Differential expression of insulin-dependent diabetes mellitus-associated HLA-DQA1 alleles in vivo

The strong association of HLA-DQ genes with insulin-dependent diabetes mellitus (IDDM) susceptibility is persuasive evidence of their central role in the etiology of this autoimmune disease. Among other possibilities, it has been proposed that an unbalanced expression of IDDM-associated DQA, and/or DQB alleles may lead to alterations in the composition of ?? heterodimers and preferential expression of a particular heterodimer on the antigen-presenting cell surface, leading to self-recognition. In this report, we demonstrate the differential expression of DQA1 alleles in vivo, in particular of the two diabetogenic alleles DQA1(*)0301 and DQA1(*)0501. Family studies suggest that unequal HLA-DQA1 allele expression in heterozygous individuals is not associated in cis with the HLA-DQA1 gene, but may be affected by trans-acting determinant(s). We also discuss the segregation of this phenotype in IDDM-affected members. Furthermore, we examined historical samples of PBL from an IDDM-affected individual and an HLA-identical unaffected sibling acting in a kidney transplant program as donor and recipient, respectively. This analysis allowed us to establish that unbalanced expression of DQA1(*)0301 and DQA1(*)0501 can be induced by microenvironmental conditions. Inducible differential expression of HLA-DQA1 alleles may account for the discordance in the outcome of autoimmune disease in monozygotic twins and HLA-identical siblings.