Cell surface Fc receptor for IgM antibody (FcμR) is the most recently identified member among FcRs. We determined the cellular distribution of mouse FcμR and the functional consequences of Fcmr disruption. Surface FcμR expression was restricted to B-lineage cells, from immature B to plasma cells, except for a transient downmodulation during germinal center reactions. Fcmr ablation had no significant effect on overall B-and T-cell development, but led to a reduction of marginal zone B cells and an increase in splenic B1 B cells. Preimmune serum IgM in mutant mice was significantly elevated as were natural autoantibodies. When immunized with live attenuated pneumococci, mutant mice mounted robust antibody responses against phosphorylcholine, but not protein, determinants compared with wild-type mice. By contrast, upon immunization with a hapten-carrier conjugate, nitrophenyl-coupled chicken γ-globulin (NP-CGG), the mutant mice had a diminished primary IgG1 response to both NP and CGG. These findings suggest that FcμR has an important role in IgM homeostasis and regulation of humoral immune responses.natural antibody | B-cell tolerance | B-cell subset | autoimmunity

IgM exists as both a monomer on the surface of B cells and a pentamer secreted by plasma cells. Both preimmune “natural” and antigen-induced “immune” IgM antibodies are important for protective immunity and for immune regulation of autoimmune processes by recognizing pathogens and self-antigens. Effector proteins interacting with the Fc portion of IgM, such as complement and complement receptors, have thus far been proposed but fail to fully account for the IgM-mediated protection and regulation. A major reason for this deficit in our understanding of IgM function seems to be lack of data on a long elusive Fc receptor for IgM (FcμR). We have recently identified a bona fide FcμR in both humans and mice. In this article we briefly review what we have learned so far about FcμR.

IgM is the first Ig isotype to appear during phylogeny, ontogeny and the immune response. The importance of both pre-immune "natural" and antigen-induced "immune" IgM antibodies in immune responses to pathogens and self-antigens has been established by studies of mutant mice deficient in IgM secretion. Effector proteins interacting with the Fc portion of IgM, such as complement and complement receptors, have thus far been proposed, but fail to fully account for the IgM-mediated immune protection and regulation of immune responses. Particularly, the role of the Fc receptor for IgM (FcμR) in such effector functions has not been explored until recently. We have identified an authentic FcμR in humans using a functional cloning strategy and subsequently in mice by RT-PCR and describe here its salient features and the immunological consequences of FcμR deficiency in mice. Since the FcμR we cloned was identical to Toso or Fas inhibitory molecule 3 (FAIM3), there have been spirited debates regarding the real function of FcμR/Toso/FAIM3 and we will also comment on this topic.

Unlike humans, FcμR expression in mice is restricted to B cells with a hierarchy of cell surface expression level: follicular > marginal zone (MZ) > newly formed in spleen and B-2 = B-1a > B-1b in peritoneal cavity. To define the in vivo function of FcμR, Fcmr-deficient (KO) mice were generated by gene targeting. While total splenic CD19+ B and CD3+ T cell-numbers were comparable in KO and littermate control (WT) mice, MZ B cells were reduced ~4 fold and B-1 cells were increased ~2 fold in KO as compared with WT mice. Both serum IgM and IgG3 antibody (Ab) levels in naïve animals were significantly elevated in KO than WT mice. IgM and IgG3 natural Abs reacting with the nucleus or cytoplasm of HEp-2 cells were also elevated in KO mice. When immunized i.p. with a live avirulent strain of S. pneumoniae (R36A), much more robust and long-lasting IgM, IgG3 and IgA Ab-responses to phosphorylcholine developed in KO at low doses of R36A compared with WT. By contrast, when immunized i.p. with nitrophenyl (NP)-coupled chicken γ-globulin in alum, primary IgM anti-NP responses were comparable in both groups of mice, but secondary IgM responses were significantly impaired in KO mice. In contrast, the primary IgG1 anti-NP responses were impaired in KO, however secondary IgG1 responses were indistinguishable in both KO and WT mice irrespective of the antigen dose. These results show that Fcmr ablation results in altered Ab responses to both T-independent and -dependent antigens.