B1 cell-produced anti-phosphatidylserine antibodies contribute to lupus nephritis development via TLR-mediated Syk activation

Abstract Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). However, both the cellular source of anti-phospholipid antibodies and their contributions to the development of lupus nephritis (LN) remain largely unclear. Here, we report a pathogenic role ofanti-phosphatidylserine (PS) autoantibodies in the development of LN. In cohort study and mouse models, elevated serum PS-specific IgG levels were detected in SLE patients, especially in those with nephritis, and lupus mice. The deposition of PS-specific IgG was detected in kidney biopsied of lupus nephritis patients. Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice. ELISPOT analysis identified B1a cells as the main cell type for secreting PS-specific IgG in both lupus mice and patients. Adoptive transfer of PS-specific B1a cells accelerated PS-specific autoimmune response and renal damage in recipient lupus mice whereas depletion of B1a cells attenuated lupus progression. In culture, PS-specific B1a cells were significantly expanded upon treatment with chromatin components while blockade of TLR signal cascades by DNase I digestion, inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells. Thus, our study has demonstrated that the novel anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development. Our findings that blockade of TLR/Syk signaling cascade inhibits PS-specific B1 cell expansion may provide new insight in understanding lupus pathogenesis and may help develop novel therapeutic targets for the treatment of LN in SLE.