pathogenesis

Celiac disease is multifactorial: multiple genetic and environmental factors must combine for the disease to manifest.

Overview of the Pathway

flowchart TD
    A[Dietary gluten ingestion] --> B[Prolamins: gliadin, hordein, secalin<br/>resist gut proteases]
    B --> C[Cross-intestinal epithelial barrier<br/>zonulin / larazotide-sensitive]
    C --> D[tTG / TG2 modifies gliadin peptides]
    D --> E[Deamidation: glutamine to glutamate<br/>better HLA binding]
    D --> F[Transamidation: gliadin cross-links to tTG<br/>neoepitopes and anti-tTG antibodies]
    E --> G[HLA-DQ2 / HLA-DQ8 on APCs<br/>bind modified peptides]
    F --> G
    G --> H[CD4+ T-cell activation via antigen presentation<br/>adaptive immune response]
    H --> I[Cytokine release: IFN-gamma, IL-18, IL-21, IL-6]
    I --> J[Villous atrophy plus crypt hyperplasia<br/>malabsorption]

Key Molecular Players

Prolamins

Storage proteins rich in proline (prol-) and glutamine (-amin). They dissolve in alcohols and are resistant to gut proteases — this is why they persist and cross the intestinal barrier.

• Wheat: gliadin and glutenin
• Barley: hordein
• Rye: secalin
• Oats: avenin

Tissue Transglutaminase (tTG / TG2)

A ubiquitous enzyme that modifies gliadin in two ways:

1. Deamidation — converts glutamine → glutamate by cleaving the epsilon-amino group. The negatively charged residue binds more tightly to HLA-DQ2/DQ8.
2. Transamidation — cross-links gliadin to a lysine residue in tTG itself (covalent bond). This creates novel neoepitopes that drive the anti-tTG autoantibody response.

Autoantibodies against tTG (anti-tTG IgA) are detectable in serum and form the basis of the primary diagnostic blood test.

HLA-DQ2 / HLA-DQ8

Part of the MHC class II antigen presentation system. These variants bind deamidated gluten peptides with high affinity → stable HLA-peptide complex → robust T cell activation. See causes for genetics.

Innate Immune Component

IL-15 released in the intestinal epithelium activates the innate immune system via a shorter gluten peptide (p31–43/49), which may independently contribute to villous damage and crypt hyperplasia.

Intestinal Damage: Villous Atrophy

The inflammatory cascade leads to:

• Intraepithelial lymphocytosis — elevated IEL count (>25–40 per 100 enterocytes)
• Crypt hyperplasia — elongated crypts of Lieberkühn
• Villous atrophy — shortening or complete absence of villi → drastically reduced absorptive surface area → malabsorption

This damage is graded by the Marsh-Oberhuber classification (see diagnosis).

Extraintestinal Autoimmunity

The anti-tTG response is systemic. tTG is expressed in many tissues — liver, bone, brain, heart. This partly explains extraintestinal manifestations (hepatitis, neuropathy, osteoporosis). See symptoms.

Bone Metabolism (Schematic Summary)

• Villous atrophy → ↓ Ca²⁺, Vit D, B12 absorption
• → Endocrine effects: ↓ IGF-1, PTH dysregulation, ↓ estrogen
• → Inflammation (IFN-γ, IL-18, etc.) → bone resorption
• → Dysfunctional bone metabolism → osteoporosis

Backlinks

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