Marginal zone B cells contribute to autoimmunity in the NZM2410 lupus prone mouse model. (159.13)

Abstract

Abstract Lupus is an autoimmune disease in which the affected individual generates antibodies (Abs) against nuclear antigens such as DNA. Our NZM2410-derived triple congenic (TC) model of lupus expresses 3 previously characterized lupus susceptibility loci. We have previously shown that the breach of follicular exclusion of TC MZB cells is associated with disease progression. The production of nuclear autoAbs occurred in tandem with a large influx of TC MZB cells in the follicles. We also found an expansion of MZB cells in TC mice as compared to non-autoimmune B6 mice that occurs prior to the production of anti-DNA autoAbs, further suggesting that MZB cells may contribute to autoimmunity. MZB cell expansion is associated with the upregulation of Notch2 signaling in these cells. Adoptive transfer of TC or B6 splenic B cells into B6.Rag1-/- recipients indicated no difference in the homeostatic expansion of MZB cells from either donor strain, whether the recipients were treated or not with CpG. However, CpG-treated recipients of TC B cells produced more anti-ssDNA IgM than recipients of B6 B cells. Our transfer results showed that although TC MZB cells do not expand more than B6 MZB cells in a lymphopenic host, TC splenic B cells produce higher level of anti-ssDNA IgM in response to CpG stimulation. Further characterization of the TC MZB cells will determine more precisely how they contribute to autoimmunity.