ImmunologyTier 1Medical Sciences concept

Coeliac disease immunology (T-cell mediated, HLA-DQ2/8, IgA deficiency association)

Core concept

T-cell mediated (not primarily antibody-mediated, though antibodies serve as markers) hypersensitivity to gliadin (a gluten peptide) in genetically susceptible individuals
Requires HLA-DQ2 (~90-95%) or HLA-DQ8 (~most of the remainder) -- necessary but not sufficient (both alleles are common in the general population; most carriers never develop coeliac disease)
Mechanism: tissue transglutaminase (tTG) deamidates gliadin -> deamidated gliadin binds DQ2/DQ8 on APCs with higher affinity -> presented to CD4+ T cells -> Th1-driven inflammatory response -> villous atrophy, crypt hyperplasia, intraepithelial lymphocytosis

Serology: anti-tTG IgA (first-line), anti-endomysial antibody IgA (high specificity, more operator-dependent), anti-deamidated gliadin peptide (DGP) IgG (useful when IgA deficient)
IgA deficiency is over-represented in coeliac disease (~10x general population rate) -- always check total IgA alongside tTG IgA, since a deficient patient will have a false-negative tTG IgA despite active disease
DQ2/DQ8-negative result has very high negative predictive value -- effectively excludes coeliac disease, useful when a patient is already gluten-free and serology/biopsy cannot be reliably interpreted

Diagnosis requires gluten in the diet at the time of testing -- both serology and duodenal biopsy (histology) can normalise/improve on a gluten-free diet, giving false-negative results if already excluded
Trap: ordering tTG IgA without total IgA in a patient with unexplained iron deficiency or malabsorption -- a selective IgA-deficient coeliac patient will be missed
Biopsy remains reference standard in most adult diagnostic pathways: duodenal histology (Marsh classification) showing villous atrophy correlates disease activity with serology titre in established cases

Associated conditions: T1DM, autoimmune thyroid disease, dermatitis herpetiformis (a cutaneous manifestation with its own IgA/tTG-3 deposition), Down syndrome, selective IgA deficiency
HLA-DQ2/DQ8 association parallels other HLA-disease associations (see separate note) -- necessary-but-not-sufficient logic is shared with HLA-B27/ankylosing spondylitis
Untreated disease carries increased risk of enteropathy-associated T-cell lymphoma (EATL) and other GI malignancy -- the long-term complication driving dietary adherence

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