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 centra l role in the etiology of this autoimmune disease. Among other possibi lities, it has been proposed that an unbalanced expression of IDDM-ass ociated DQA, and/or DQB alleles may lead to alterations in the composi tion of alpha beta heterodimers and preferential expression of a parti cular heterodimer on the antigen-presenting cell surface, leading to s elf-recognition. In this report, we demonstrate the differential expre ssion of DQA1 alleles in vivo, in particular of the two diabetogenic a lleles DQA10301 and DQA1*0501. Family studies suggest that unequal HL A-DQA1 allele expression in heterozygous individuals is not associated in cis with the HLA-DQA1 gene, but may be affected by trans-acting de terminant(s). We also discuss the segregation of this phenotype in IDD M-affected members. Furthermore, we examined historical samples of PBL from an IDDM-affected individual and an HLA-identical unaffected sibl ing acting in a kidney transplant program as donor and recipient, resp ectively. This analysis allowed us to establish that unbalanced expres sion of DQA10301 and DQA1*0501 can be induced by microenvironmental c onditions. Inducible differential expression of HLA-DQA1 alleles may a ccount for the discordance in the outcome of autoimmune disease in mon ozygotic twins and HLA-identical siblings.