Celiac Disease

name: Celiac Disease
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-02-17T21:53:14Z'
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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
- name: Bloating
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abdominal Distention
    term:
      id: HP:0003270
      label: Abdominal distention
- name: Weight Loss
  category: Systemic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Weight Loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:38914866
    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
    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
- 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
- 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
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: 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.
- name: Nutritional Supplementation
  description: Iron, calcium, vitamin D, B12 as needed.
- name: Monitoring
  description: Regular serology and bone density monitoring.
- name: Corticosteroids
  description: For refractory celiac disease.
- name: Dietitian Counseling
  description: Essential for dietary compliance.
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: []