Identification of TOSO/FAIM3 as an Fc receptor for IgM

Shima, Hideaki; Takatsu, Hiroyuki; Fukuda, Shinji; Ohmae, Masumi; Hase, Koji; Kubagawa, Hiromi; Wang, Ji Yang; Ohno, Hiroshi

doi:10.1093/intimm/dxp121

Cited by 115 publications

(98 citation statements)

References 32 publications

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“…These results reveal a critical role for FcμR in B-cell survival following antigen stimulation and humoral immune responses. One unique feature of FcμR is its specific expression on B cells in mice, as shown by FACS analysis in our previous (17) and current studies. Consistently, microarray analysis revealed that Fcmr transcripts were only detectable in isolated B cells, as well as in spleen and lymph node tissues, but not in any other mouse tissues or cell types examined.…”

Section: Discussionsupporting

confidence: 69%

“…Our previous studies revealed that FcμR was expressed in B cells but not in T cells, dendritic cells, and macrophages in mice (17). We further analyzed FcμR expression during B-cell development, maturation, and activation.…”

Section: Resultsmentioning

confidence: 95%

“…The existence of an Fc receptor for IgM (FcμR) was first suggested 40 y ago (13)(14)(15), but its gene identity was revealed only recently (16,17). FcμR is unique among FcRs in that it is expressed only by lymphoid cells, B cells in mice, and B and T cells in humans (16,17).…”

mentioning

confidence: 99%

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

Ouchida

Mori

Hase³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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

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Section: Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 95%

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

Ouchida

Mori

Hase³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

109

154

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“…For example, the role of IgM might be linked to its binding to a putative Fc receptor (47)(48)(49) or perhaps attributable to simple aggregation of the Ag, thereby making it more immunogenic. Moreover, mice lacking secretory IgM have developmental defects in their B-cell compartment secondary to the lack of secretory IgM, and it is conceivable that this explains their impaired Ab responses (37,50).…”

Section: Discussionmentioning

confidence: 99%

Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

Rutemark

Alicot

Bergman

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Animals lacking complement factors C1q, C2, C3, or C4 have severely impaired Ab responses, suggesting a major role for the classic pathway. The classic pathway is primarily initiated by antigen–Ab complexes. Therefore, its role for primary Ab responses seems paradoxical because only low amounts of specific Abs are present in naive animals. A possible explanation could be that the classic pathway is initiated by IgM from naive mice, binding with sufficient avidity to the antigen. To test this hypothesis, a knock-in mouse strain, Cμ13, with a point mutation in the gene encoding the third constant domain of the μ-heavy chain was constructed. These mice produce IgM in which proline in position 436 is substituted with serine, a mutation previously shown to abrogate the ability of mouse IgM to activate complement. Unexpectedly, the Ab response to sheep erythrocytes and keyhole limpet hemocyanin in Cμ13 mice was similar to that in WT mice. Thus, although secreted IgM and the classic pathway activation are both required for the normal primary Ab response, this does not require that IgM activate C. This led us to test Ab responses in animals lacking one of three other endogenous activators of the classic pathway: specific intracellular adhesion molecule-grabbing nonintegrin R1, serum amyloid P component, and C-reactive protein. Ab responses were also normal in these animals.

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“…Furthermore, since monomeric IgM is the only virgin B-cell receptor in swine, pigs lacking IgD [39], IgM cleavage might inhibit B-cell activation and thus have far reaching consequences for cell mediated immunity. It has been shown that FcµR, expressed on B-lymphocytes, is an uptake receptor for IgM labeled pathogens [40]. It is therefore reasonable to assume that cleavage of IgM bound to the bacterial surface might hinder uptake of IgM labeled bacteria by B-lymphocytes and thus encumber their antigen presenting ability.…”

Section: Discussionmentioning

confidence: 99%

IgM cleavage by Streptococcus suis reduces IgM bound to the bacterial surface and is a novel complement evasion mechanism

et al. 2018

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Streptococcus suis (S. suis) causes meningitis, arthritis and endocarditis in piglets. The aim of this study was to characterize the IgM degrading enzyme of S. suis (IdeSsuis) and to investigate the role of IgM cleavage in evasion of the classical complement pathway and pathogenesis. Targeted mutagenesis of a cysteine in the putative active center of IdeSsuis abrogated IgM cleavage completely. In contrast to wt rIdeSsuis, point mutated rIdeSsuis_C195S did not reduce complement-mediated hemolysis indicating that complement inhibition by rIdeSsuis depends on the IgM proteolytic activity. A S. suis mutant expressing IdeSsuis_C195S did not reduce IgM labeling, whereas the wt and complemented mutant showed less IgM F(ab’)2 and IgM Fc antigen on the surface. IgM cleavage increased survival of S. suis in porcine blood ex vivo and mediated complement evasion as demonstrated by blood survival and C3 deposition assays including the comparative addition of rIdeSsuis and rIdeSsuis_C195S. However, experimental infection of piglets disclosed no significant differences in virulence between S. suis wt and isogenic mutants without IgM cleavage activity. This work revealed for the first time in vivo labeling of S. suis with IgM in the cerebrospinal fluid of piglets with meningitis. In conclusion, this study classifies IdeSsuis as a cysteine protease and emphasizes the role of IgM cleavage for bacterial survival in porcine blood and complement evasion though IgM cleavage is not crucial for the pathogenesis of serotype 2 meningitis.

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Identification of TOSO/FAIM3 as an Fc receptor for IgM

Cited by 115 publications

References 32 publications

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

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

Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

IgM cleavage by Streptococcus suis reduces IgM bound to the bacterial surface and is a novel complement evasion mechanism

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