Critical Role Of The Igm Fc Receptor In Igm Homeostasis, B-Cell Survival, And Humoral Immune Responses

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 (Fc mu R) 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. Fc mu R did not affect steady-state B-cell survival but specifically enhanced the survival and proliferation induced by B-cell receptor cross-linking. Moreover, Fc mu R-deficient mice produced far more autoantibodies than control mice as they aged, suggesting that Fc mu R is also required for maintaining tolerance to self-antigens. Our results thus define a unique pathway mediated by the Fc mu R 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 Fc mu R.