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.
name: Celiac Disease
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-04-06T00:30:00Z'
category: Complex
parents:
- Gastrointestinal Disease
- Autoimmune Disease
disease_term:
preferred_term: celiac disease
term:
id: MONDO:0005130
label: celiac disease
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:39273359
reference_title: "Expression of MicroRNAs in Adults with Celiac Disease: A Narrative Review."
supports: PARTIAL
snippet: "CD induces an altered immune response that leads to chronic inflammation
and duodenal mucosal damage."
explanation: Chronic inflammation and mucosal damage from immune response to
gluten leads to malabsorption and chronic diarrhea as a cardinal symptom.
- 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
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
snippet: "Typical gastrointestinal symptoms include diarrhea, abdominal discomfort, bloating, and constipation."
explanation: Bloating is a typical gastrointestinal symptom of 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: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: Weight loss results from impaired nutrient absorption due to
villous atrophy and loss of epithelial cell differentiation and absorptive
capacity.
- name: Iron Deficiency Anemia
category: Hematologic
frequency: FREQUENT
notes: From malabsorption
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
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: Anemia results from malabsorption of iron and other nutrients
due to villous atrophy and impaired epithelial absorptive function in
damaged small intestine.
- 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
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.
- name: Dermatitis Herpetiformis
category: Dermatological
frequency: OCCASIONAL
notes: Skin manifestation of celiac
phenotype_term:
preferred_term: Skin Rash
term:
id: HP:0000988
label: Skin rash
evidence:
- reference: PMID:29757210
reference_title: "Dermatitis Herpetiformis: A Common Extraintestinal Manifestation of Coeliac Disease."
supports: SUPPORT
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.
- name: Osteoporosis
category: Musculoskeletal
frequency: OCCASIONAL
notes: From calcium/vitamin D malabsorption
phenotype_term:
preferred_term: Reduced Bone 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
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 due to calcium and vitamin D malabsorption.
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
- name: HLA-DQ8
association: Risk Factor
notes: Most remaining patients
- 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
- name: Gut Microbiome
notes: May modulate risk
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.
- name: Nutritional Supplementation
description: Iron, calcium, vitamin D, B12 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: MAXO:0000058
label: pharmacotherapy
- 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: digestive system disorder
- classification_value: autoimmune disease
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: []