Abstract
Abstract C57BL/6 (B6) mice carrying the Sle1b sub-locus that harbors the lupus-associated NZM2410/NZW SLAM family genes produce anti-nuclear antibodies (ANA). However, the role and mechanisms of alteration in the germinal center (GC) checkpoint in the development of autoantibodies in these mice (named B6.Sle1b mice) is not clear. Here we show significantly higher spontaneously formed GC (Spt-GC) response in aged B6.Sle1b mice compared to B6 controls. The increased Spt-GC response in B6.Sle1b mice did not result from a generalized defect in the response of B cells expressing Sle1b as no difference was observed between two groups of mice in the anti-sheep red blood cell (sRBC) GC responses. We found a significant increase in CD4+CXCR5hiPD-1hi follicular helper T cells (TFH) within Spt-GC and anti-sRBC GCs in B6.Sle1b mice. The increase in Spt-GC and TFH cell responses in B6.Sle1b mice was not due to reduced CD4+CD25+Foxp3+ T effector (iTreg) and TFH regulatory (TFR) cells in GCs. Sle1b GCs compared to controls had significantly higher proliferating B cells. This elevated Spt-GC response in B6.Sle1b mice was associated with increased DNA and nucleosome-specific plasma cells (PCs), memory B cells and ANAs. These data indicate that the mechanisms that control the formation of Spt-GCs and generation of autoreactive B and TFH cells in GCs are altered by the NZM2410/NZW SLAM family genes located in Sle1b.
Published Version
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