 inhibition blocked survival and proliferation of
      malignant refractory-disease cells in vitro, which is direct functional
      support for the driver role of this step. Some lymphomas arise without a
      recognized refractory-disease stage, and other small-intestinal lymphomas
      have different causal wiring.
    evidence:
    - reference: PMID:33579790
      reference_title: "Oncogenetic landscape of lymphomagenesis in coeliac disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We demonstrate the outstanding frequency of JAK1 and STAT3 gain-of-function (GOF) mutations but also reveal the frequent occurrence of deleterious mutations in negative regulators of NF-κB and in several epigenetic regulators, thus revealing candidate targets for therapeutic intervention."
      explanation: >-
        The driver landscape this edge turns on, from whole-exome and targeted
        sequencing of refractory-disease and lymphoma biopsies: the
        JAK1/STAT3 gain-of-function lesions plus the cooperating NF-kB and
        epigenetic changes named in the edge description.
    - reference: PMID:33579790
      reference_title: "Oncogenetic landscape of lymphomagenesis in coeliac disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "JAK1 inhibitors, and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines."
      explanation: >-
        Functional support for the driver role rather than mere association:
        blocking the pathway blocks survival and proliferation of the malignant
        clone. Graded IN_VITRO because the perturbation was performed on
        refractory-disease cell lines.
- name: Autoantibody Production
  description: >
    B cells produce antibodies against tTG (anti-tTG IgA) and
    deamidated gliadin peptides (anti-DGP). These serve as diagnostic
    markers and may contribute to pathology.
  cell_types:
  - preferred_term: Plasma Cell
    term:
      id: CL:0000786
      label: plasma cell
  evidence:
  - reference: PMID:18803427
    reference_title: "Celiac disease: risk assessment, diagnosis, and monitoring."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The serum levels of immunoglobulin (Ig)A anti-tissue transglutaminase (or TG2) are the first choice in screening for celiac disease, displaying the highest levels of sensitivity (up to 98%) and specificity (around 96%)."
    explanation: Documents IgA anti-tissue transglutaminase (anti-tTG/TG2) autoantibodies as the primary celiac serological marker, supporting B-cell/plasma-cell autoantibody production against tTG; the same review reports deamidated gliadin peptide (DGP) antibodies as an additional marker.
  - reference: PMID:27352981
    reference_title: "Seronegative celiac disease: Shedding light on an obscure clinical entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fourteen fulfilled the diagnostic criteria for seronegative celiac disease based on antibody negativity, villous atrophy, HLA-DQ2/-DQ8 positivity and clinical/histological improvement after gluten free diet"
    explanation: >-
      Bounds the autoantibody node. A small minority of patients develop villous
      atrophy that remits on a gluten-free diet with no detectable serum
      antibodies, so the humoral arm is a near-universal accompaniment and
      diagnostic handle rather than a required step for enteropathy. The study
      used HLA typing and diet response as inclusion criteria and did not measure
      gluten-specific T cells, so it does not itself demonstrate that the T-cell
      pathway is intact in these patients.
  downstream:
  - target: Dermatitis Herpetiformis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The humoral response spreads from TG2 to the related epidermal enzyme
      transglutaminase 3 (TG3), and patients with dermatitis herpetiformis carry
      an antibody population specific for TG3 with markedly higher avidity for
      it than for TG2. The granular IgA precipitates that define the skin lesion
      contain TG3, so the antigen and the deposit are established. The terminal
      sequence - immune-complex deposition in dermal papillae, complement and
      endothelial activation, neutrophil recruitment and protease-mediated
      injury at the dermal-epidermal junction - is the part not fully
      demonstrated, and dermal IgA deposits can occur without clinical disease,
      so the edge is recorded as indirect.
    evidence:
    - reference: PMID:11901200
      reference_title: "Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the IgA precipitates in the papillary dermis of patients with dermatitis herpetiformis, the defining signs of the disease, contain epidermal transglutaminase, but not tissue transglutaminase or keratinocyte transglutaminase"
      explanation: >-
        Identifies the antigen inside the lesion-defining deposit, which is what
        makes this a specific route from the autoantibody node to this
        phenotype rather than a shared-susceptibility association. The same
        study shows dermatitis herpetiformis patients have a TG3-specific
        antibody population with higher avidity for TG3 than for TG2.
  - target: Female infertility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Anti-TG2 antibodies from untreated patients bind TG2 on the
      maternal-facing syncytiotrophoblast and inhibit its local activity, and in
      primary human trophoblasts they reduce invasiveness and matrix
      metalloprotease activity and increase apoptosis — the proposed route from
      the humoral arm to impaired implantation and placentation.
      Epidemiologically, the excess of adverse reproductive outcomes is
      confined to undiagnosed disease and attenuates after diagnosis and
      gluten-free diet, tying the phenotype to disease activity. Mechanism
      attribution remains contested: malabsorption-related nutrient deficiency
      and systemic inflammation are credible parallel contributors, and the
      antibody evidence is from human tissue and cell systems with no in vivo
      perturbation in women, so the edge is recorded as indirect. How much weight
      that tissue-level and cell-level work can carry is itself unsettled in the
      literature, which is why the chain is placed no more strongly than
      indirect.
    evidence:
    - reference: PMID:19228395
      reference_title: "Maternal celiac disease autoantibodies bind directly to syncytiotrophoblast and inhibit placental tissue transglutaminase activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These data indicate that direct immune effects in untreated CD women may compromise placental function."
      explanation: >-
        Celiac IgA bound the maternal-facing syncytiotrophoblast surface
        significantly more than control IgA, staining was reduced by
        pre-absorption with recombinant TG2, and bound IgA inhibited local
        transglutaminase activity — direct human placental-tissue evidence for
        the antibody arm of this edge. Graded IN_VITRO because the binding and
        activity assays were performed on placental tissue ex vivo.
    - reference: PMID:20571491
      reference_title: "Anti-tissue transglutaminase antibodies from celiac patients are responsible for trophoblast damage via apoptosis in vitro."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the binding of anti-tTG antibodies to trophoblast might represent a key mechanism by which the embryo implantation and pregnancy outcome are impaired in untreated celiac pregnant women"
      explanation: >-
        Primary human trophoblasts exposed to anti-TG2 IgG, including IgG from
        untreated celiac women, showed impaired invasiveness, decreased matrix
        metalloprotease activity and increased apoptosis — the functional
        counterpart of the binding shown by the placental study.
    - reference: PMID:36593803
      reference_title: "Adverse pregnancy outcomes in women with celiac disease: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The subgroup analysis demonstrated that only undiagnosed CD increased risk for fetal growth restriction, stillbirth, preterm delivery and lower mean birthweight, whereas early diagnosis of CD was not linked to any adverse pregnancy outcomes."
      explanation: >-
        Cited for one thing only: the excess risk falls on undiagnosed disease
        and not on early-diagnosed disease, which is the disease-activity
        dependence this edge asserts. The outcomes measured are pregnancy
        outcomes — fetal growth restriction, stillbirth, preterm delivery,
        birthweight — not conception failure, so this item does not evidence the
        infertility endpoint itself, and it does not distinguish the antibody
        route from nutritional or inflammatory contributions.
- name: Barrier Dysfunction
  description: >
    Increased intestinal permeability allows greater gluten peptide
    translocation. Zonulin upregulation disrupts tight junctions.
  evidence:
  - reference: PMID:38914866
    reference_title: "Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease."
    supports: SUPPORT
    snippet: "ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group."
    explanation: TG2 inhibition preserves mucosal-morphology, differentiation and nutrient-absorption transcriptomic signatures — indirect support that mucosal/barrier integrity is downstream of gluten-driven immune activation. The specific zonulin/tight-junction mechanism in the node description is mechanistic context and is not directly established by this transcriptomic citation.
  downstream:
  - target: Elevated Hepatic Transaminases
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reversible hepatocellular injury ("celiac hepatitis") is present in
      roughly a third to two-fifths of untreated patients and normalizes on a
      gluten-free diet in the large majority, so the hepatic injury tracks
      gluten-driven intestinal disease activity. The leading proposed route is
      the gut-liver axis: increased intestinal permeability delivering
      microbial products, antigens and cytokines to the liver through the
      portal circulation. The responsible portal mediator has not been
      identified in patients, and anti-TG2 deposition and systemic cytokines
      remain alternative contributors, so the edge is recorded as indirect.
    evidence:
    - reference: PMID:7657290
      reference_title: "Prevalence of hypertransaminasemia in adult celiac patients and effect of gluten-free diet."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "in adult celiac patients elevated serum transaminases are a frequent finding and normalize in most cases after GFD"
      explanation: >-
        158-patient adult cohort in which 67 (42%) had raised transaminases at
        diagnosis and 60 of the 67 (95%) normalized on a gluten-free diet — the
        dietary-withdrawal reversal that ties the hepatic injury causally to
        intestinal disease activity rather than to a coincident liver disease.
    - reference: PMID:23434875
      reference_title: "Pediatric celiac disease, cryptogenic hypertransaminasemia, and autoimmune hepatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A gluten-free diet normalized transaminase levels in 77% to 100% of patients with CD within 4 to 8 months"
      explanation: >-
        Pediatric meta-analysis reproducing the gluten-free-diet reversal of the
        transaminase elevation, supporting the same disease-activity-dependent
        hepatic injury in children.
    - reference: PMID:39796519
      reference_title: "Celiac Disease and Liver Damage: The Gut-Liver Axis Strikes Back (Again)? A Retrospective Analysis in the Light of a Literature Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Liver damage might be a consequence of the increased IP, which allows toxins, cytokines, and antigens to reach the liver via the portal circulation and cause liver injury through the release of pro-inflammatory mediators."
      explanation: >-
        States the permeability route this edge runs through, which is what
        grounds Barrier Dysfunction rather than another node as the source. The
        review's own framing is that these mechanisms "are still speculative",
        which is the reason the edge is indirect and the portal mediator is left
        unnamed.
- name: Microbiome Dysbiosis
  description: >
    Alterations in gut microbial composition and metabolic activity
    contribute to disease initiation and progression. Dysbiosis occurs
    in genetically at-risk individuals prior to disease onset, persists
    in active disease, and may not be fully restored by gluten-free diet.
    Dysbiosis impairs microbial-mediated gluten degradation, reduces
    production of short-chain fatty acids, and compromises intestinal
    barrier integrity and immune homeostasis.
  cell_types:
  - preferred_term: Intestinal Epithelial Cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: Response to Bacterium
    term:
      id: GO:0009617
      label: response to bacterium
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:42386020
    reference_title: "Decoding gut microbiome alterations in celiac disease: Implications for pathogenesis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The gut microbiome has emerged as a key modulator of immune homeostasis, intestinal barrier integrity, and gluten metabolism, implicating microbial dysbiosis in both the initiation and progression of CD"
    explanation: The microbiome plays a key mechanistic role in disease pathogenesis through immune regulation, barrier function, and gluten degradation.
  - reference: PMID:42386020
    reference_title: "Decoding gut microbiome alterations in celiac disease: Implications for pathogenesis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alterations in microbial composition and metabolic activity have been documented in genetically at-risk individuals prior to disease onset, in patients with active disease, and in treated patients on a GFD"
    explanation: Dysbiosis signatures appear early in disease development and persist despite treatment, suggesting dysbiosis as both an initiating and maintaining mechanism.
  - reference: PMID:42386020
    reference_title: "Decoding gut microbiome alterations in celiac disease: Implications for pathogenesis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "accumulating evidence indicates that it does not consistently restore gut microbiome composition or function, and many patients experience persistent symptoms despite good dietary adherence"
    explanation: Gluten-free diet does not reliably restore dysbiotic microbiota, suggesting dysbiosis as a mechanism underlying persistent symptoms in diet-adherent patients.
phenotypes:
- name: Chronic Diarrhea
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Chronic Diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  evidence:
  - reference: PMID:28722929
    reference_title: "Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typical gastrointestinal symptoms include diarrhea, abdominal discomfort, bloating, and constipation."
    explanation: Diarrhea is listed as a typical gastrointestinal symptom of celiac disease.
- name: Abdominal Pain
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abdominal Pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:28722929
    reference_title: "Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typical gastrointestinal symptoms include diarrhea, abdominal discomfort, bloating, and constipation."
    explanation: Abdominal pain/discomfort is a typical gastrointestinal symptom of celiac disease.
- name: Bloating
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abdominal Distention
    term:
      id: HP:0003270
      label: Abdominal distention
  evidence:
  - reference: PMID:28722929
    reference_title: "Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typical gastrointestinal symptoms include diarrhea, abdominal discomfort, bloating, and constipation."
    explanation: Bloating is a typical gastrointestinal symptom of celiac disease.
- name: Constipation
  category: Gastrointestinal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:28722929
    reference_title: "Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typical gastrointestinal symptoms include diarrhea, abdominal discomfort, bloating, and constipation."
    explanation: Constipation is listed as a typical GI symptom, though less common than diarrhea.
- name: Villous Atrophy
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  notes: Histological hallmark of celiac disease on small bowel biopsy
  phenotype_term:
    preferred_term: Villous atrophy
    term:
      id: HP:0011473
      label: Villous atrophy
  evidence:
  - reference: PMID:28722929
    reference_title: "Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "villous atrophy, crypt hyperplasia, and infiltration of the lamina propria by immune cells"
    explanation: Villous atrophy is the defining histopathological finding in celiac disease.
- name: Weight Loss
  category: Systemic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Weight Loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:28722929
    reference_title: "Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "celiac disease can also present with extraintestinal manifestations such as fatigue, weight loss, skin rashes, anemia, and osteoporosis."
    explanation: Weight loss is a common extraintestinal manifestation of celiac disease due to malabsorption.
- name: Iron Deficiency Anemia
  category: Hematologic
  frequency: FREQUENT
  notes: From malabsorption of iron in proximal small bowel
  phenotype_term:
    preferred_term: Iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  evidence:
  - reference: PMID:28722929
    reference_title: "Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "malabsorption of essential nutrients, including micronutrients, fat-soluble vitamins, iron, vitamin B12, and folate"
    explanation: Iron malabsorption in the damaged proximal small intestine leads to iron deficiency anemia.
  - reference: PMID:30759885
    reference_title: "Neurological Manifestations of Neuropathy and Ataxia in Celiac Disease: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "iron-deficiency anemia, osteoporosis, dermatitis herpetiformis, and neurologic disorders"
    explanation: Iron deficiency anemia is listed among the common extra-intestinal manifestations of celiac disease.
- name: Fatigue
  category: Systemic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:28722929
    reference_title: "Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "celiac disease can also present with extraintestinal manifestations such as fatigue, weight loss, skin rashes, anemia, and osteoporosis."
    explanation: Fatigue is a common extraintestinal manifestation of celiac disease.
  - reference: PMID:30400298
    reference_title: "Fatigue as an Extra-Intestinal Manifestation of Celiac Disease: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Celiac disease may present with a range of different symptoms, including abdominal problems in a broader sense, iron deficiency and \"constant tiredness\""
    explanation: Systematic review confirming fatigue/tiredness as a recognized extra-intestinal manifestation.
- name: Growth Failure in Children
  category: Growth
  frequency: FREQUENT
  notes: Primarily seen in pediatric celiac disease; childhood onset
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:28722929
    reference_title: "Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Growth failure is a frequent additional symptom in children with celiac disease"
    explanation: Growth failure is explicitly described as frequent in pediatric celiac disease.
- name: Dermatitis Herpetiformis
  category: Dermatological
  frequency: OCCASIONAL
  notes: Specific cutaneous manifestation with granular IgA deposits at dermal papillae
  phenotype_term:
    preferred_term: Dermatitis herpetiformis
    term:
      id: HP:0033804
      label: Subepidermal blistering
  evidence:
  - reference: PMID:29757210
    reference_title: "Dermatitis Herpetiformis: A Common Extraintestinal Manifestation of Coeliac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dermatitis herpetiformis (DH) is a common extraintestinal manifestation of coeliac disease presenting with itchy papules and vesicles on the elbows, knees, and buttocks."
    explanation: Dermatitis herpetiformis is the specific cutaneous manifestation of celiac disease.
  - reference: PMID:29757210
    reference_title: "Dermatitis Herpetiformis: A Common Extraintestinal Manifestation of Coeliac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The DH to coeliac disease prevalence ratio is 1:8 in Finland and the United Kingdom (U.K.)"
    explanation: DH occurs in approximately 1 in 8 celiac patients, supporting OCCASIONAL frequency.
- name: Reduced Bone Mineral Density
  category: Musculoskeletal
  frequency: FREQUENT
  notes: Includes both osteopenia and osteoporosis from calcium/vitamin D malabsorption
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:10071918
    reference_title: "Osteoporosis in adult patients with celiac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "26% of all celiac patients, but only 5% of control subjects, were classified as having osteoporosis"
    explanation: Osteoporosis is significantly more prevalent in celiac disease patients.
  - reference: PMID:10071918
    reference_title: "Osteoporosis in adult patients with celiac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "celiac disease constitutes a risk factor for osteoporosis. This finding applies particularly to untreated and poorly treated patients"
    explanation: Untreated celiac disease is a particular risk factor for reduced bone density.
- name: Dental Enamel Defects
  category: Dental
  frequency: FREQUENT
  notes: Bilaterally symmetrical enamel defects, particularly in permanent dentition
  phenotype_term:
    preferred_term: Dental enamel defects
    term:
      id: HP:0000682
      label: Abnormal dental enamel morphology
  evidence:
  - reference: PMID:37373569
    reference_title: "Beyond the Gut: A Systematic Review of Oral Manifestations in Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "enamel defects (42.47%), delayed dental eruption (47.34%)"
    explanation: Systematic review finds dental enamel defects in over 42% of celiac disease patients.
  - reference: PMID:34244963
    reference_title: "Dental enamel defects and oral cavity manifestations in Asian patients with celiac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall higher number of patients with CeD (66.9%), both treatment naïve (69.4%) and those on GFD (65.8%) had DED in comparison to controls (20%)"
    explanation: Two-thirds of celiac patients have dental enamel defects regardless of treatment status.
- name: Recurrent Aphthous Stomatitis
  category: Oral
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent aphthous stomatitis
    term:
      id: HP:0011107
      label: Recurrent aphthous stomatitis
  evidence:
  - reference: PMID:37373569
    reference_title: "Beyond the Gut: A Systematic Review of Oral Manifestations in Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent aphthous stomatitis (34.6%), atrophic glossitis and geographic tongue (15.26%)"
    explanation: Systematic review reports aphthous stomatitis in ~35% of celiac patients.
  - reference: PMID:34244963
    reference_title: "Dental enamel defects and oral cavity manifestations in Asian patients with celiac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent aphthous ulcers were also significantly higher in patients with CeD"
    explanation: Controlled study confirms significantly elevated aphthous ulcers in celiac disease.
- name: Peripheral Neuropathy
  category: Neurological
  frequency: OCCASIONAL
  notes: Predominantly sensory, may precede GI symptoms
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:30759885
    reference_title: "Neurological Manifestations of Neuropathy and Ataxia in Celiac Disease: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gluten neuropathy was a neurological manifestation in CD (up to 39%) in 13 studies"
    explanation: Systematic review reports gluten neuropathy prevalence up to 39% across studies.
  - reference: PMID:12771245
    reference_title: "Celiac neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurologic complications are estimated to occur in 10% of affected patients, with ataxia and peripheral neuropathy being the most common problems"
    explanation: Peripheral neuropathy is one of the most common neurological complications of celiac disease.
  - reference: PMID:12771245
    reference_title: "Celiac neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD is commonly associated with sensory neuropathy and should be considered even in the absence of gastrointestinal symptoms"
    explanation: Celiac-associated neuropathy is predominantly sensory and can occur without GI symptoms.
- name: Cerebellar Ataxia
  category: Neurological
  frequency: OCCASIONAL
  notes: Gluten ataxia; may improve with strict gluten-free diet
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:36555205
    reference_title: "Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression"
    explanation: Cerebellar ataxia is listed among the key neurological manifestations of celiac disease.
  - reference: PMID:30759885
    reference_title: "Neurological Manifestations of Neuropathy and Ataxia in Celiac Disease: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine studies reported a lower risk and/or prevalence of gluten ataxia with a range of 0%⁻6%"
    explanation: Systematic review reports gluten ataxia prevalence of 0-6% in celiac patients.
- name: Elevated Hepatic Transaminases
  category: Hepatic
  frequency: FREQUENT
  notes: Celiac hepatitis; typically resolves with gluten-free diet
  phenotype_term:
    preferred_term: Elevated hepatic transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:23434875
    reference_title: "Pediatric celiac disease, cryptogenic hypertransaminasemia, and autoimmune hepatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD is associated with elevated transaminase levels in about one-third of newly diagnosed children"
    explanation: Meta-analysis shows ~36% of newly diagnosed celiac patients have elevated transaminases.
  - reference: PMID:23434875
    reference_title: "Pediatric celiac disease, cryptogenic hypertransaminasemia, and autoimmune hepatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A gluten-free diet normalized transaminase levels in 77% to 100% of patients with CD within 4 to 8 months"
    explanation: Elevated transaminases in celiac disease are typically reversible with gluten-free diet.
- name: Vitamin D Deficiency
  category: Metabolic
  frequency: FREQUENT
  notes: From fat-soluble vitamin malabsorption
  phenotype_term:
    preferred_term: Vitamin D deficiency
    term:
      id: HP:0100512
      label: Decreased circulating vitamin D concentration
  evidence:
  - reference: PMID:10071918
    reference_title: "Osteoporosis in adult patients with celiac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A low 25-(OH)D vitamin concentration was a typical biochemical abnormality in our patients (64% of men and 71% of women)"
    explanation: Vitamin D deficiency is found in the majority of celiac patients due to fat-soluble vitamin malabsorption.
  - reference: PMID:28722929
    reference_title: "Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "malabsorption of essential nutrients, including micronutrients, fat-soluble vitamins, iron, vitamin B12, and folate"
    explanation: Fat-soluble vitamin malabsorption including vitamin D is a direct consequence of mucosal damage.
- name: "Small intestinal lymphoma"
  category: Neoplasm
  description: "Untreated celiac disease carries an increased long-term risk of small intestinal lymphoma."
  phenotype_term:
    preferred_term: "Small intestinal lymphoma"
    term:
      id: HP:0002665
      label: "Lymphoma"
  evidence:
  - reference: PMID:31331324
    reference_title: "Celiac disease: a comprehensive current review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "preventing the occurrence of refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma"
    explanation: "This review notes a gluten-free diet prevents occurrence of small intestinal lymphoma in celiac disease."
- name: "Osteoporosis"
  category: Skeletal
  description: "Osteoporosis is a recognized extraintestinal manifestation of celiac disease, driven by malabsorption."
  phenotype_term:
    preferred_term: "Osteoporosis"
    term:
      id: HP:0000939
      label: "Osteoporosis"
  evidence:
  - reference: PMID:24395055
    reference_title: "Celiac disease: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as dermatitis herpetiformis, anemia, dental enamel hypoplasia, recurrent oral aphthae, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminase levels, and female infertility"
    explanation: "This review lists osteoporosis among extraintestinal manifestations of celiac disease."
- name: "Arthritis"
  category: Musculoskeletal
  description: "Arthritis occurs as an extraintestinal manifestation of celiac disease."
  phenotype_term:
    preferred_term: "Arthritis"
    term:
      id: HP:0001369
      label: "Arthritis"
  evidence:
  - reference: PMID:24395055
    reference_title: "Celiac disease: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as dermatitis herpetiformis, anemia, dental enamel hypoplasia, recurrent oral aphthae, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminase levels, and female infertility"
    explanation: "This review lists arthritis among extraintestinal manifestations of celiac disease."
- name: "Short stature"
  category: Growth
  description: "Short stature is a common presenting extraintestinal feature of celiac disease in children."
  phenotype_term:
    preferred_term: "Short stature"
    term:
      id: HP:0004322
      label: "Short stature"
  evidence:
  - reference: PMID:24395055
    reference_title: "Celiac disease: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as dermatitis herpetiformis, anemia, dental enamel hypoplasia, recurrent oral aphthae, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminase levels, and female infertility"
    explanation: "This review lists short stature among extraintestinal manifestations of celiac disease."
- name: "Female infertility"
  category: Reproductive
  description: "Female infertility is a recognized extraintestinal association of untreated celiac disease."
  phenotype_term:
    preferred_term: "Female infertility"
    term:
      id: HP:0008222
      label: "Female infertility"
  evidence:
  - reference: PMID:24395055
    reference_title: "Celiac disease: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as dermatitis herpetiformis, anemia, dental enamel hypoplasia, recurrent oral aphthae, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminase levels, and female infertility"
    explanation: "This review lists female infertility among extraintestinal manifestations of celiac disease."
- name: Hypoproteinemia
  category: Metabolic
  frequency: FREQUENT
  description: >-
    Low serum protein in active disease, the second most common extra-digestive
    finding after iron deficiency anemia in a 108-patient adult series at 18.5%.
  phenotype_term:
    preferred_term: Hypoproteinemia
    term:
      id: HP:0003075
      label: Hypoproteinemia
  evidence:
  - reference: PMID:39234463
    reference_title: "Extra-digestive manifestations of celiac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Iron deficiency anemia was the most common extra-digestive manifestation, affecting 20.37% of patients, followed by hypoproteinemia (18.52%) and Hashimoto's thyroiditis (14.81%)."
    explanation: >-
      Establishes hypoproteinemia as a frequent finding in an adult celiac
      cohort, second only to iron deficiency anemia. Single tertiary-centre
      series of 108 patients, so the figure is a cohort prevalence rather than a
      population estimate.
- name: Arthralgia
  category: Musculoskeletal
  frequency: FREQUENT
  description: >-
    Joint pain without objective synovitis, reported in 20-30% of patients at
    diagnosis. Distinct from the separately recorded Arthritis phenotype: the
    literature describes joint complaints in celiac disease generally as
    arthralgia rather than as demonstrable joint inflammation, though subclinical
    synovial effusion and sacroiliitis are also reported.
  notes: >-
    Not merged into Arthritis, because the distinction is the substance of the
    disagreement about celiac joint disease - whether there is an inflammatory
    arthropathy at all, or predominantly pain without synovitis. Its mechanism is
    unresolved for the same reasons recorded in the
    gap_celiac_gfd_responsive_extraintestinal_mechanisms discussion, and studies
    of gluten withdrawal on joint pain conflict.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:38931169
    reference_title: "Associations between Celiac Disease, Extra-Gastrointestinal Manifestations, and Gluten-Free Diet: A Narrative Overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Joint pain is a frequent musculoskeletal manifestation occurring in 20–30% of patients at CeD diagnosis."
    explanation: >-
      Gives the frequency and establishes joint pain as a recognized
      musculoskeletal manifestation at diagnosis.
  - reference: PMID:38931169
    reference_title: "Associations between Celiac Disease, Extra-Gastrointestinal Manifestations, and Gluten-Free Diet: A Narrative Overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Symptoms are usually described in a general way as arthralgia rather than objective synovitis"
    explanation: >-
      The sentence that justifies recording this separately from Arthritis rather
      than treating the two as one phenotype.
biochemical:
- name: Anti-tTG IgA
  presence: Elevated
  context: Primary diagnostic marker
  loinc_term:
    id: LOINC:31017-7
    label: Tissue transglutaminase IgA Ab [Units/volume] in Serum
- name: Anti-Endomysial Antibodies
  presence: Elevated
  context: Highly specific
  loinc_term:
    id: LOINC:10863-9
    label: Endomysium IgA Ab [Titer] in Serum
- name: Anti-DGP Antibodies
  presence: Elevated
  context: Useful when IgA deficient
  loinc_term:
    id: LOINC:58710-5
    label: Gliadin peptide IgG Ab [Units/volume] in Serum
- name: Total IgA
  presence: Variable
  context: IgA deficiency common in celiac
  loinc_term:
    id: LOINC:2458-8
    label: IgA [Mass/volume] in Serum or Plasma
genetic:
- name: HLA-DQ2
  association: Risk Factor
  relationship_type: RISK_FACTOR
  notes: >-
    Present in ~95% of patients (DQ2 alone ~90%, DQ8 covers most remainder). This is the
    CELIAC1 locus of OMIM phenotypic series PS212750 (OMIM:212750, HLA-DQA1/HLA-DQB1 at
    6p21.32) — one of only three rows in that series with a known molecular basis. No
    gene_term is bound because DQ2 is a serotype encoded by an HLA-DQA1/HLA-DQB1 haplotype
    rather than a single gene. MONDO holds the locus as MONDO:0008930 "celiac disease,
    susceptibility to, 1", which predisposes_towards celiac disease rather than subclassing
    it — the reason the PS212750 members are risk-factor rows here and not grouping members.
  evidence:
  - reference: PMID:31331324
    reference_title: "Celiac disease: a comprehensive current review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A genetic background (HLA-DQ2/DQ8 positivity and non-HLA genes) is a mandatory determinant of the development of the disease"
    explanation: HLA-DQ2/DQ8 positivity is a mandatory genetic determinant for celiac disease development.
- name: HLA-DQ8
  association: Risk Factor
  relationship_type: RISK_FACTOR
  notes: >-
    Most remaining patients not carrying DQ2. Like DQ2, a serotype encoded by an
    HLA-DQA1/HLA-DQB1 haplotype rather than by a single gene, so no gene_term is bound.
- name: IL2
  association: Risk Factor
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: IL2
    term:
      id: hgnc:6001
      label: IL2
  notes: >-
    T cell growth factor at 4q27, the region OMIM codes as the CELIAC6 susceptibility locus
    (OMIM:611598).
- name: IL21
  association: Risk Factor
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: IL21
    term:
      id: hgnc:6005
      label: IL21
  notes: Adjacent to IL2 in the 4q27 (CELIAC6) susceptibility region.
- name: BACH2
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: BACH2
    term:
      id: hgnc:14078
      label: BACH2
  notes: Transcription factor regulating Treg/effector T cell balance and B cell class switching
- name: TNFAIP3
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: TNFAIP3
    term:
      id: hgnc:11896
      label: TNFAIP3
  notes: Encodes A20, a ubiquitin-editing enzyme that negatively regulates NF-kB signaling
- name: CD28
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: CD28
    term:
      id: hgnc:1653
      label: CD28
  notes: T cell co-stimulatory receptor required for T cell activation
- name: EGR2
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: EGR2
    term:
      id: hgnc:3239
      label: EGR2
  notes: Transcription factor involved in T cell anergy and peripheral tolerance
- name: ETS1
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: ETS1
    term:
      id: hgnc:3488
      label: ETS1
  notes: Transcription factor regulating T and B cell development and immune cell differentiation
- name: IRF4
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: IRF4
    term:
      id: hgnc:6119
      label: IRF4
  notes: Transcription factor essential for Th17 and Th2 cell differentiation and plasma cell development
- name: SMAD3
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: SMAD3
    term:
      id: hgnc:6769
      label: SMAD3
  notes: TGF-beta signaling mediator regulating T cell differentiation and immune tolerance
- name: PTPN22
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: PTPN22
    term:
      id: hgnc:9652
      label: PTPN22
  notes: Protein tyrosine phosphatase modulating T cell receptor signaling threshold
environmental:
- name: Gluten Exposure
  notes: Required trigger
  evidence:
  - reference: PMID:37332011
    reference_title: "Relationship between gluten availability and celiac disease prevalence: A geo-epidemiologic systematic review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: requiring genetic susceptibility and gluten exposure to trigger immune-mediated
      enteropathy
    explanation: States gluten exposure as a necessary condition alongside genetic
      susceptibility, which is what "required trigger" asserts.
  influences_mechanisms:
  - target: Gluten-Triggered Immune Response
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: Gluten ingestion is the necessary environmental trigger for the immune response against deamidated gliadin peptides in HLA-DQ2/DQ8 carriers.
    evidence:
    - reference: PMID:37332011
      reference_title: "Relationship between gluten availability and celiac disease prevalence: A geo-epidemiologic systematic review"
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: requiring genetic susceptibility and gluten exposure to trigger immune-mediated enteropathy
      explanation: States gluten exposure as a condition required to trigger the immune-mediated enteropathy, which is the claim this edge makes.
- name: Wheat Food Products
  notes: Common gluten-containing dietary source
  food_source:
    preferred_term: wheat food product
    term:
      id: FOODON:00001141
      label: wheat food product
  evidence:
  - reference: PMID:29941778
    reference_title: Celiac Disease and Glandular Autoimmunity
    supports: SUPPORT
    evidence_source: OTHER
    snippet: triggered and maintained by the ingestion of the storage proteins (gluten)
      of wheat, barley, and rye
    explanation: Names this grain among the three whose gluten storage proteins trigger
      and maintain the enteropathy.
  influences_mechanisms:
  - target: Gluten-Triggered Immune Response
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: Wheat is one of the three grains whose gluten storage proteins trigger and maintain the enteropathy.
    evidence:
    - reference: PMID:29941778
      reference_title: "Celiac Disease and Glandular Autoimmunity"
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye
      explanation: Names wheat among the grains whose ingested storage proteins trigger and maintain the immune response this node represents.
- name: Barley
  notes: Common gluten-containing dietary source
  food_source:
    preferred_term: barley
    term:
      id: FOODON:00003108
      label: barley seed (raw)
  evidence:
  - reference: PMID:29941778
    reference_title: Celiac Disease and Glandular Autoimmunity
    supports: SUPPORT
    evidence_source: OTHER
    snippet: triggered and maintained by the ingestion of the storage proteins (gluten)
      of wheat, barley, and rye
    explanation: Names this grain among the three whose gluten storage proteins trigger
      and maintain the enteropathy.
  influences_mechanisms:
  - target: Gluten-Triggered Immune Response
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: Barley is one of the three grains whose gluten storage proteins trigger and maintain the enteropathy.
    evidence:
    - reference: PMID:29941778
      reference_title: "Celiac Disease and Glandular Autoimmunity"
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye
      explanation: Names barley among the grains whose ingested storage proteins trigger and maintain the immune response this node represents.
- name: Rye
  notes: Common gluten-containing dietary source
  food_source:
    preferred_term: rye
    term:
      id: FOODON:00003734
      label: rye kernel
  evidence:
  - reference: PMID:29941778
    reference_title: Celiac Disease and Glandular Autoimmunity
    supports: SUPPORT
    evidence_source: OTHER
    snippet: triggered and maintained by the ingestion of the storage proteins (gluten)
      of wheat, barley, and rye
    explanation: Names this grain among the three whose gluten storage proteins trigger
      and maintain the enteropathy.
  influences_mechanisms:
  - target: Gluten-Triggered Immune Response
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: Rye is one of the three grains whose gluten storage proteins trigger and maintain the enteropathy.
    evidence:
    - reference: PMID:29941778
      reference_title: "Celiac Disease and Glandular Autoimmunity"
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye
      explanation: Names rye among the grains whose ingested storage proteins trigger and maintain the immune response this node represents.
- name: Early Gluten Introduction
  notes: Randomized trials found the timing of gluten introduction does not alter
    celiac disease risk in genetically at-risk infants
  evidence:
  - reference: PMID:25271603
    reference_title: Randomized feeding intervention in infants at high risk for celiac
      disease
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: the introduction of small quantities of gluten at 16 to 24 weeks of age
      did not reduce the risk of celiac disease by 3 years of age
    explanation: The PreventCD randomized trial (944 HLA-DQ2/DQ8-positive infants
      with an affected first-degree relative) refutes the earlier observational
      "window of opportunity" hypothesis that this exposure had recorded as "timing
      may affect risk".
- name: Gastrointestinal Infections
  exposure_term:
    preferred_term: Infectious agent exposure
    term:
      id: ECTO:3000000
      label: exposure to organism
  influences_mechanisms:
  - target: Gluten-Triggered Immune Response
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Gluten remains the necessary trigger; enteric infection is proposed to
      raise the chance that a genetically susceptible person loses tolerance
      to it. It contributes rather than causes, which is why this is
      predisposing.
    evidence:
    - reference: PMID:31331324
      reference_title: "Celiac disease: a comprehensive current review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota)"
      explanation: >-
        Names viral infections among the environmental factors contributing to
        disease development, alongside the necessary gluten trigger.
  notes: May trigger onset
  evidence:
  - reference: PMID:31331324
    reference_title: "Celiac disease: a comprehensive current review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota)"
    explanation: Viral infections are recognized environmental cofactors in celiac disease onset.
- name: Gut Microbiome
  influences_mechanisms:
  - target: Microbiome Dysbiosis
    environmental_effect: MODULATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Targets the entry's own dysbiosis node rather than the gluten trigger.
      MODULATES rather than PREDISPOSES because the direction of causation here
      is genuinely unsettled: dysbiosis is both a proposed contributor to loss
      of tolerance and a consequence of established disease, and the cited
      source describes the microbiome as a modulator rather than a risk factor.
    evidence:
    - reference: PMID:42386020
      reference_title: "Decoding gut microbiome alterations in celiac disease: Implications for pathogenesis and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The gut microbiome has emerged as a key modulator of immune homeostasis, intestinal barrier integrity, and gluten metabolism, implicating microbial dysbiosis in both the initiation and progression of CD"
      explanation: >-
        Describes the gut microbiome as a key modulator of immune homeostasis,
        barrier integrity and gluten handling, a modulating role rather than
        an initiating one.
  notes: Dysbiosis modulates disease initiation, progression, and symptom burden
  evidence:
  - reference: PMID:31331324
    reference_title: "Celiac disease: a comprehensive current review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota)"
    explanation: Gut microbiota dysbiosis is recognized as an environmental factor contributing to celiac disease.
  - reference: PMID:42386020
    reference_title: "Decoding gut microbiome alterations in celiac disease: Implications for pathogenesis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The gut microbiome has emerged as a key modulator of immune homeostasis, intestinal barrier integrity, and gluten metabolism, implicating microbial dysbiosis in both the initiation and progression of CD"
    explanation: Dysbiosis is mechanistically implicated in both disease initiation and progression through impaired immune homeostasis, barrier function, and gluten degradation.
  - reference: PMID:42386020
    reference_title: "Decoding gut microbiome alterations in celiac disease: Implications for pathogenesis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alterations in microbial composition and metabolic activity have been documented in genetically at-risk individuals prior to disease onset"
    explanation: Dysbiosis occurs in pre-disease individuals with genetic risk, supporting dysbiosis as an initiating environmental factor.
treatments:
- name: Gluten-Free Diet
  description: Lifelong strict gluten avoidance is the only effective treatment.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Gluten-free diet
    term:
      id: NCIT:C15447
      label: Dietary Intervention
    dietary_modifications:
    - action: AVOID
      food:
        preferred_term: wheat food product
        term:
          id: FOODON:00001141
          label: wheat food product
    - action: AVOID
      food:
        preferred_term: barley
        term:
          id: FOODON:00003108
          label: barley seed (raw)
    - action: AVOID
      food:
        preferred_term: rye
        term:
          id: FOODON:00003734
          label: rye kernel
  target_mechanisms:
  - target: Gluten-Triggered Immune Response
    treatment_effect: INHIBITS
    description: >-
      Removing dietary gluten withdraws the antigen the entire cascade depends
      on, shutting off TG2-deamidated peptide presentation and gluten-reactive
      CD4 T-cell activation upstream of mucosal injury.
    evidence:
    - reference: PMID:31331324
      reference_title: "Celiac disease: a comprehensive current review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the only treatment for celiac disease is a life-long, strict gluten-free diet leading to improvement in quality of life, ameliorating symptoms, and preventing the occurrence of refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma"
      explanation: >-
        Gluten withdrawal reverses symptoms and prevents complications, which is
        the clinical demonstration that the treatment acts by removing the
        trigger of the gluten-driven immune response.
  evidence:
  - reference: PMID:39273359
    reference_title: "Expression of MicroRNAs in Adults with Celiac Disease: A Narrative Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The only available treatment strategy is lifelong adherence to a gluten-free diet."
    explanation: Gluten-free diet is established as the only effective treatment for celiac disease.
  - reference: PMID:31331324
    reference_title: "Celiac disease: a comprehensive current review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the only treatment for celiac disease is a life-long, strict gluten-free diet leading to improvement in quality of life, ameliorating symptoms, and preventing the occurrence of refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma"
    explanation: Comprehensive review confirms GFD as the sole treatment with benefits for symptom relief and complication prevention.
- name: Nutritional Supplementation
  description: Iron, calcium, vitamin D, B12, folate as needed.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Nutritional supplementation
    term:
      id: NCIT:C15447
      label: Dietary Intervention
- name: Monitoring
  description: Regular serology and bone density monitoring.
- name: Corticosteroids
  description: For refractory celiac disease.
  treatment_term:
    preferred_term: Corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
- name: Dietitian Counseling
  description: Essential for dietary compliance.
  evidence:
  - reference: PMID:39273359
    reference_title: "Expression of MicroRNAs in Adults with Celiac Disease: A Narrative Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The only available treatment strategy is lifelong adherence to a gluten-free diet."
    explanation: Dietitian counseling is essential to ensure proper adherence to the gluten-free diet.
- name: Probiotics and Prebiotics
  description: >
    Emerging microbiome-modulating strategies to restore dysbiotic microbiota and
    improve gluten metabolism and immune regulation. May serve as adjunctive
    therapeutic approaches to complement gluten-free diet.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Probiotics and Prebiotics
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:42386020
    reference_title: "Decoding gut microbiome alterations in celiac disease: Implications for pathogenesis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We further discuss emerging strategies aimed at modulating the gut microbiome, including probiotics, prebiotics, postbiotics and precision probiotics, as potential adjunctive therapeutic approaches"
    explanation: Recent review identifies probiotics, prebiotics, and postbiotics as emerging microbiome-modulating strategies that may improve outcomes when combined with gluten-free diet.
diagnosis:
- name: HLA-DQ2/DQ8 genetic testing
  description: >-
    HLA-DQ2/DQ8 typing is used for diagnostic clarification in selected cases
    rather than as a primary diagnostic test.
  notes: >-
    The test's clinical utility rests on its negative predictive value - absence
    of both haplotypes makes coeliac disease very unlikely - but that rationale
    is not stated in the cited guideline abstract and is recorded here rather
    than asserted against it.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: Presence or absence of the HLA-DQ2 and HLA-DQ8 haplotypes.
  evidence:
  - reference: PMID:40999951
    reference_title: "European Society for the Study of Coeliac Disease 2025 Updated Guidelines on the Diagnosis and Management of Coeliac Disease in Adults. Part 1: Diagnostic Approach."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HLA-DQ2/DQ8 typing is recommended for diagnostic clarification in select cases."
    explanation: The 2025 ESsCD updated guidelines recommend HLA-DQ2/DQ8 typing for diagnostic clarification in selected cases of suspected coeliac disease.

histopathology:
- name: Marsh Classification of Duodenal Mucosal Injury
  description: >-
    The histological grading scheme for celiac enteropathy, applied to duodenal
    biopsy and reported in ascending order of injury: infiltrative change with
    raised intraepithelial lymphocyte counts and preserved architecture (Marsh
    1), the addition of crypt hyperplasia (Marsh 2), and villous atrophy graded
    partial, subtotal and total (Marsh 3a to 3c). The Oberhuber revision is the
    form in routine diagnostic use. Grade is not a proxy for clinical severity:
    an entry-level caveat worth keeping in view is that vitamin and mineral
    deficiencies in newly diagnosed patients do not track the histological grade.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:10524652
    reference_title: "The histopathology of coeliac disease: time for a standardized report scheme for pathologists."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we review the histological features of coeliac disease and propose a standardized report scheme based on the Marsh classification"
    explanation: >-
      The source of the revised reporting scheme built on Marsh's grades, which
      is the classification named here.
  notes: >-
    Recorded as a single graded finding rather than one record per grade, because
    the grades are ordered states of one lesion. The individual architectural
    components already appear as phenotypes (Villous Atrophy) and as
    pathophysiology (Intestinal Epithelial Damage); this record is the
    classification that orders them. The intraepithelial lymphocyte threshold is
    not fixed across implementations - historically 30 per 100 enterocytes,
    commonly 25 in contemporary practice - so a grade is only interpretable
    alongside the threshold the reporting laboratory used.
- name: Corazza-Villanacci Grading of Duodenal Mucosal Injury
  description: >-
    A simplified alternative to Marsh grading, collapsing the scheme to three
    categories - grade A, non-atrophic, with raised intraepithelial lymphocytes
    and normal villous architecture; grade B1, atrophic, with villi shortened but
    still identifiable; and grade B2, atrophic-flat, with complete villous
    flattening. Its purpose is reproducibility: the larger Marsh-Oberhuber
    category set carries substantial interobserver disagreement, and collapsing
    the atrophic grades removes the boundary judgements that drive most of it.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:33179621
    reference_title: "Celiac disease: histology-differential diagnosis-complications. A practical approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biopsy of duodenal mucosa remains the gold standard in the diagnosis of celiac disease with the recognition of the spectrum of histological changes and classification of mucosa damage based on updated Corazza-Villanacci system."
    explanation: >-
      A diagnostic-pathology review naming this system as the basis for grading
      mucosal damage, which is what this record captures alongside the older
      Marsh scheme.
  notes: >-
    Recorded beside the Marsh record rather than replacing it. Both are in live
    use, a report may carry either, and they are not interconvertible at the
    boundary between Marsh 3a, 3b and 3c, which grade B2 collapses.
has_subtypes:
- name: Classical
  display_name: Classical (symptomatic malabsorptive)
  description: >-
    Presents with the malabsorptive syndrome - diarrhea, steatorrhea, weight
    loss and nutrient deficiency - on a background of villous atrophy.
- name: Non-classical
  display_name: Non-classical (extraintestinal or minor GI presentation)
  description: >-
    Presents without the malabsorptive syndrome, through extraintestinal
    features such as anemia, reduced bone mineral density, transaminase
    elevation or neurological manifestations, or with non-specific bowel
    symptoms including constipation.
- name: Subclinical
  display_name: Subclinical / silent (screen-detected)
  description: >-
    Positive serology and villous atrophy on biopsy with no attributable
    symptoms, usually found by screening a risk group. "Subclinical" is the Oslo
    term; "silent" is the older usage and is sometimes restricted to
    asymptomatic villous atrophy specifically.
  evidence:
  - reference: PMID:33179621
    reference_title: "Celiac disease: histology-differential diagnosis-complications. A practical approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2011, the Oslo Classification ranked the clinical presentation of CD in classical, non classical, subclinical and refractory"
    explanation: >-
      The naming authority for the clinical forms recorded in this block, and the
      source of "subclinical" as the preferred term for this one.
- name: Latent
  description: >-
    A historically ambiguous label, used both for disease that was previously
    abnormal and has normalized on diet, and for currently normal mucosa that
    later becomes abnormal. Recorded because it appears in older literature;
    because the two senses are opposites, a report using it has to say which is
    meant.
- name: Nonresponsive
  display_name: Nonresponsive celiac disease
  description: >-
    Persistent or recurrent symptoms, laboratory abnormalities or enteropathy
    after six to twelve months of prescribed gluten withdrawal. This is not a
    synonym for refractory disease and is the more common situation: most cases
    turn out to be continued gluten exposure, a second diagnosis, or a
    complication, and evaluation for those comes before a refractory label.
- name: Potential
  description: >-
    Positive celiac serology and a compatible HLA genotype with normal duodenal
    architecture. Some, but not all, progress to enteropathy. This form and the
    seronegative form are defined by the absence of one of the two components the
    standard diagnosis requires - positive serology on a gluten-containing diet
    and characteristic small-bowel histology - which is what makes each of them a
    named exception rather than simply an incomplete workup.
  evidence:
  - reference: PMID:20301720
    reference_title: "Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The diagnosis of celiac disease is established in an individual with positive celiac serologic testing results while on a gluten-containing diet"
    explanation: >-
      The GeneReviews chapter's statement of the diagnostic standard. The same
      sentence continues by requiring "characteristic histologic findings on
      small bowel biopsy", so the standard has two components; it is quoted here
      only to its first component because the intervening parenthetical lists the
      antibodies in brackets, which snippet normalization strips. That
      two-component baseline is what makes the potential form (serology without
      histology) and the seronegative form (histology without serology) named
      exceptions rather than incomplete workups.
- name: Seronegative
  description: >-
    Villous atrophy with HLA-DQ2/DQ8 positivity that responds to a gluten-free
    diet, in a patient with no detectable celiac antibodies. Roughly 1.7% of
    cases, and the boundary condition on the entry's autoantibody node.
- name: Refractory Type I
  display_name: Refractory celiac disease type I
  description: >-
    Persistent or recurrent malabsorptive symptoms with villous atrophy after
    more than twelve months of strict gluten withdrawal, with a normal
    (polyclonal) intraepithelial lymphocyte phenotype. Reported five-year
    survival reaches about 95%, with five-year progression to
    enteropathy-associated T-cell lymphoma below 14%.
  review_notes: >-
    Deliberately not bound to a MONDO term. MONDO carries only the parent
    concept, MONDO:0018353 refractory celiac disease, with no type-level terms
    (checked against cache/mondo/terms.csv and an OLS MONDO search, both of
    which return that single term). Binding the parent identically to type I and
    type II would make the two subtypes indistinguishable in any query on
    subtype_term, and the distinction between them is the clinically
    consequential one - clonality, lymphoma risk and survival all differ. The
    parent term is the right binding for the refractory concept as a whole if a
    grouping is ever created for it.
- name: Refractory Type II
  display_name: Refractory celiac disease type II (RCDII)
  description: >-
    Refractory disease carrying a clonal population of phenotypically aberrant
    intraepithelial lymphocytes, commonly with JAK1 or STAT3 gain-of-function
    mutations. This is the premalignant form, and the clinical counterpart of the
    Aberrant Clonal Intraepithelial Lymphocyte Expansion node; it precedes most
    enteropathy-associated T-cell lymphoma. Reported five-year survival is about
    58%, substantially below type I.
  review_notes: >-
    Deliberately not bound to a MONDO term, for the reason recorded on Refractory
    Type I: MONDO has only the parent concept MONDO:0018353, and binding it to
    both types would collapse the distinction this subtype exists to make.
  evidence:
  - reference: PMID:33579790
    reference_title: "Oncogenetic landscape of lymphomagenesis in coeliac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII)"
    explanation: >-
      Defines this subtype as the clonal intraepithelial lymphoproliferation that
      commonly precedes lymphoma, which is what distinguishes it from type I.
animal_models:
- name: IL-15 overexpressing HLA-DQ8 transgenic mouse
  species: Mouse
  genotype: >-
    HLA-DQ8 transgenic with IL-15 overexpression in both the intestinal
    epithelium and the lamina propria, gluten-sensitized
  publication: PMID:32051586
  modeled_mechanisms:
  - target: Intestinal Epithelial Damage
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The first model to reproduce gluten-dependent villous atrophy, and the
      experimental basis of the three-signal model (gluten plus HLA-DQ plus
      IL-15). "First" rather than "only" is what the source supports: it reports
      that no such model existed before this one, which is not a claim that none
      has been produced since.
    limitations: >-
      Villous atrophy here requires engineered IL-15 overexpression in two
      compartments simultaneously, which is a construction of the model rather
      than a demonstrated configuration in patients. The strong reading of it is
      contradicted in humans by the AMG 714 trial, where anti-IL-15 antibody did
      not prevent gluten-induced mucosal injury. Treat the model as establishing
      joint sufficiency, not the separate necessity of each signal.
    evidence:
    - reference: PMID:32051586
      reference_title: "IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease."
      explanation: >-
        States what the model shows and the compartmental requirement that makes
        it a constructed configuration.
  notes: >-
    The open question this model raises is tracked in the
    mismatch_three_signal_villous_atrophy_requirement discussion; this record is
    the model itself rather than a restatement of that argument.
clinical_trials:
- name: EUCTR2017-002241-30-DE
  phase: PHASE_II
  status: COMPLETED
  description: >-
    CEC-3: phase IIa randomized, double-blind, placebo-controlled dose-finding
    trial of the transglutaminase 2 inhibitor ZED1227 over six weeks of gluten
    challenge in patients with well-controlled celiac disease. Registered on
    EUCTR rather than ClinicalTrials.gov. The first causal human perturbation of
    the TG2 node: all three doses attenuated the gluten-induced fall in the
    villus-height to crypt-depth ratio.
  target_phenotypes:
  - preferred_term: Villous atrophy
    term:
      id: HP:0011473
      label: Villous atrophy
  evidence:
  - reference: ICTRP:EUCTR2017-002241-30-DE
    reference_title: "Clinical trial with ZED1227 capsules compared to placebo in subjects with celiac disease during a 6-week treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| Primary sponsor | Dr. Falk Pharma GmbH |"
    explanation: >-
      WHO ICTRP registration record establishing the trial's identity and design;
      a registration document rather than study evidence, hence OTHER.
  - reference: PMID:34192430
    reference_title: "A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury."
    explanation: The trial's primary result.
- name: NCT02637141
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Phase 2a randomized, double-blind, placebo-controlled trial of the
    anti-IL-15 monoclonal antibody AMG 714 during gluten challenge. It missed
    its mucosal-injury endpoint, which is the human result that bounds the
    three-signal model derived from the IL-15 transgenic mouse.
  target_phenotypes:
  - preferred_term: Villous atrophy
    term:
      id: HP:0011473
      label: Villous atrophy
  evidence:
  - reference: clinicaltrials:NCT02637141
    reference_title: "A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of AMG 714 in Adult Patients With Celiac Disease"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This study is designed to evaluate the efficacy and safety of AMG 714 for the attenuation of the effects of gluten exposure in adult patients with celiac disease during a gluten challenge."
    explanation: >-
      ClinicalTrials.gov record establishing the trial's identity and design.
  - reference: PMID:31494096
    reference_title: "Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AMG 714 did not prevent mucosal injury due to gluten challenge."
    explanation: >-
      The trial's primary result, which was negative: anti-IL-15 antibody did not
      protect mucosal architecture during gluten challenge. Graded SUPPORT
      because on a trial record the evidence bears on the trial - it reports what
      this trial found - and a negative finding is still a faithful report of it.
      The same quote carries REFUTE in the
      mismatch_three_signal_villous_atrophy_requirement discussion, where the
      claim at issue is IL-15 as a strictly required signal and the result does
      cut against it.
classifications:
  harrisons_chapter:
  - classification_value: GASTROINTESTINAL
  - classification_value: IMMUNE_RHEUMATOLOGIC
discussions:
- discussion_id: mismatch_three_signal_villous_atrophy_requirement
  prompt: >-
    Is dual epithelial and lamina propria IL-15 overexpression a genuine
    co-requirement for villous atrophy in human celiac disease, as it is in the
    engineered HLA-DQ8 mouse, or is IL-15 an amplifier whose removal does not by
    itself prevent gluten-induced mucosal injury?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#canonical_gluten_hladq_ttg_enteropathy_model
  - pathophysiology#Intestinal Epithelial Damage
  - phenotypes#Villous Atrophy
  rationale: >-
    The three-signal model (gluten + HLA-DQ + IL-15) is the single most
    consequential expansion the 2026 openscientist report proposed, and the
    canonical hypothesis description leans on it. Its direct demonstration is a
    mouse engineered to overexpress IL-15 in two gut compartments while
    expressing HLA-DQ8; that construction shows the three signals are jointly
    sufficient in the model, not that each is separately necessary in patients.
    Human biopsy work supports IL-15 involvement and shows epithelial stress and
    adaptive antigluten immunity acting in synergy, but it does not establish the
    engineered configuration as a universal human rule. The published anti-IL-15
    trial cuts the other way: AMG 714 did not prevent mucosal injury during
    gluten challenge, which is what removing one of three strictly required
    signals should have done. Curate the three-signal model as strong
    model-organism support plus a human mechanistic hypothesis, and do not assert
    a proven human co-requirement.
  proposed_experiments:
  - experiment_id: exp_celiac_il15_blockade_active_disease
    name: IL-15 blockade in gluten-exposed celiac disease, powered for histology and stratified by HLA-DQ
    description: >-
      Building on the AMG 714 phase 2a result, run an adequately powered
      randomized trial of IL-15 or IL-15Ralpha blockade during a standardized
      gluten challenge, stratified by HLA-DQ2 homozygosity, DQ2 heterozygosity
      and DQ8, with predefined co-primary histologic and intraepithelial
      lymphocyte endpoints and mucosal transcriptomics. Include an arm combining
      IL-15 blockade with TG2 inhibition to separate additive from synergistic
      action of the innate and adaptive arms.
    would_support:
    - pathophysiology#Intestinal Epithelial Damage
    would_refute:
    - mechanistic_hypotheses#canonical_gluten_hladq_ttg_enteropathy_model
    supporting_outcome:
    - >-
      IL-15 blockade alone prevents the gluten-induced fall in villus
      height-to-crypt depth ratio, establishing IL-15 as a required signal in
      humans rather than an amplifier.
    refuting_outcome:
    - >-
      Adequately powered IL-15 blockade again fails to protect mucosal
      architecture while TG2 inhibition in the same trial does, indicating that
      the human requirement is carried by the adaptive arm and that the
      engineered mouse configuration does not transfer.
  evidence:
  - reference: PMID:32051586
    reference_title: "IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease."
    explanation: >-
      The primary source of the three-signal claim. The requirement is
      established inside an engineered mouse that expresses HLA-DQ8 and
      overexpresses IL-15 in two compartments, which is why the claim is curated
      as model-organism evidence.
  - reference: PMID:26001928
    reference_title: "Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The adaptive immune response to gluten appears to act in synergy with epithelial stress to allow intraepithelial cytotoxic T cells to kill epithelial cells and induce villous atrophy in patients with active celiac disease."
    explanation: >-
      Human tissue evidence that epithelial stress and antigluten adaptive
      immunity are both involved and synergistic. It supports two contributing
      arms without demonstrating that a specific two-compartment IL-15
      configuration is necessary in every patient.
  - reference: PMID:31494096
    reference_title: "Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "AMG 714 did not prevent mucosal injury due to gluten challenge."
    explanation: >-
      The strong reading of the three-signal model predicts that removing IL-15
      should block villous atrophy. A randomized anti-IL-15 antibody trial in
      gluten-challenged patients missed that endpoint, which is the central
      reason this is recorded as an open human-model mismatch rather than as an
      established human co-requirement. Note the trial was in treated patients
      undergoing short gluten challenge and did show a smaller intraepithelial
      lymphocyte rise at 300 mg, so it constrains the necessity claim without
      excluding an IL-15 contribution.
- discussion_id: gap_celiac_tolerance_breaking_trigger
  prompt: >-
    What event converts an HLA-DQ2/DQ8 carrier who is orally tolerant to gluten
    into one who mounts the pathogenic gluten-specific CD4 T-cell response?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Gluten-Triggered Immune Response
  - mechanistic_hypotheses#canonical_gluten_hladq_ttg_enteropathy_model
  - environmental#Gastrointestinal Infections
  rationale: >-
    The canonical model starts at gluten presentation and is silent on what
    licenses that presentation to break tolerance. HLA-DQ2 or DQ8 is carried by a
    large minority of the general population and only about 1 percent develop
    disease, so the haplotype fixes susceptibility rather than timing or
    penetrance. The candidate triggers this entry already records as
    environmental factors are individually inconclusive: enteric infection is
    supported by reovirus work in mice without human replication, dysbiosis is
    correlative and bidirectional, and randomized trials found that the timing of
    infant gluten introduction does not alter risk. Because this gap sits
    upstream of every node in the entry, it is the step whose resolution would do
    most for primary prevention.
  proposed_experiments:
  - experiment_id: exp_celiac_prospective_virome_before_seroconversion
    name: Serial virome, microbiome and mucosal immune phenotyping in at-risk infants through seroconversion
    description: >-
      Extend an existing HLA-DQ2/DQ8 at-risk birth cohort with serial stool
      virome and microbiome sequencing, interferon-signature profiling and, where
      ethically possible, mucosal sampling, anchored on the date of anti-TG2
      seroconversion rather than on diagnosis, so that candidate triggers can be
      ordered before and after the loss of tolerance instead of being sampled
      after disease is established.
    would_support:
    - environmental#Gastrointestinal Infections
    supporting_outcome:
    - >-
      A specific exposure window, viral taxon or interferon signature reproducibly
      precedes anti-TG2 seroconversion in at-risk carriers and is absent in
      matched carriers who remain tolerant.
    refuting_outcome:
    - >-
      No exposure or immune signature separates carriers who seroconvert from
      those who do not, which would move the trigger to host-intrinsic or
      stochastic explanations rather than an environmental event.
- discussion_id: gap_celiac_rcd2_gluten_independent_clonal_expansion
  prompt: >-
    What sustains the clonal intraepithelial lymphocyte expansion of refractory
    celiac disease type II once it no longer depends on gluten stimulation, and
    at what point does the canonical model stop applying?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#canonical_gluten_hladq_ttg_enteropathy_model
  - pathophysiology#Intestinal Epithelial Damage
  - treatments#Corticosteroids
  rationale: >-
    Refractory celiac disease type II is the clearest boundary condition on the
    canonical model in this entry. Dominant T-cell receptor beta clonotypes
    recovered from these patients are patient-specific and bear no homology to
    known gliadin-specific sequences, and the clones persist stably for years on
    a strict gluten-free diet, so the driving stimulus is no longer the antigen
    the rest of the entry is built around. Genetic susceptibility to the
    progression also appears to be separate from susceptibility to celiac disease
    itself. What the entry cannot yet say is what does drive the expansion, which
    matters because this is the pre-lymphomatous state that the gluten-free diet
    does not treat.
  evidence:
  - reference: PMID:28188172
    reference_title: "T-cell repertoires in refractory coeliac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dominant TCRβ sequences identified in patients with RCD type II are unique and not homologous to known gliadin-specific TCR sequences, supporting the assumption that these clonal T-cells expand independent of gluten stimulation."
    explanation: >-
      High-throughput sequencing of the duodenal T-cell repertoire is the direct
      evidence that the expanded clones are not the gluten-specific cells the
      canonical model describes. The authors themselves frame this as supporting
      an assumption rather than proving stimulus independence.
  - reference: PMID:29787419
    reference_title: "A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10, odds ratio=2.36) but not with CeD susceptibility."
    explanation: >-
      A susceptibility variant specific to the progression and absent from celiac
      susceptibility indicates the refractory state has partly separate genetic
      determinants, reinforcing it as a boundary rather than a late stage of the
      same mechanism.
- discussion_id: gap_celiac_integrated_feedback_loops
  prompt: >-
    Do the proposed amplification loops of celiac disease operate as one
    integrated system, and would disrupting a single loop collapse the cascade?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#canonical_gluten_hladq_ttg_enteropathy_model
  - pathophysiology#Autoantibody Production
  - pathophysiology#Barrier Dysfunction
  rationale: >-
    Three amplification loops are commonly invoked to explain why celiac disease
    escalates quickly and heals slowly: secretory IgA delivering gliadin peptides
    back across the epithelium through CD71, IFN-gamma driving thioredoxin
    release that reactivates extracellular TG2, and TG2-reactive B cells
    presenting gluten peptides to gluten-specific T cells. Each has separate
    experimental support, but they were characterized in different reductionist
    systems and have never been perturbed together in one system, so their joint
    contribution is an inference rather than a measurement. The follow-up cohorts
    that document delayed or incomplete mucosal recovery on a gluten-free diet
    describe the outcome without attributing it to these loops.
  proposed_experiments:
  - experiment_id: exp_celiac_combinatorial_loop_perturbation
    name: Combinatorial loop perturbation in patient-derived intestinal organoid immune co-cultures
    description: >-
      In duodenal organoid or air-liquid-interface cultures retaining
      tissue-resident immune cells from celiac patients, block CD71-mediated
      retrotranscytosis, extracellular TG2 activity and B-cell antigen
      presentation singly and in combination during gliadin exposure, reading out
      gluten-specific T-cell activation, epithelial injury and anti-TG2 output.
    would_support:
    - pathophysiology#Autoantibody Production
    supporting_outcome:
    - >-
      Blocking any single loop produces a disproportionate reduction in
      gluten-specific T-cell activation and epithelial injury, which is the
      signature of a coupled amplifying system.
    refuting_outcome:
    - >-
      Single blockades produce only additive, proportionate reductions, indicating
      three parallel contributors rather than one nested self-amplifying circuit.
  evidence:
  - reference: PMID:22750506
    reference_title: "Interactions among secretory immunoglobulin A, CD71, and transglutaminase-2 affect permeability of intestinal epithelial cells to gliadin peptides."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In the presence of celiac IgA or SIgA against p31-49, transport of intact 3H-p31-49 increased significantly across Caco-2 monolayers; this transport was inhibited by soluble CD71 or Tgase2 inhibitors."
    explanation: >-
      Demonstrates the retrotranscytosis loop as a transport mechanism in
      epithelial cell monolayers. It establishes that the route exists and is
      CD71 and TG2 dependent, and deliberately does not establish that it is the
      dominant route to the lamina propria in patients.
  - reference: PMID:31285344
    reference_title: "Efficient T cell-B cell collaboration guides autoantibody epitope bias and onset of celiac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Production of antibodies against N-terminal epitopes coincided with clinical onset of disease, suggesting that TG2-reactive B cells with certain epitope specificities could be the main antigen-presenting cells for pathogenic, gluten-specific T cells."
    explanation: >-
      Supports the B-cell antigen-presenting loop from patient-derived plasma
      cells, with the authors' own hedge that these B cells could be the main
      presenting cells, which is the level of claim curated here.
- discussion_id: mismatch_celiac_ati_tlr4_adjuvant
  prompt: >-
    Do wheat amylase-trypsin inhibitors contribute to human celiac disease as a
    TLR4-dependent innate adjuvant, or is the evidence confined to cell lines,
    mice and non-celiac inflammatory settings?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - environmental#Wheat Food Products
  - pathophysiology#Gluten-Triggered Immune Response
  rationale: >-
    Amylase-trypsin inhibitors are a non-gluten wheat component proposed as a
    parallel innate signal that lowers the threshold for the adaptive gluten
    response, and they are one reason wheat is singled out among cereals. The
    supporting work is TLR4 reporter activation in mouse and human cell lines
    plus modest intestinal inflammation in healthy mice fed dietary
    concentrations of ATIs. The most frequently paired second citation concerns
    ATIs as adjuvants of allergic inflammation in PBMC-humanized mice, which is a
    different disease context. No cited experiment shows an ATI contribution to
    initiation or enteropathy in celiac patients, and the gluten-free diet that
    treats the disease removes ATIs and gluten together, so the clinical
    observation cannot separate them. Recorded here rather than as a
    pathophysiology node, because adding a node would assert a human celiac
    mechanism the evidence does not reach.
  evidence:
  - reference: PMID:27993525
    reference_title: "Nutritional Wheat Amylase-Trypsin Inhibitors Promote Intestinal Inflammation via Activation of Myeloid Cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Concentrations of ATIs found in a normal daily gluten-containing diet increased low-level intestinal inflammation."
    explanation: >-
      Establishes that dietary-level ATI intake produces measurable intestinal
      inflammation, in healthy mice and via TLR4-responsive cell lines. This is
      the strongest form of the claim the primary literature supports, and it is
      not a celiac-specific or human result.
- discussion_id: gap_celiac_enamel_defect_mechanism
  prompt: >-
    Are the developmental enamel defects of celiac disease produced by
    calcium/vitamin-D/micronutrient deficiency during amelogenesis, by
    ameloblast-directed IgA autoimmunity arising from broken peripheral
    tolerance to shared dietary/enamel antigens, or by both?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Dental Enamel Defects
  - pathophysiology#Autoantibody Production
  rationale: >-
    Two live mechanistic hypotheses have never been separated in patients. The
    nutrient-deficiency hypothesis rests on cross-sectional nutrient
    measurements usually taken after the developmental window, and defect
    burden does not track Marsh grade. The autoimmunity hypothesis gained
    antigen-level human evidence in 2023 (IgA against ameloblast-specific
    proteins in celiac cohorts, with kappa-casein cross-reactivity), but the
    decisive serum-transfer experiments were performed in animals modeling
    APS-1 rather than ordinary celiac disease. Even the association is
    heterogeneous - one matched case-control study found no significant excess
    of enamel hypoplasia. Because enamel records injury only while a crown is
    mineralizing, established defects are irreversible and diet-response
    designs cannot arbitrate; no causal edge is recorded in the pathograph for
    this phenotype until the mechanism is resolved.
  proposed_experiments:
  - experiment_id: exp_celiac_enamel_inception_cohort
    name: Pediatric inception cohort spanning permanent-tooth mineralization
    description: >-
      Prospective cohort of genetically at-risk children enrolled before
      permanent-tooth mineralization, with serial ameloblast-protein
      autoantibody titers, calcium/phosphate/vitamin-D status, verified gluten
      exposure, and blinded standardized dental imaging as permanent teeth
      erupt, comparing promptly treated, delayed-diagnosis and nutrient-matched
      non-celiac children.
    would_support:
    - pathophysiology#Autoantibody Production
    supporting_outcome:
    - >-
      Ameloblast-directed autoantibody titers during mineralization predict
      enamel defects independently of calcium and vitamin-D status.
    refuting_outcome:
    - >-
      Enamel defects track nutrient status during the mineralization window
      with no independent contribution from ameloblast-directed antibodies.
  evidence:
  - reference: PMID:37993717
    reference_title: "Autoimmune amelogenesis imperfecta in patients with APS-1 and coeliac disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins"
    explanation: >-
      The human-serology observation behind the autoimmune hypothesis: enamel
      defects in celiac disease are accompanied by IgA against
      ameloblast-specific proteins. The paper's causal transfer experiments are
      animal work in an APS-1 model, so the human claim here is the antibody
      observation, not established causation.
  - reference: PMID:17537244
    reference_title: "Lack of association between celiac disease and dental enamel hypoplasia in a case-control study from an Italian central region."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of enamel hypoplasia was not higher in the study population than in the control group."
    explanation: >-
      A matched case-control study in which even the association was absent
      (26% vs 16%, not significant), supporting this discussion's framing that
      both the strength of the association and its mechanism remain unsettled
      across cohorts.
- discussion_id: gap_celiac_gfd_responsive_extraintestinal_mechanisms
  prompt: >-
    By what mechanism does gluten exposure produce recurrent aphthous
    stomatitis, sterile inflammatory arthropathy, constipation-predominant
    bowel dysfunction, fatigue, and peripheral neuropathy in celiac disease,
    when each improves on a gluten-free diet but no intermediate step has been
    demonstrated in patients?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Recurrent Aphthous Stomatitis
  - phenotypes#Arthritis
  - phenotypes#Constipation
  - phenotypes#Fatigue
  - phenotypes#Peripheral Neuropathy
  rationale: >-
    For each of these five phenotypes the association and a gluten-free-diet
    response are documented, but the mechanism is not, so no causal edge is
    recorded in the pathograph. Recurrent aphthous stomatitis: candidate routes
    are hematinic (iron/folate/B12) deficiency from malabsorption versus
    gluten-driven mucosal immune inflammation; the diet-response evidence is
    four adherent responders in an uncontrolled series, and nutrient correction
    has never been factorially separated from gluten withdrawal. Arthritis: a
    rigorously investigated case of sterile non-erosive polyarthritis remitted
    within three weeks of gluten withdrawal, and ultrasound series report more
    subclinical synovitis with gluten exposure, but synovial tissue has rarely
    been profiled and shared immune susceptibility to coincident rheumatic
    disease is a live alternative. Constipation: four weeks of gluten-free diet
    shortened small-bowel and colonic transit and increased contractility in
    newly diagnosed patients, yet the treatment diet itself - low in fiber and
    rich in refined substitutes - can cause constipation, so the phenotype can
    arise from the disease and from its treatment in the same patient.
    Fatigue: a prospective controlled study found it substantially reduced after
    twelve months of gluten-free diet yet still higher than in matched controls,
    and associated with depression and pain rather than with disease activity or
    nutritional deficiency - so neither the hematinic nor the inflammatory route
    is established and a psychosocial contribution cannot be separated out.
    Peripheral neuropathy: nerve biopsies show axonopathy, loss of myelinated
    fibers and perivascular inflammatory infiltration, which points to immune
    injury without settling whether the effector is humoral (anti-TG6 or
    antiganglioside antibodies) or cell-mediated; B12 or copper deficiency,
    diabetes and coincident autoimmune neuropathy also have to be excluded.
  proposed_experiments:
  - experiment_id: exp_celiac_blinded_gluten_challenge_extraintestinal
    name: Blinded gluten challenge with phenotype-specific endpoints
    description: >-
      In patients in remission on a gluten-free diet with a history of one of
      these manifestations, a randomized blinded gluten challenge with
      phenotype-specific endpoints (blinded ulcer counts, ultrasound synovitis
      scoring, wireless motility capsule transit), stratified by corrected
      versus uncorrected hematinic deficiency and with quantified fiber intake,
      to separate gluten-driven from nutritional and diet-composition routes.
    would_support:
    - pathophysiology#Gluten-Triggered Immune Response
    supporting_outcome:
    - >-
      The manifestation recurs or objectively worsens during blinded gluten
      challenge and not on placebo, independent of nutrient status and fiber
      intake.
    refuting_outcome:
    - >-
      No difference between gluten and placebo challenge, indicating the
      manifestation tracks nutrient status, diet composition, or a coincident
      disease rather than gluten-driven immunity.
  evidence:
  - reference: PMID:17537244
    reference_title: "Lack of association between celiac disease and dental enamel hypoplasia in a case-control study from an Italian central region."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RAS was significantly more frequent in patients with CD."
    explanation: >-
      Matched case-control association for recurrent aphthous stomatitis (36%
      vs 12%), documenting the association whose mechanism this gap records.
  - reference: PMID:19534771
    reference_title: "Gluten sensitivity enteropathy in patients with recurrent aphthous stomatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients who adhered to a strict gluten-free diet showed noticeable improvement in their aphthous lesions over a period of 6 months."
    explanation: >-
      The gluten-withdrawal response for aphthous stomatitis - supportive of a
      gluten-dependent process but uncontrolled and based on four responders,
      which is why it grounds a knowledge gap rather than a causal edge.
  - reference: PMID:37434897
    reference_title: "Isolated polyarthritis revealing celiac disease: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her joint symptoms resolved in 3 weeks."
    explanation: >-
      Dechallenge observation in a case of sterile, seronegative, non-erosive
      polyarthritis with an otherwise negative etiological workup: joint
      disease remitted on gluten withdrawal alone. A single case supports
      gluten dependence without establishing the immune mechanism.
  - reference: PMID:38541941
    reference_title: "Effect of a Gluten-Free Diet on Whole Gut Transit Time in Celiac Disease (CD) and Non-Celiac Gluten Sensitivity (NCGS) Patients: A Study Using the Wireless Motility Capsule (WMC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD patients experienced significant reductions in both intestinal and colonic transit times, along with enhanced small intestine contractility"
    explanation: >-
      Wireless motility measurement showing gluten-dependent, reversible
      slowing of intestinal and colonic transit in newly diagnosed patients -
      the objective dysmotility candidate behind constipation, in a 12-patient
      series without healthy controls.
  - reference: PMID:33800620
    reference_title: "Gluten-Free Diet: Nutritional Strategies to Improve Eating Habits in Children with Celiac Disease: A Prospective, Single-arm Intervention Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elimination of gluten-containing cereals and consumption of ultra-processed gluten-free foods might cause an unbalanced diet, deficient in fiber and rich in sugar and fat, circumstances that may predispose celiac children to chronic constipation."
    explanation: >-
      The competing non-disease route for constipation: the treatment diet
      itself. Recorded so the gap states both directions - enteropathy
      dysmotility and diet composition - rather than assuming the disease
      route.
  - reference: PMID:37766922
    reference_title: "Less, but not gone-gluten-free diet effects on fatigue in celiac disease: a prospective controlled study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Higher fatigue scores were associated with depression and pain, but not with signs of disease activity or nutritional deficiency."
    explanation: >-
      The result that leaves fatigue unwired. Fatigue fell markedly on a
      gluten-free diet, so it is gluten-dependent, but it tracked depression and
      pain rather than the two mechanisms a pathograph edge would have to run
      through - disease activity or nutrient deficiency.
  - reference: PMID:32244870
    reference_title: "The Neuropathology of Gluten-Related Neurological Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with large-fiber neuropathy, nerve biopsies revealed axonopathy, loss of myelinated fibers and focal and perivascular infiltration by inflammatory cells."
    explanation: >-
      Human nerve pathology establishing immune-mediated axonal injury as the
      lesion, which is why the phenotype is a gap rather than unexplained. It
      does not identify the effector, and the same review states the mechanism
      "is not yet clear" and calls for characterization of the infiltrates and
      target epitopes - so no causal edge is asserted.
- discussion_id: gap_celiac_proposed_but_unplaced_chains
  prompt: >-
    Cerebellar ataxia, abdominal pain and bloating each have a coherent proposed
    chain from celiac disease and no demonstrated intermediate step in patients.
    What evidence would place any of them in the pathograph?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Cerebellar Ataxia
  - phenotypes#Abdominal Pain
  - phenotypes#Bloating
  rationale: >-
    These three differ from the wholly unexplained manifestations: each has a
    specific proposed route, and each route stops one step short of what a causal
    edge would assert. Cerebellar ataxia is the closest to placement and the most
    instructive. Its proposed chain mirrors the dermatitis herpetiformis chain
    that is wired in this entry - a transglutaminase isoform outside the gut,
    here TG6, with antibodies plus tissue pathology - and cerebellar
    neuropathology is documented: Purkinje cell loss, gliosis, and lymphocytic
    infiltration with perivascular cuffing. What is missing is the step that
    makes the dermatitis herpetiformis edge assertable: there, the antigen was
    demonstrated inside the lesion-defining deposit, whereas TG6 remains a
    candidate antigen and antibody sufficiency has not been shown. Neurologic
    gluten sensitivity also occurs without enteropathy, and genetic,
    paraneoplastic, nutritional and other autoimmune ataxias compete. Abdominal
    pain and bloating have physiologically coherent chains - mucosal nociception
    and luminal distension for the former, brush-border enzyme loss to
    carbohydrate maldigestion, microbial fermentation and gas for the latter -
    but neither has been demonstrated end to end in celiac patients, and
    irritable bowel syndrome, lactose or FODMAP intolerance and bacterial
    overgrowth produce both.
  proposed_experiments:
  - experiment_id: exp_celiac_tg6_antibody_sufficiency
    name: TG6 antibody sufficiency and cerebellar target engagement in gluten ataxia
    description: >-
      Establish for TG6 what is already established for TG3 in dermatitis
      herpetiformis: demonstrate the antigen within the cerebellar lesion, then
      test sufficiency by passive transfer or by an ex vivo cerebellar
      preparation exposed to patient IgA, with titer tracked against imaging and
      ataxia severity before and during gluten withdrawal in antibody-positive
      and antibody-negative patients.
    would_support:
    - pathophysiology#Autoantibody Production
    supporting_outcome:
    - >-
      TG6 is demonstrated in cerebellar tissue lesions and patient antibody
      produces Purkinje cell injury in a preparation free of other celiac
      factors, with titer tracking ataxia severity.
    refuting_outcome:
    - >-
      Anti-TG6 titer is unrelated to cerebellar injury and ataxia severity, or
      cerebellar pathology occurs as often in antibody-negative patients,
      indicating the antibodies are a marker of gluten exposure rather than the
      effector.
  evidence:
  - reference: PMID:32244870
    reference_title: "The Neuropathology of Gluten-Related Neurological Disorders: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In gluten ataxia, loss of Purkinje cells, atrophy, gliosis and astrocytosis were apparent, as well as diffuse lymphocytic infiltration and perivascular cuffing with lymphocytes."
    explanation: >-
      The human cerebellar pathology of gluten ataxia, which establishes that a
      lesion exists and is inflammatory. It does not identify the effector, which
      is the step this gap records as missing.
datasets:
- accession: geo:GSE319777
  title: Therapeutic TG2 Inhibition Reverses Systemic Multiomic Dysregulation in Celiac Disease
  description: 'Background and Aims: Celiac disease (CeD) is an autoimmune disease triggered by dietary gluten in genetically predisposed individuals. Deamidation of gluten peptides by the CeD autoantigen and enzyme transglutaminase 2 (TG2) is central to the pathogenesis of CeD. Inhibition of TG2 with the specific inhibitor ZED1227 effectively prevents gluten-induced histological damage in CeD patients. Here we aimed to explore the blood DNA methylomic changes in ZED1227-treated CeD patients undergoing a gluten challenge. Results: Drug treatment revealed consistent patterns suggesting normalization of the DNA methylome indicating that ZED1227 attenuated the systemic responses to gluten challenge.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: METHYLATION
  sample_count: 72
  publication: PMID:42032651
  notes: Identified by GEO DataSets index search for Celiac Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE200075
  title: 'A human autoimmune organoid model reveals IL-7 function in celiac disease '
  description: In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Celiac disease (CeD) is an autoimmune disease where dietary gluten-derived peptides bind the MHC- II molecules HLA-DQ2 or -DQ8 to initiate immune-mediated duodenal mucosal injury. Here, we generated air-liquid interface (ALI) duodenal organoids from endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The ALI organoid immune diversity spanned T, B, plasma, NK and myeloid cells with extensive T and B cell receptor repertoires.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 30
  publication: PMID:39048815
  notes: Identified by GEO DataSets index search for Celiac Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE315138
  title: Single Cell RNA Sequencing Unveils Distinct Cellular Dynamics in Celiac Disease Duodenal Biopsies
  description: Celiac disease (CeD) is the most common autoimmune disorder in the U.S., affecting at least 1% of the population. The ingestion of gluten-containing proteins triggers an adaptive immune response, causing intestinal damage and leading to both gastrointestinal and systemic symptoms. Despite a strong genetic predisposition, the mechanistic understanding of CeD remains limited. The lack of approved therapy, other than dietary avoidance of gluten which is difficult and often unsuccessful, underscores the need to identify new mechanisms that can provide insights for developing therapeutics.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 8
  publication: PMID:41642982
  notes: Identified by GEO DataSets index search for Celiac Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001000849
  title: Celiac disease case-control North Indian Immunochip dataset
  description: Illumina Immunochip genotype data for coeliac disease and control samples of North Indian samples origin. Data is in PLINK binary format. Calling algorithm for genotypes is based on GenomeStudio (GenTrain), with manual clustering of selected variants.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Celiac Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003017
  title: Celiac disease-specific intestinal T cells analyzed with HLA-class II tetramers, RNA-seq and mass cytometry have a narrow, autoimmune-associated phenotype
  description: Celiac disease (CD) is an HLA-DQ2/8-associated autoimmune enteropathy driven by activation of gluten-specific CD4+ T lymphocytes upon gluten consumption. Much less is known about the phenotype and function of these cells or their correlation, if any, to disease-relevant cells in other autoimmune disorders. Here we use mass cytometry and RNA seq to show that gluten-specific blood and gut T cells occupy a small and phenotypically distinct T-cell subset.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Celiac Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003658
  title: Epitope-linked Ig-seq of self-reactive plasma cells in celiac disease
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Celiac Disease"); description-level mentions were not accepted. EGA study_type: Transcriptome Analysis. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: massive:MSV000080859
  title: Different Binding Motifs of the Celiac Disease Associated HLA Molecules DQ2.5, DQ2.2 and DQ7.5 Revealed by Relative Quantitative Proteomics of Endogenous Peptide Repertoires
  description: In this study relative quantitative analysis of endogenous peptides by mass spectrometry combined with neural network analysis have been used to address why the alpha- or beta-chain sharing human leukocyte antigen (HLA)-DQ molecules DQ2.5, DQ2.2 and DQ7.5 display different risks for celiac disease. Celiac disease is caused by intolerance to cereal gluten proteins, and HLA-DQ molecules are involved in the disease pathogenesis by presentation of gluten peptides to CD4+ T cells.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Celiac Disease"). Retrieved 2026-08-02.
- accession: massive:MSV000080779
  title: Gluten-specific antibodies of celiac disease gut plasma cells recognize long proteolytic fragments that typically harbor T-cell epitopes
  description: This study aimed to identify proteolytic fragments of gluten proteins recognized by recombinant IgG1 monoclonal antibodies generated from single IgA plasma cells of celiac disease lesions. Peptides bound by monoclonal antibodies in complex gut-enzyme digests of gluten treated with the deamidating enzyme transglutaminase 2, were identified by mass spectrometry after antibody pull-down with protein G beads. The antibody bound peptides were long deamidated peptide fragments that contained the substrate recognition sequence of transglutaminase 2.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Celiac Disease"). Retrieved 2026-08-02.
- accession: dbgap:phs000274
  title: Genome-Wide Association Study of Celiac Disease
  description:  Celiac disease (gluten-sensitive enteropathy, celiac sprue) is a common disease with significant morbidity and mortality. It is caused by sensitivity to the dietary protein gluten, resulting in a chronic enteropathy in the small intestine. Celiac disease is now recognized to be a common disease, with reports that the disease frequency is 1:133 in the United States, similar to European estimates. There is recent evidence to suggest that the incidence of the disease is rising. Occult disease is frequently present with minimal classic symptoms or signs.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Celiac Disease"). Retrieved 2026-08-02.
references:
- reference: PMID:20301720
  title: "Celiac Disease."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:28722929
  title: "Celiac Disease."
  tags:
  - StatPearls
  findings: []
- reference: DOI:10.1038/s41590-024-01867-0
  title: Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease
  findings: []
- reference: DOI:10.1136/bmj-2024-081353
  title: Advances in the pathophysiology, diagnosis, and management of celiac disease
  findings: []
- reference: DOI:10.20944/preprints202504.1947.v1
  title: Intraepithelial Lymphocytes and LAIR1 Expression in Celiac Disease
  findings: []
- reference: DOI:10.3390/ijms25179412
  title: 'Expression of MicroRNAs in Adults with Celiac Disease: A Narrative Review'
  findings: []

📚

References & Deep Research

References

6

PMID:20301720

Celiac Disease.

No top-level findings curated for this source.

PMID:28722929

Celiac Disease.

No top-level findings curated for this source.

DOI:10.1038/s41590-024-01867-0

Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease

No top-level findings curated for this source.

DOI:10.1136/bmj-2024-081353

Advances in the pathophysiology, diagnosis, and management of celiac disease

No top-level findings curated for this source.

DOI:10.20944/preprints202504.1947.v1

Intraepithelial Lymphocytes and LAIR1 Expression in Celiac Disease

No top-level findings curated for this source.

DOI:10.3390/ijms25179412

Expression of MicroRNAs in Adults with Celiac Disease: A Narrative Review

No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Wire mechanism-to-phenotype edges from targeted Edison deep research · 2026-09-26T00:21:03Z · View source

Two targeted Edison (falcon) deep-research runs asked for the mechanism-to-phenotype wiring layer rather than another pathophysiology survey, since a generic falcon report for this disease already existed from 2025-12. Before the runs the entry had 22 evidenced phenotypes and 0 causally connected, with three pathophysiology nodes (Autoantibody Production, Barrier Dysfunction, Microbiome Dysbiosis) carrying no downstream edges at all. Added three pathophysiology nodes (Generalized Nutrient Malabsorption, Secondary Hyperparathyroidism, Aberrant Clonal Intraepithelial Lymphocyte Expansion) and 16 causal edges, taking phenotype causal-inlink coverage to 13 of 22. Also wired the gluten-free diet to the mechanism it acts on. Every edge carries its own evidence with exact snippets verified against newly cached references. Nine phenotypes remain unconnected, and all nine are now dispositioned across three KNOWLEDGE_GAP discussions. Five (constipation, fatigue, recurrent aphthous stomatitis, peripheral neuropathy, arthritis) were graded NOT_ESTABLISHED by the reports. Three (cerebellar ataxia, abdominal pain, bloating) were graded PROPOSED and are recorded in a separate gap, because each has a coherent proposed route that stops one step short of what an edge would assert - ataxia most instructively, since its shape mirrors the TG3/dermatitis herpetiformis chain that IS wired, and the difference is that TG3 was demonstrated inside the lesion-defining deposit while TG6 remains a candidate antigen. Dental enamel defects have their own gap. Two reports disagreed on one chain. The deep dive graded the female infertility chain CONTESTED and the wiring sweep graded it NOT_ESTABLISHED, from the same human placental-tissue and primary-trophoblast evidence; they differ on whether tissue-level and cell-level work can place the antibody route causally with no in vivo perturbation in women. The edge was retained at INDIRECT_UNKNOWN_INTERMEDIATES on that evidence plus the treatment-stratified epidemiology. An earlier draft narrated this disagreement inside the edge description itself; review (#12866) correctly identified that as session narration in content, per the CLAUDE.md rule on notes prose and #12535, so it lives here instead and the edge states only the biology. Review round 1 (#12866) also corrected four things worth recording. The unconnected count was stated as six in the first PR body and history record when it is nine, and three of the nine were not addressed at all. The Secondary Hyperparathyroidism node cited a review that never mentions parathyroid hormone (PMID:24290593 contains no occurrence of "parathyroid" or "PTH"); it now rests on PMID:36904090, which states the calcium-PTH-bone-turnover step directly. The Vitamin D edge cited a methods sentence that recorded only that the analyte was measured; the reviewer proposed a result sentence from the same cache, which turned out to be a row in that review's literature-summary table attributing the figure to a different study (Lerner 2012), so it was not used - the edge now cites PMID:10071918's own celiac-cohort result instead. The lymphoma edge cited a background framing sentence; it now cites the JAK1/STAT3 gain-of-function finding, with the JAK1-inhibitor cell-line result as a separate IN_VITRO item.

Disorder ▸

Disorder

Name: Celiac Disease
Category: Complex
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 16

Key Pathophysiology Nodes

Gluten-Triggered Immune Response
Intestinal Epithelial Damage
Autoantibody Production
Barrier Dysfunction
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1038/s41590-024-01867-0
DOI:10.1136/bmj-2024-081353
DOI:10.20944/preprints202504.1947.v1
DOI:10.3390/ijms25179412

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Disease Pathophysiology Research Report

Edison Scientific Literature 14 citations 2025-12-17T23:36:53.040017

Disease Pathophysiology Research Report

Target Disease - Disease Name: Celiac Disease - MONDO ID: MONDO:0005130 - Category: Complex

Pathophysiology description Celiac disease (CeD) is an immune-mediated enteropathy initiated by dietary gluten in HLA-DQ2/DQ8–positive individuals. Core steps are: (1) epithelial translocation of gluten peptides via paracellular and transcytotic routes, (2) transglutaminase 2 (TG2) deamidation of gluten peptides increasing affinity for HLA-DQ2/DQ8 on antigen-presenting cells, (3) activation of gluten-specific CD4+ T cells with downstream inflammatory cascades, (4) cytokine-driven epithelial stress responses and cytotoxic intraepithelial lymphocyte (IEL)–mediated epithelial injury, and (5) humoral autoimmunity with anti-TG2 autoantibodies. Recent interventional transcriptomics demonstrate that pharmacologic TG2 inhibition prevents gluten-induced mucosal injury at the molecular level, reinforcing the centrality of TG2-mediated peptide editing and HLA-restricted T cell activation in disease pathogenesis (published online 24 Jun 2024; https://doi.org/10.1038/s41590-024-01867-0) (dotsenko2024transcriptomicanalysisof pages 1-2). Mechanistic overviews further detail epithelial crossing routes, CD4+ T cell cytokines (IFN-γ, IL-17A, IL-21), IL-15–driven IEL cytotoxicity via NK receptors (e.g., NKG2D/CD94–NKG2C) and diagnostic anti-TG2 autoimmunity (Aug 2024; https://doi.org/10.3390/ijms25179412) (rigo2024expressionofmicrornas pages 3-6). Authoritative synthesis confirms IEL cytotoxic effectors are characterized by up-regulation of NKG2D and CD94/NKG2C with epithelial ligands (MICA, HLA-E), and positions IL-15 as a key stress cytokine in driving epithelial damage (Oct 2025; https://doi.org/10.1136/bmj-2024-081353) (doyle2025advancesinthe pages 4-4).

Core Pathophysiology - Primary mechanisms - TG2 deamidation of gluten peptides increases negative charge and HLA-DQ2/DQ8 binding, enabling robust CD4+ T cell activation and proinflammatory mucosal responses; TG2 inhibition (ZED1227) preserved epithelial differentiation, absorptive programs, and prevented gluten-induced injury during challenge (Nature Immunology, 24 Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2). - Gluten peptide transport across epithelium: paracellular (zonulin-associated tight-junction changes) and transcytotic routes (CD71-mediated retrotranscytosis of sIgA–gluten–TG2 complexes) (Aug 2024) (rigo2024expressionofmicrornas pages 3-6). - IEL cytotoxicity: epithelial IL-15 upregulates NK receptors on IELs (e.g., NKG2D), with ligation of stress ligands (MICA/HLA-E) promoting killing of enterocytes; mechanistic reviews emphasize IL-15–NKG2D axis in epithelial destruction (Oct 2025) (doyle2025advancesinthe pages 4-4). - Interferon-driven epithelial response: nearly half of gluten-induced gene-expression changes during challenge were linked to epithelial IFN-γ response and type I/II IFN signaling (STAT1/RELA/IRF1 motifs), indicating an IFN-centric transcriptional reprogramming of the mucosa (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2). - Dysregulated pathways and cellular processes - Antigen processing/presentation: TG2-modified gluten peptides presented by HLA-DQ2/DQ8 to CD4+ T cells (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2). - Cytokine networks: IFN-γ, IL-17A, IL-21 (CD4+ effector signals) and IL-15 (epithelial stress cytokine) (Aug 2024; Oct 2025) (rigo2024expressionofmicrornas pages 3-6, doyle2025advancesinthe pages 4-4). - Barrier and transport programs: TG2 inhibitor preserved epithelial differentiation and nutrient transport signatures under gluten exposure (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2).

Key Molecular Players - Genes/Proteins (HGNC) - TGM2 (transglutaminase 2): deamidates gluten peptides; pharmacologic target of ZED1227 (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2). - HLA-DQA1/HLA-DQB1 (DQ2/DQ8) risk alleles: necessary for disease antigen presentation (Jun 2024; Oct 2025) (dotsenko2024transcriptomicanalysisof pages 1-2, doyle2025advancesinthe pages 4-4). - IFNG (interferon gamma), STAT1, IRF1: mediators/TFs in epithelial IFN responses during gluten challenge (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2). - IL15 (interleukin-15), KLRK1 (NKG2D), KLRC2 (NKG2C), MICA, HLAE: drivers and ligands of IEL cytotoxicity (Oct 2025) (doyle2025advancesinthe pages 4-4). - B cell/autoantibody axis: TG2 (autoantigen) underlies anti-TG2 IgA (Aug 2024) (rigo2024expressionofmicrornas pages 3-6). - Chemical entities (ChEBI) - Gluten immunogenic peptides (proline-/glutamine-rich cereal prolamins) as disease trigger; ZED1227 (small-molecule TG2 inhibitor) as therapeutic probe validating mechanism (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2). - Cell types (CL) - Gluten-specific CD4+ T helper cells (CL:0000624) drive Th1/Th17/IL-21 responses (Aug 2024) (rigo2024expressionofmicrornas pages 3-6). - Intraepithelial lymphocytes (IELs), primarily CD8+ T cells with NK receptor expression (e.g., NKG2D) mediating cytotoxicity (Oct 2025) (doyle2025advancesinthe pages 4-4). - B cells/plasma cells producing anti-TG2 (Aug 2024) (rigo2024expressionofmicrornas pages 3-6). - Anatomical locations (UBERON) - Duodenum/small intestinal mucosa (UBERON:0002114/0000160): site of villous atrophy, crypt hyperplasia, IEL expansion, and inflammatory signaling; transcriptomics sampled by biopsy (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2).

Biological Processes (GO terms; exemplars) - Antigen processing and presentation of peptide antigen via MHC class II (GO:0002495): HLA-DQ2/DQ8 presentation of TG2-deamidated gluten (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2). - Cytokine-mediated signaling pathway (GO:0019221): IFN-γ, IL-17A, IL-21, IL-15 cascades (Aug 2024; Jun 2024) (rigo2024expressionofmicrornas pages 3-6, dotsenko2024transcriptomicanalysisof pages 1-2). - Response to interferon-gamma (GO:0034341) and type I interferon signaling pathway (GO:0060337): epithelial signatures under gluten exposure (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2). - Regulation of T cell activation (GO:0050863) and NK cell activation (GO:0030101): IEL cytotoxicity via NKG2D/CD94–NKG2C (Oct 2025) (doyle2025advancesinthe pages 4-4). - Humoral immune response (GO:0006959): anti-TG2 antibody generation (Aug 2024) (rigo2024expressionofmicrornas pages 3-6).

Cellular Components (GO terms) - MHC class II protein complex (GO:0042613): HLA-DQ2/DQ8 on APCs (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2). - External side of plasma membrane (GO:0009897): NKG2D/CD94–NKG2C on IELs; MICA/HLA-E on stressed enterocytes (Oct 2025) (doyle2025advancesinthe pages 4-4). - Extracellular region (GO:0005576): secreted cytokines (IFN-γ, IL-15, IL-21) (Aug 2024) (rigo2024expressionofmicrornas pages 3-6).

Disease Progression (sequence of events) - Triggering antigen exposure (gluten) → epithelial translocation (paracellular and CD71-mediated routes) → TG2 deamidation in the lamina propria → HLA-DQ2/DQ8 presentation to CD4+ T cells → Th1/Th17/IL-21 cytokine milieu and B cell activation (anti-TG2) → epithelial stress cytokines (IL-15) and NK receptor upregulation on IELs → cytotoxic killing of enterocytes with villous atrophy and crypt hyperplasia → symptomatic malabsorption (Aug 2024; Oct 2025) (rigo2024expressionofmicrornas pages 3-6, doyle2025advancesinthe pages 4-4). Molecular interruption of TG2 deamidation blocks much of the ensuing cascade during gluten challenge (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2).

Phenotypic Manifestations (HP terms; exemplars) - Chronic diarrhea (HP:0002028), weight loss (HP:0001824), malabsorption (HP:0002242), anemia (HP:0001903), osteopenia/osteoporosis (HP:0000938/HP:0000939): clinical correlates of villous atrophy and inflammation (contextualized by mechanism in sources cited above) (doyle2025advancesinthe pages 4-4, rigo2024expressionofmicrornas pages 3-6).

Recent developments and latest research (2023–2024 priority) - Interventional human transcriptomics validates TG2 as a causal therapeutic node: In a randomized, double-blind 6-week gluten-challenge study, oral TG2 inhibitor ZED1227 (100 mg/day) “effectively prevented gluten-induced intestinal damage and inflammation” and preserved epithelial differentiation, nutrient absorption and transporter gene programs; nearly half of gluten-induced changes were attributable to epithelial IFN-γ response with type I/II IFN signatures (published online 24 Jun 2024; DOI:10.1038/s41590-024-01867-0; URL above) (dotsenko2024transcriptomicanalysisof pages 1-2). - Updated mechanistic synthesis: comprehensive reviews emphasize epithelial translocation mechanisms (CD71-mediated retrotranscytosis), the Th1/Th17/IL-21 axis, and IL-15–driven IEL cytotoxicity via NKG2D/CD94–NKG2C interactions with MICA/HLA-E (Oct 2025; https://doi.org/10.1136/bmj-2024-081353) and highlight anti-TG2 autoimmunity as diagnostic hallmark (Aug 2024; https://doi.org/10.3390/ijms25179412) (doyle2025advancesinthe pages 4-4, rigo2024expressionofmicrornas pages 3-6).

Current applications and real-world implementations - Pharmacologic probe of mechanism: TG2 inhibitor ZED1227 has been shown in human biopsy transcriptomics to protect mucosa during gluten exposure, supporting potential disease-modifying strategies targeting TG2 (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2). - Diagnostics in clinical practice: anti-TG2 IgA serology and confirmatory duodenal histology remain central; mechanistic reviews describe epithelial transport, T cell responses, and IEL cytotoxicity underlying the histologic lesion (Aug 2024; Oct 2025) (rigo2024expressionofmicrornas pages 3-6, doyle2025advancesinthe pages 4-4).

Expert opinions and analysis (authoritative sources) - Nature Immunology investigators conclude that “deamidated gluten–induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis,” and that transcriptomic protection by TG2 inhibition extends across epithelial morphology, inflammation, and absorptive functions, with HLA-DQ2 gene dose potentially modulating IFN-γ–induced damage (24 Jun 2024; DOI above) (dotsenko2024transcriptomicanalysisof pages 1-2). - BMJ overview underscores that IEL cytotoxicity is characterized by upregulation of NKG2D and CD94/NKG2C and ligation of MICA/HLA-E, with IL-15 induction on enterocytes facilitating IEL-mediated killing—converging on the IL-15–NKG2D stress axis as a principal effector of epithelial injury (Oct 2025; https://doi.org/10.1136/bmj-2024-081353) (doyle2025advancesinthe pages 4-4).

Relevant statistics and data (recent) - Prevalence: CeD affects approximately 1% of many populations (preprint summary; Apr 2025; https://doi.org/10.20944/preprints202504.1947.v1) (carreras2025intraepitheliallymphocytesand pages 3-5). - Transcriptomic proportioning: nearly half of gluten-induced expression changes are linked to epithelial IFN-γ responses during challenge (Jun 2024) (dotsenko2024transcriptomicanalysisof pages 1-2).

Evidence items (with URLs and publication dates) - Dotsenko V, et al. Transcriptomic analysis following TG2 inhibitor ZED1227 during gluten challenge (Nature Immunology; published online 24 Jun 2024). URL: https://doi.org/10.1038/s41590-024-01867-0 (dotsenko2024transcriptomicanalysisof pages 1-2). - Rigo FF, et al. Narrative review of miRNAs summarizing epithelial transport routes, T cell cytokines and anti-TG2 autoimmunity (International Journal of Molecular Sciences; Aug 2024). URL: https://doi.org/10.3390/ijms25179412 (rigo2024expressionofmicrornas pages 3-6). - Doyle JB, et al. BMJ review detailing NKG2D/CD94–NKG2C on IELs, IL-15 and epithelial ligands (MICA/HLA-E) (BMJ; Oct 2025). URL: https://doi.org/10.1136/bmj-2024-081353 (doyle2025advancesinthe pages 4-4). - Carreras J, et al. Preprint overview noting ~1% prevalence, HLA dependence and IEL increases (Preprints; 27 Apr 2025). URL: https://doi.org/10.20944/preprints202504.1947.v1 (carreras2025intraepitheliallymphocytesand pages 3-5). - Siukola E. Spatial transcriptomics thesis/paper summarizing TG2–HLA-DQ2/DQ8 mechanism and genetic/epigenetic contributors (2024; source repository). Citations within describe TG2 deamidation enabling HLA-DQ binding (siukola2024spatialtranscriptomicsofa pages 15-19, siukola2024spatialtranscriptomicsof pages 15-19).

Structured annotations for knowledge base - Genes/Proteins (HGNC): TGM2; HLA-DQA1/HLA-DQB1; IFNG; STAT1; IRF1; IL15; KLRK1 (NKG2D); KLRC2 (NKG2C); MICA; HLAE (dotsenko2024transcriptomicanalysisof pages 1-2, rigo2024expressionofmicrornas pages 3-6, doyle2025advancesinthe pages 4-4). - Biological Processes (GO): antigen presentation via MHC II (GO:0002495); cytokine-mediated signaling (GO:0019221); response to interferon-gamma (GO:0034341); type I interferon signaling (GO:0060337); regulation of T cell activation (GO:0050863); NK cell activation (GO:0030101); humoral immune response (GO:0006959) (dotsenko2024transcriptomicanalysisof pages 1-2, rigo2024expressionofmicrornas pages 3-6, doyle2025advancesinthe pages 4-4). - Cellular Components (GO): MHC class II complex (GO:0042613); external side of plasma membrane (GO:0009897); extracellular region (GO:0005576) (dotsenko2024transcriptomicanalysisof pages 1-2, doyle2025advancesinthe pages 4-4, rigo2024expressionofmicrornas pages 3-6). - Cell Types (CL): CD4+ T helper cell (CL:0000624); intraepithelial T lymphocyte (subset of T cells with NK receptors); B cell/plasma cell (rigo2024expressionofmicrornas pages 3-6, doyle2025advancesinthe pages 4-4). - Anatomical Sites (UBERON): small intestine (UBERON:0000160), duodenum (UBERON:0002114), intestinal epithelium (UBERON:0004811) (dotsenko2024transcriptomicanalysisof pages 1-2, doyle2025advancesinthe pages 4-4). - Chemical Entities (ChEBI): gluten peptides (cereal prolamins); small-molecule TG2 inhibitor ZED1227 (dotsenko2024transcriptomicanalysisof pages 1-2). - Phenotypes (HP): chronic diarrhea (HP:0002028); malabsorption (HP:0002242); weight loss (HP:0001824); anemia (HP:0001903); osteoporosis (HP:0000939) (mechanistically linked in cited reviews) (doyle2025advancesinthe pages 4-4, rigo2024expressionofmicrornas pages 3-6).

Gaps and open questions (partial evidence) - Epithelial pyroptosis and IFN–GSDMD axes, refractory CeD clonal evolution with JAK/STAT mutations, viral/microbiome triggers, and flow-cytometric IEL lymphogram performance were not recoverable in the citable context here; these remain active research areas with growing but heterogeneous evidence. Future updates should incorporate primary studies on pyroptosis signatures, RCD genomics, early-life viral exposures, and prospective IEL lymphogram validation cohorts once accessible (dotsenko2024transcriptomicanalysisof pages 1-2, rigo2024expressionofmicrornas pages 3-6, doyle2025advancesinthe pages 4-4).

Citations - TG2 inhibition prevents gluten-induced injury and reveals IFN-centric epithelial responses: Nature Immunology, 24 Jun 2024. https://doi.org/10.1038/s41590-024-01867-0 (dotsenko2024transcriptomicanalysisof pages 1-2). - Epithelial transport routes, T helper cytokines, IL-15/IEL cytotoxicity, anti-TG2 autoimmunity: Int J Mol Sci, Aug 2024. https://doi.org/10.3390/ijms25179412 (rigo2024expressionofmicrornas pages 3-6). - IEL cytotoxic receptors (NKG2D, CD94–NKG2C), ligands (MICA, HLA-E), IL-15 axis: BMJ, Oct 2025. https://doi.org/10.1136/bmj-2024-081353 (doyle2025advancesinthe pages 4-4). - Population prevalence ≈1%, HLA risk, IEL increases (overview): Preprints, 27 Apr 2025. https://doi.org/10.20944/preprints202504.1947.v1 (carreras2025intraepitheliallymphocytesand pages 3-5). - TG2–HLA-DQ2/DQ8 canonical mechanism summarized in spatial transcriptomics context: 2024 repository (siukola2024spatialtranscriptomicsofa pages 15-19, siukola2024spatialtranscriptomicsof pages 15-19).

References

(dotsenko2024transcriptomicanalysisof pages 1-2): Valeriia Dotsenko, Bernhard Tewes, Martin Hils, Ralf Pasternack, Jorma Isola, Juha Taavela, Alina Popp, Jani Sarin, Heini Huhtala, Pauliina Hiltunen, Timo Zimmermann, Ralf Mohrbacher, Roland Greinwald, Knut E. A. Lundin, Detlef Schuppan, Markku Mäki, Keijo Viiri, Karin Kull, Jari Koskenpato, Mika Scheinin, Marja-Leena Lähdeaho, Michael Schumann, Yurdagül Zopf, Andreas Stallmach, Ansgar W. Lohse, Stefano Fusco, Jost Langhorst, Helga Paula Török, Valerie Byrnes, Juozas Kupcinskas, Øistein Hovde, Jørgen Jahnsen, Luc Biedermann, and Jonas Zeitz. Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease. Nature Immunology, 25:1218-1230, Jun 2024. URL: https://doi.org/10.1038/s41590-024-01867-0, doi:10.1038/s41590-024-01867-0. This article has 34 citations and is from a highest quality peer-reviewed journal.
(rigo2024expressionofmicrornas pages 3-6): Francielen Furieri Rigo, Ellen Cristina Souza de Oliveira, Ana Elisa Valencise Quaglio, Bruna Damásio Moutinho, Luiz Claudio Di Stasi, and Ligia Yukie Sassaki. Expression of micrornas in adults with celiac disease: a narrative review. International Journal of Molecular Sciences, 25:9412, Aug 2024. URL: https://doi.org/10.3390/ijms25179412, doi:10.3390/ijms25179412. This article has 6 citations and is from a poor quality or predatory journal.
(doyle2025advancesinthe pages 4-4): John B Doyle, Jocelyn Silvester, Jonas F Ludvigsson, and Benjamin Lebwohl. Advances in the pathophysiology, diagnosis, and management of celiac disease. BMJ, 391:e081353, Oct 2025. URL: https://doi.org/10.1136/bmj-2024-081353, doi:10.1136/bmj-2024-081353. This article has 1 citations and is from a domain leading peer-reviewed journal.
(carreras2025intraepitheliallymphocytesand pages 3-5): J Carreras, G Roncador, R Hamoudi, and JA Bombi. Intraepithelial lymphocytes and lair1 expression in celiac disease. Apr 2025. URL: https://doi.org/10.20944/preprints202504.1947.v1, doi:10.20944/preprints202504.1947.v1.
(siukola2024spatialtranscriptomicsofa pages 15-19): E Siukola. Spatial transcriptomics of celiac disease small intestine in different stages of inflammation. Unknown journal, 2024.
(siukola2024spatialtranscriptomicsof pages 15-19): E Siukola. Spatial transcriptomics of celiac disease small intestine in different stages of inflammation. Unknown journal, 2024.

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