Celiac Disease

🏷

Classifications

Harrison's Chapter

👪

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.

◈

Mechanistic Hypotheses

1

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

canonical_gluten_hladq_ttg_enteropathy_model CANONICAL

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 co-required IL-15-driven innate epithelial activation (three-signal model), 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 (preserved villus-height/crypt-depth during gluten challenge) 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 preserves villous architecture during gluten challenge — first causal human perturbation), HLA-DQ2 tetramer studies (0.1–1.8% of intestinal CD4 T cells are gluten-specific, correlating with Marsh grade and anti-TG2 antibodies), and gluten-free-diet remission. Five required expansions: (1) IL-15 / innate immunity is co-required for villous atrophy — three-signal model (IL-15 + HLA-DQ + gluten); neither adaptive nor innate alone is sufficient; (2) the cytokine response is mixed Th1/Th17/IL-21, not pure Th1/IFN-γ; (3) three nested positive feedback loops (IgA-CD71 retrotranscytosis, IFN-γ/ thioredoxin/TG2 activation, B-cell APC amplification) drive disease chronicity; (4) wheat amylase-trypsin inhibitors (ATIs) provide parallel TLR4-mediated innate signaling as adjuvant; (5) transcellular IgA-CD71 retrotranscytosis is the dominant gluten transport route to the lamina propria, not paracellular permeability. 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 (2 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 most definitive causal evidence for the canonical gluten/HLA/TG2 axis: pharmacological TG2 inhibition preserved villus- height/crypt-depth ratio during gluten challenge, directly validating TG2 as a necessary node in the pathogenic chain.

⚙

Pathophysiology

4

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

Show evidence (3 references)

PMID:10684852 SUPPORT

"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.

PMID:10684852 SUPPORT

"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.

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.

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

Show evidence (4 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.

+ 1 more reference

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

Show evidence (1 reference)

PMID:39273359 NO_EVIDENCE

"Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of proline- and glutamine-rich proteins, widely termed "gluten", in genetically susceptible individuals. CD induces an altered immune response that leads to chronic inflammation and duodenal mucosal damage."

Describes the immune-mediated nature of celiac disease, which includes both cellular and humoral (antibody) responses to gluten antigens.

Barrier Dysfunction

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

Show evidence (1 reference)

PMID:38914866 PARTIAL

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

Blocking TG2 prevents gluten-induced disruption of epithelial barrier integrity and differentiation programs, indicating barrier dysfunction is downstream of adaptive immune activation.

●

Phenotypes

22

Blood 2

Iron Deficiency Anemia FREQUENT Iron deficiency anemia 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 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 3

Chronic Diarrhea FREQUENT Chronic diarrhea 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 Constipation 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.

Genitourinary 1

Female infertility 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 1

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.

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 1

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.

Musculoskeletal 3

Reduced Bone Mineral Density FREQUENT Reduced bone mineral density 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 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 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 1

Peripheral Neuropathy OCCASIONAL Peripheral neuropathy 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.

Constitutional 2

Abdominal Pain FREQUENT Abdominal pain 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 Fatigue 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.

Growth 3

Weight Loss FREQUENT Weight loss 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 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.

Other 4

Villous Atrophy VERY_FREQUENT Villous atrophy 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.

Recurrent Aphthous Stomatitis FREQUENT Recurrent aphthous stomatitis 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.

Cerebellar Ataxia OCCASIONAL Nonprogressive cerebellar ataxia HP:0002470

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.

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.

🧬

Genetic Associations

12

HLA-DQ2 (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)

IL2 (Risk Factor)

IL21 (Risk Factor)

BACH2 (GWAS)

TNFAIP3 (GWAS)

CD28 (GWAS)

EGR2 (GWAS)

ETS1 (GWAS)

IRF4 (GWAS)

SMAD3 (GWAS)

PTPN22 (GWAS)

💊

Medical Actions

5

Gluten-Free Diet

Action: Gluten-free diet Ontology label: dietary intervention MAXO:0000088

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

Lifelong strict gluten avoidance is the only effective treatment.

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 MAXO:0000088

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.

🌍

Environmental Factors

7

Gluten Exposure

Required trigger

Wheat Food Products

Common gluten-containing dietary source

Barley

Common gluten-containing dietary source

Rye

Common gluten-containing dietary source

Early Gluten Introduction

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.

Gut Microbiome

Dysbiosis may modulate risk

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)"

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

🔬

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

{ }

Source YAML

click to show

name: Celiac Disease
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-04-30T12:00:00Z'
category: Complex
parents:
- Gastrointestinal Disease
- Autoimmune Disease
disease_term:
  preferred_term: celiac disease
  term:
    id: MONDO:0005130
    label: celiac disease
prevalence:
- population: General
  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 co-required IL-15-driven innate epithelial activation (three-signal model), 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 (preserved villus-height/crypt-depth during gluten challenge)
    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 preserves
    villous architecture during gluten challenge — first causal
    human perturbation), HLA-DQ2 tetramer studies (0.1–1.8% of
    intestinal CD4 T cells are gluten-specific, correlating with
    Marsh grade and anti-TG2 antibodies), and gluten-free-diet
    remission. Five required expansions: (1) IL-15 / innate
    immunity is co-required for villous atrophy — three-signal
    model (IL-15 + HLA-DQ + gluten); neither adaptive nor innate
    alone is sufficient; (2) the cytokine response is mixed
    Th1/Th17/IL-21, not pure Th1/IFN-γ; (3) three nested positive
    feedback loops (IgA-CD71 retrotranscytosis, IFN-γ/
    thioredoxin/TG2 activation, B-cell APC amplification) drive
    disease chronicity; (4) wheat amylase-trypsin inhibitors
    (ATIs) provide parallel TLR4-mediated innate signaling as
    adjuvant; (5) transcellular IgA-CD71 retrotranscytosis is the
    dominant gluten transport route to the lamina propria, not
    paracellular permeability. 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 most
      definitive causal evidence for the canonical gluten/HLA/TG2
      axis: pharmacological TG2 inhibition preserved villus-
      height/crypt-depth ratio during gluten challenge, directly
      validating TG2 as a necessary node in the pathogenic chain.
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
    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.
  - 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
    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.
  - 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.
- 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: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.
- 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:39273359
    reference_title: "Expression of MicroRNAs in Adults with Celiac Disease: A Narrative Review."
    supports: NO_EVIDENCE
    snippet: "Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of proline- and glutamine-rich proteins, widely termed \"gluten\", in genetically susceptible individuals. CD induces an altered immune response that leads to chronic inflammation and duodenal mucosal damage."
    explanation: Describes the immune-mediated nature of celiac disease, which includes both cellular and humoral (antibody) responses to gluten antigens.
- 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: PARTIAL
    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: Blocking TG2 prevents gluten-induced disruption of epithelial barrier integrity and differentiation programs, indicating barrier dysfunction is downstream of adaptive immune activation.
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:0002470
      label: Nonprogressive cerebellar 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."
biochemical:
- name: Anti-tTG IgA
  presence: Elevated
  context: Primary diagnostic marker
- name: Anti-Endomysial Antibodies
  presence: Elevated
  context: Highly specific
- name: Anti-DGP Antibodies
  presence: Elevated
  context: Useful when IgA deficient
- name: Total IgA
  presence: Variable
  context: IgA deficiency common in celiac
genetic:
- name: HLA-DQ2
  association: Risk Factor
  notes: Present in ~95% of patients (DQ2 alone ~90%, DQ8 covers most remainder)
  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
  notes: Most remaining patients not carrying DQ2
- name: IL2
  association: Risk Factor
- name: IL21
  association: Risk Factor
- name: BACH2
  association: GWAS
  notes: Transcription factor regulating Treg/effector T cell balance and B cell class switching
- name: TNFAIP3
  association: GWAS
  notes: Encodes A20, a ubiquitin-editing enzyme that negatively regulates NF-kB signaling
- name: CD28
  association: GWAS
  notes: T cell co-stimulatory receptor required for T cell activation
- name: EGR2
  association: GWAS
  notes: Transcription factor involved in T cell anergy and peripheral tolerance
- name: ETS1
  association: GWAS
  notes: Transcription factor regulating T and B cell development and immune cell differentiation
- name: IRF4
  association: GWAS
  notes: Transcription factor essential for Th17 and Th2 cell differentiation and plasma cell development
- name: SMAD3
  association: GWAS
  notes: TGF-beta signaling mediator regulating T cell differentiation and immune tolerance
- name: PTPN22
  association: GWAS
  notes: Protein tyrosine phosphatase modulating T cell receptor signaling threshold
environmental:
- name: Gluten Exposure
  notes: Required trigger
- 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
- name: Barley
  notes: Common gluten-containing dietary source
  food_source:
    preferred_term: barley
    term:
      id: FOODON:00003108
      label: barley seed (raw)
- name: Rye
  notes: Common gluten-containing dietary source
  food_source:
    preferred_term: rye
    term:
      id: FOODON:00003734
      label: rye kernel
- name: Early Gluten Introduction
  notes: Timing may affect risk
- name: Gastrointestinal Infections
  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
  notes: Dysbiosis may modulate risk
  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.
treatments:
- name: Gluten-Free Diet
  description: Lifelong strict gluten avoidance is the only effective treatment.
  treatment_term:
    preferred_term: Gluten-free diet
    term:
      id: MAXO:0000088
      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
  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.
  treatment_term:
    preferred_term: Nutritional supplementation
    term:
      id: MAXO:0000088
      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.
classifications:
  harrisons_chapter:
  - classification_value: GASTROINTESTINAL
  - classification_value: IMMUNE_RHEUMATOLOGIC
datasets:
references:
- 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

4

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

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

Falcon ▸

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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