A combination of a particular HLA-DPβ allele and an HLA-DQ heterodimer confers susceptibility to coeliac disease

COELIAC disease is an autoimmune disease of the intestinal mucosa, elicited by ingestion of wheat gluten in genetically susceptible individuals¹. Susceptibility to coeliac disease has been associated with the serologically defined variants DR3 and DR7 of the class II antigens encoded by the HLA-D region^2,3. Three related class II antigens, each consisting of an alpha and a beta glycoprotein chain, have been identified and are designated HLA-DR, HLA-DQ, and HLA-DP. These highly polymorphic transmembrane proteins bind peptides derived from the processing of foreign antigens^4-8 and present them to T lymphocytes; they also influence the specificity of the mature T-cell repertoire^9-12. The role of HLA-DP polymorphism in susceptibility has not been as fully explored as that of the other class II antigens because of the complexity of the ′d lymphocyte typing (PLT) method for determining DPw specificities^13-15. Here we use a new DNA-based method of HLA-DP typing¹⁶ to analyse the distribution of DPβ alleles in a group of coeliac disease patients and healthy controls. Two specific DPβ alleles (DPB4.2 and DPB3) are increased in the patient population. Comparison of the DPβ sequences suggests 470 that the polymorphic residues at position 69 and at 56 and 57 may be critical in conferring susceptibility. Further, the contribution of the susceptible DPβ alleles appears to be independent of linkage to the previously reported DR3 and DR7 markers for coeliac disease. The distribution of DQα and β alleles in patients suggests that a specific DQ heterodimer may be responsible for the observed DR associations. Individuals with both this DQ antigen and a specific DPβ allele are at increased risk for coeliac disease.