We report that lymphoid cells originating from the non-obese diabetic (NOD) autoimmune prone mouse strain are resistant to several signals known to induce programmed cell death. In vitro culturing of lymphoid cells of splenic or lymph node origin showed that B cells and T cells of both CD4+ and CD8+ phenotypes from NOD mice display extended survival in vitro. By cytofluorimetric analysis, immature CD4+ CD8+ NOD thymocytes were shown to partially resist in vivo treatment with corticosteroids. Finally, immunization with protein antigens induced enhanced and prolonged immune responses in NOD mice compared with normal C57BL/6, BALB/c, and C3H/Tif control mice. We conclude that the NOD mouse displays a defect in the mechanism(s) mediating programmed cell death in T and B lymphocytes. These findings provide a novel explanation for the B cell aberrations observed in the NOD mouse and may have implications for the understanding of the autoimmune pathogenesis in this mouse strain.

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The immunoglobulin (Ig) heavy chain variable (VH) gene complexity and the VH gene utilisation pattern of the non-obese diabetic (NOD) mouse were investigated. We found that the NOD mouse displays a VH gene complexity which appears to be identical to that of the C57BL/6 mouse. Thus, Southern hybridisation using probes specific for 9 of the murine VH gene families revealed identical restriction fragment length polymorphism (RFLP) patterns in both mouse strains. As indicated by immunofluorescence analysis using allotype specific monoclonal antibodies the NOD mice were also found to carry the IgCH-1b allele. Collectively, these data suggest that the NOD mice carry an IgVH locus identical to that carried by C57BL/6. In contrast to the apparent identity at the level of germline VH gene repertoires, the pattern of VH gene utilisation differed considerably between these two mouse strains. Thus, in NOD mice the neonatal preference of D-proximal VH genes was found to be more pronounced than in C57BL/6 mice. Moreover, in contrast to adult C57BL/6 mice a D-proximal bias was evident also in adult NOD mice. On the basis of these findings we discuss the possibility that the distorted development of B cell repertoires in the NOD mouse could be directly or indirectly related to the T cell mediated, autoimmune process in the NOD mouse.

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