Sex-Specific Loss of SMS2-regulated Germinal Center B Cell Tolerance in Systemic Lupus Erythematosus 2257381

Introduction Systemic Lupus Erythematosus (SLE) is an antibody-mediated autoimmune disease with a striking female predominance. However, the mechanisms underlying this female bias remain poorly understood. Germinal Center (GC) B cell tolerance, a critical self-protective process that eliminates spontaneously generated autoreactive B cells, is essential for preventing SLE. However, whether impairment of GC B cell tolerance is sex-specific remains unclear. We previously identified the sphingomyelin synthetase 2 (SMS2)/protein kinase C δ (PKCδ) pathway as a critical regulator of GC B cell tolerance in mice, and that this pathway is impaired in lupus patients. Here, we investigated whether this impairment is specific to females using a lupus-prone mouse model. Methods Lupus prone NZBWF1 mice were used as the female bias of disease incidence is similar to that seen in humans. C57BL/6 mice were used as non-autoimmune controls. Untouched GC B cells and naïve B cells were isolated from male and female NZBWF1 mice for RT-PCR analysis of Sgms2 mRNA levels. In addition, GC and non-GC B cell SMS2 protein levels in male and female NZBWF1 mice were analyzed by flow cytometry. To understand the significance of reduced GC B cell SMS2 in lupus development, female NZBWF1 mice were treated with 2OHOA, a SMS activator, to test whether activation of the SMS2/PKCδ tolerance pathway could alleviate lupus pathogenesis. Results RT-PCR revealed that Sgms2 mRNA was significantly reduced in female NZBWF1 GC B cells when compared to males, but not in female C57BL/6 mice. Flow cytometry analysis also revealed a significant reduction in GC B cell SMS2 protein levels in female NZBWF1 mice compared to males. Activation of the SMS2/PKCδ tolerance pathway with 2OHOA significantly alleviated lupus pathogenesis in female NZBWF1 mice Conclusion These findings support that loss of GC B cell SMS2 expression is a female-specific deficit in SLE, which likely contributes to female bias in lupus.