Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses

Abstract

IgM antibodies have been known for decades to enhance humoral immune responses in an antigen-specific fashion. This enhancement has been thought to be dependent on complement activation by IgM-antigen complexes; however, recent genetic studies render this mechanism unlikely. Here, we describe a likely alternative explanation; mice lacking the recently identified Fc receptor for IgM (FcμR) on B cells produced significantly less antibody to protein antigen during both primary and memory responses. This immune deficiency was accompanied by impaired germinal center formation and decreased plasma and memory B-cell generation. FcμR did not affect steady-state B-cell survival but specifically enhanced the survival and proliferation induced by B-cell receptor cross-linking. Moreover, FcμR-deficient mice produced far more autoantibodies than control mice as they aged, suggesting that FcμR is also required for maintaining tolerance to self-antigens. Our results thus define a unique pathway mediated by the FcμR for regulating immunity and tolerance and suggest that IgM antibodies promote humoral immune responses to foreign antigen yet suppress autoantibody production through at least two pathways: complement activation and FcμR.B-cell activation | autoimmune disease | complement receptor

FcμR (Toso/Faim3) is not an inhibitor of Fas-mediated cell death in mouse T and B cells

“…middle panels). Consistent with our recent studies, 5,6 FcmR was only expressed by B cells but not by thymocytes or T cells before and after activation ( Figure 1A bottom panels).…”

Involvement of Toso in activation of monocytes, macrophages, and granulocytes

“…In particular, vasculitis is associated with enhanced granulocyte activation and/or autoantibodies directed against granulocytic components (31,32). Consistent with this disease, Tosodeficient animals exhibit autoantibody formation (33). Future studies will examine the exciting possibility that Toso also influences granulocyte activation in human inflammatory diseases.…”

Function and regulation of self-reactive marginal zone B cells in autoimmune arthritis

“…30 By binding to the recently identified FcmR on B cells, secreted IgM can enhance B-cell survival and the following humoral immune response. 31 IgM also activates complement, and complement-opsonized immune complexes containing CII can be deposited on FO dendritic cells, thereby facilitating a germinal center reaction with affinity maturation and isotype switching of CII-reactive FO B cells. Indeed, this initial IgM-dominated autoimmunity observed in the spleen preceded the development of numerous IgG 1 anti-CII FO B cells, mainly residing in the lymph nodes.…”