INSULIN EXPRESSION IN HUMAN THYMUS IS MODULATED BY INS VNTR ALLELES AT THE IDDM2 LOCUS

Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) is due t o autoimmune destruction of pancreatic beta-cells. Genetic susceptibil ity to IDDM is encoded by several loci, one of which (IDDM2) maps to a variable number of tandem repeats (VNTR) minisatellite, upstream of t he insulin gene (INS)(1-5). The short class 1 VNTR alleles (26-63 repe ats) predispose to IDDM, while class III alleles (140-210 repeats) hav e a dominant protective effect(1-6). We have reported that, in human a dult(4,6) and fetal(7) pancreas in vivo, class III alleles are associa ted with marginally lower INS mRNA levels than class I, suggesting tra nscriptional effects of the VNTR. These may be related to type 1 diabe tes pathogenesis, as insulin is the only known beta-cell specific IDDM autoantigen. In search of a more plausible mechanism for the dominant effect of class III alleles, we analysed expression of insulin in hum an fetal thymus, a critical site for tolerance induction to self prote ins. Insulin was detected in all thymus tissues examined and class III VNTR alleles were associated with 2- to 3-fold higher INS mRNA levels than class I. We therefore propose higher levels of thymic INS expres sion, facilitating immune tolerance induction, as a mechanism for the dominant protective effect of class III alleles.