Translational mini-review series on the immunogenetics of gut disease: immunogenetics of coeliac disease

Abstract

Recent advances in immunological and genetic research in coeliac disease provide new and complementary insights into the immune response driving this chronic intestinal inflammatory disorder. Both approaches confirm the central importance of T cell-mediated immune responses to disease pathogenesis and have further begun to highlight other relevant components of the mucosal immune system, including innate immunity and the control of lymphocyte trafficking to the mucosa. In the last year, the first genome wide association study in celiac disease led to the identification of multiple new risk variants. These risk regions implicate genes involved in the immune system. Overlap with autoimmune diseases is striking with several of these regions being shown to confer susceptibility to other chronic immune-mediated diseases, particularly type 1 diabetes.

Fig. 1

Classical haplotype combinations encoding the human leucocyte antigen (HLA)-DQ2 and -DQ8 heterodimers. Adapted from Sollid [36]. HLA proteins at the cell surface, and structure of the protein encoding DNA region, are shown.

Fig. 2

Model of gluten induced immune response in coeliac disease, and the sites of action of coeliac susceptibility genes. The most likely gene from each region is shown, although note that causality of a genetic variant in any one gene has not yet been proved.

Fig. 3

Current estimates of effect size conferred by the coeliac disease-associated risk variants. Allelic odds ratios are shown for the best tag markers from the Genome-Wide Association Study, along with the most likely candidate gene(s) from each region. It is probable that the effect of the true causal variants, once identified, will be larger.