GENETIC-ANALYSIS OF IMMUNE DYSFUNCTION IN NONOBESE DIABETIC (NOD) MICE - MAPPING OF A SUSCEPTIBILITY LOCUS CLOSE TO THE BCL-2 GENE CORRELATES WITH INCREASED RESISTANCE OF NOD T-CELLS TO APOPTOSIS INDUCTION

The non-obese diabetic (NOD) mouse strain provides a remarkable model for investigating the mechanisms of autoimmunity. Independent genetic analyses of this model have previously shown that chromosome 1-linked loci were involved in the control of periinsulitis and sialitis on the one hand and of insulitis and diabetes on the other hand. In the pres ent work, analysis of a [NOD x (NOD x C57BL/6)F1] backcross progeny al lowed us to clearly dissociate two genetic regions: one was associated with periinsulitis and mapped to the middle region of chromosome 1, i n the vicinity of the Bcl-2 gene; the other was associated with insuli tis and mapped to the proximal part of the chromosome. Three intermedi ate markers D1Mit18, D1Mit5 and D1Mir19 covering at least 25 centiMorg ans between these two regions,were associated with neither periinsulit is nor insulitis. The role of the Bcl-2-linked region in the immune an omalies of NOD mice was further investigated in a (NOD x C57BL/6)F2 cr oss where the Bcl-2(nod) haplotype was linked to elevated serum levels of IgG (p < 0.0005). The middle region of chromosome 1 is, therefore, involved in the control of three phenotypes, including periinsulitis, sialitis and hyperIgG, pointing to Bcl-2 as a good candidate for a ca use of the NOD mouse disease. Consistent with the anti-apoptotic funct ion of the Bcl-2 gene product, activated T lymphocytes from NOD mice s howed a markedly increased resistance to induction of apoptosis follow ing deprivation of interleukin-2 when compared to those from nonautoim mune strains. After the recent observation of the Fas gene alterations in the lpr and lpr(cg) mutations, these findings indicate that deregu lation of lymphoid cell apoptosis may be a general pathogenetic mechan ism in autoimmune diseases.