AUTOIMMUNITY DEVELOPS IN LUPUS-PRONE NZB MICE DESPITE NORMAL T-CELL TOLERANCE

NZB mice spontaneously develop an autoimmune disease characterized by production of anti-RBC, -lymphocyte, and -ssDNA Abs, Evidence suggests that the NZB mouse strain has all of the immunologic defects required to produce lupus nephritis but lacks an MHC locus that allows pathoge nic anti-dsDNA Ab production. The capacity to produce diverse autoanti bodies in these mice raises the possibility that they possess a genera lized defect in self-tolerance. To determine whether this defect is fo und within the T cell subset, we backcrossed a transgene encoding bovi ne insulin (BI) onto the NZB background. In nonautoimmune BALB/c mice, the BI transgene induces a profound but incomplete state of T cell to lerance mediated predominantly by clonal anergy, Comparison of toleran ce in NZB and BALB/c BI-transgenic mice clearly demonstrated that NZB T cells were at least as tolerant to BI as BALB/c T cells. NZB BI-tran sgenic mice did not spontaneously produce anti-BI Abs, and following a ntigenic challenge, BI-specific Ab production was comparably reduced i n both BI-transgenic NZB and BALB/c mice. Further, in vitro BI-specifi c T cell proliferation and cytokine secretion were appropriately decre ased for primed lymph node and splenic T cells derived from NZB BI-tra nsgenic relative to their nontransgenic counterparts. These data indic ate that a generalized T cell tolerance defect does not underlie the a utoimmune disease in NZB mice. Instead, we propose that the T cell-dep endent production of pathogenic IgG autoantibodies in these mice arise s from abnormal activation of T cells in the setting of normal but inc omplete tolerance.