Secreted IgM Enhances B Cell Receptor Signaling and Promotes Splenic but Impairs Peritoneal B Cell Survival

Abstract

B cell survival has a central role in maintaining immune responses to foreign organisms while curbing autoimmunity. In this study, we show that mature B cell survival is impaired and B cell turnover is accelerated in the spleen of mice lacking secreted IgM. Although in vitro responses to BCR cross-linking were normal, there was a marked reduction in basal ERK and global tyrosine phosphorylation in splenic B cells from serum IgM-deficient mice, suggesting diminished interaction with cognate Ag in vivo. The provision of BAFF either in vitro or in vivo reversed the increase in B cell apoptosis, demonstrating that other survival signals can compensate for the loss of secreted IgM in the spleen. In striking contrast to the splenic compartment, peritoneal B cell survival was enhanced in secreted IgM-deficient mice, despite a similar reduction in basal BCR signaling compared with wild type mice. These results suggest that secreted IgM acts as an adjuvant, boosting BCR signals to maintain survival and maintenance of mature splenic B cells while increasing B cell apoptosis in the peritoneum. BAFF administration mitigated the consequences of secreted IgM deficiency on B cell survival in the spleen but not in the peritoneum. This work provides new insight into the regulation of B cell signaling and homeostasis in different peripheral compartments by secreted IgM.

Natural IgM Prevents Autoimmunity by Enforcing B Cell Central Tolerance Induction

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Natural Antibodies Bridge Innate and Adaptive Immunity

“…Natural IgM also plays a role in clearing apoptotic cells (87), maintaining B cell homeostasis (88), inflammation (89,90), atherosclerosis (91), and autoimmunity (92,93). Natural IgM was proposed to bind strongly to complement factor C1q and to activate the complement cascade (85,94).…”

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“…Moreover, IgG2a and IgG3 as well as IgA plasma levels are increased in sIgM −/− mice, which also show impaired IgG antibody responses at least to suboptimal doses of a T-cell–dependent antigen. 82–85 Paradoxically, Lewis et al 81 reported decreased IgG2a/c titers against CuOx-LDL in atherosclerotic sIgM −/− Ldlr −/− mice, which may reflect increased immune complex formation with OxLDL in the absence of circulating IgM. Interestingly, infusion of polyclonal IgM into Apoe −/− mice during the last 4 weeks of a 29-week atherogenic diet has been reported to delay lesion formation, whereas infusion of a monoclonal T15id + IgM preparation failed to do so in this setting.…”