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 pathogenic anti-dsDNA Ab production. The capacity to produce diverse autoantibodies in these mice raises the possibility that they possess a generalized defect in self-tolerance. To determine whether this defect is found within the T cell subset, we backcrossed a transgene encoding bovine insulin (BI) onto the NZB background. In nonautoimmune BALB/c mice, the BI transgene induces a profound but incomplete state of T cell tolerance mediated predominantly by clonal anergy. Comparison of tolerance 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-transgenic mice did not spontaneously produce anti-BI Abs, and following antigenic challenge, BI-specific Ab production was comparably reduced in both BI-transgenic NZB and BALB/c mice. Further, in vitro BI-specific T cell proliferation and cytokine secretion were appropriately decreased for primed lymph node and splenic T cells derived from NZB BI-transgenic relative to their nontransgenic counterparts. These data indicate that a generalized T cell tolerance defect does not underlie the autoimmune disease in NZB mice. Instead, we propose that the T cell-dependent production of pathogenic IgG autoantibodies in these mice arises from abnormal activation of T cells in the setting of normal but incomplete tolerance.
Wither
J
J
The Arthritis Centre-Research Unit, Toronto Hospital Research Institute, The Toronto Hospital-Western Division, Ontario, Canada.
Vukusic
B
B
D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity; D002417:Cattle; D017635:Clonal Anergy; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D007111:Immunity, Cellular; D007075:Immunoglobulin M / Q000096:biosynthesis*; D007328:Insulin / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB / Q000235:genetics / Q000276:immunology*; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D019076:Transgenes
D001323:Autoantibodies; D007075:Immunoglobulin M; D007328:Insulin; D008222:Lymphokines