Celiac disease (CD) is an intestinal disorder with multifactorial etiology. HLA and non-HLA genes together with gluten and possibly additional environmental factors are involved in disease development. Evidence suggests that CD4+ T cells are central in controlling an immune response to gluten that causes the immunopathology, but the actual mechanisms responsible for the tissue damage are as yet only partly characterized. CD provides a good model for HLA-associated diseases, and insight into the mechanism of this disease may well shed light on oral tolerance in humans. The primary HLA association in the majority of CD patients is with DQ2 and in the minority of patients with DQ8. Gluten-reactive T cells can be isolated from small intestinal biopsies of celiac patients but not of non-celiac controls. DQ2 or DQ8, but not other HLA molecules carried by patients, are the predominant restriction elements for these T cells. Lesion-derived T cells predominantly recognize deamidated gluten peptides. A number of distinct T cell epitopes within gluten exist. DQ2 and DQ8 bind the epitopes so that the glutamic acid residues created by deamidation are accommodated in pockets that have a preference for negatively charged side chains. Evidence indicates that deamidation in vivo is mediated by the enzyme tissue transglutaminase (tTG). Notably, tTG can also cross-link glutamine residues of peptides to lysine residues in other proteins including tTG itself. This may result in the formation of complexes of gluten-tTG. These complexes may permit gluten-reactive T cells to provide help to tTG-specific B cells by a mechanism of intramolecular help, thereby explaining the occurrence of gluten-dependent tTG autoantibodies that is a characteristic feature of active CD.

Keyword(s): celiac diseaseDQ2glutenHLApeptidesT cells

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  • Article Type: Review Article
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