SMS2 deficiency impairs PKCδ-regulated B cell tolerance in the germinal center

Abstract

Highlights d Sgms2 À/À and Aicda-Cre/Prkcd f/f mice exhibit similar B cell and lupus-like phenotypes d SMS2 is highly upregulated and promotes PKCd-mediated apoptosis in anti-DNA GC B cells d B cells from patients with lupus have abnormally low SMS2 expression d Pharmacologic activation of SMS2 attenuates lupus pathogenesis in NZBWF1 mice

PKCδ Protects Against Lupus Autoimmunity

“…Although lupus patients with PRKCD mutations are rare, our study of the regulation of PKCδ activity supports that a deficit in PKCδ nuclear translocation in GC B cells is actually a common abnormality in lupus [48]. We discovered that PKCδ nuclear translocation in GC B cells is activated by SMS2, whose expression is drastically decreased in lupus patients' B cells [48].…”

“…Notably, in both studies mentioned above, PKCδ nuclear translocation was found to be induced in cultured B cells, but was not in untouched naïve B cells, suggesting that some type of metabolic stress induced by culturing was promoting PKCδ nuclear localization. We reported that although naïve B cells contain much more cellular PKCδ than GC B cells, nuclear PKCδ was observed in GC B cells but was almost undetectable in naïve B cells [48], supporting that in vivo, PKCδ nuclear translocation and its tolerance activity is unique to GC B cells.…”

“…SMS has two isoforms, SMS1, which primarily resides on the Golgi membrane, and SMS2, which is prominently located on the plasma membrane [47]. However, the physiological evidence directly supporting the activation of PKCs by SMS1 or SMS2 had yet to be described, until our research group recently reported that SMS2 specifically binds to and activates PKC, but not other PKCs, in B cells [48]. PKC is a novel PKC known to prevent lupus autoimmunity in both humans and mice [49][50][51][52][53][54][55][56][57][58].…”

“…Consistently, we found that SMS2 deficient mice exhibited a similar lupus-like phenotype with reduced apoptosis in anti-dsDNA GC B cells. Therefore, we identified the SMS2/PKCδ pathway as a novel GC B cell tolerance mechanism that prevents lupus pathogenesis [48] (Figure 1), which broke new ground for understanding B cell tolerance in the GC. However, it is unclear why SMS2 expression in lupus patients' B cells is generally reduced, and further studies are required to increase our understanding of this mechanism in the future.…”

A MACS protocol for purification of untouched germinal center B cells from unimmunized or germinal center-induced mice

“…Therefore, the use of current MACS protocols is limited if GC formation is irresponsive to SRBC challenge due to gene mutations, or SRBC challenge affects the intended downstream studies. In addition, compared to FACS-purified GC B cells, the purities of MACS-isolated untouched GC B cells from immunized mice are relatively low ( Ramezani-Rad and Rickert, 2021 ), which often necessitates further enrichment by FACS via antibody labeling of MACS-enriched GC B cells, depending on the application ( Ou et al., 2021 ).…”