| In the (NZB x NZW)F1 murine model of human lupus, greater than 90% of female mice succumb to renal failure within the first year of life as a result of an immune complex mediated glomerulonephritis. One major NZB genetic contribution to autoantibody production and disease is the Nba2 locus on distal chromosome 1. C57BLJ6 mice congenic for Nba2, designated B6.Nba2, develop high-titer IgG anti-nuclear autoantibodies typical of lupus. When crossed to NZW, the F1 progeny develop lupus disease that is nearly identical to (NZB x NZW)F1 mice. In the studies presented in this thesis, the Nba2 contribution to lupus was examined by characterizing phenotypes and functions of B6.Nba2 B cells, by studying the biochemistry of and responses to signaling through the B cell receptor, and by determining whether Nba2 encodes an intrinsic B cell defect that is required for autoantibody production.; Our data revealed that Nba2 contributes to polyclonal B cell activation that was apparent at 8 weeks of age in B6.Nba2 mice. Young B6.Nba2 mice also demonstrated splenomegaly, IgM hypergammaglobulinemia, increased percentages of CD69+ and Fas+ B cells in the spleen, and increased spontaneous IgM secretion. Although NZB mice harbor expansions of B1a and marginal zone B cells, B6.Nba2 mice had no such expansions. In fact, the percentages of marginal zone B cells were significantly lower in B6.Nba2 compared versus controls. Thus, B cell expansion is not an important NZB genetic contribution to lupus as previously reported. B6.Nba2 B cells showed hyper-proliferation following anti-IgM crosslinking compared to B6 B cells and this response was T cell independent. However, calcium responses and protein tyrosine phosphorylation after BCR engagement were similar in B6.Nba2 and B6 B cells from young mice. Finally, bone marrow chimeras were generated and data showed that Nba2 expression in bone marrow derived cells mediated autoantibody production in lethally irradiated hosts. Furthermore, Nba2 mediated an intrinsic B cell defect required for IgG anti-chromatin autoantibody production.; Together, these data demonstrated that Nba2 contributes to early B cell hyperactivity, and polyclonal IgM secretion, and its expression by B cells is necessary for autoantibody production. |
