Identity of the elusive IgM Fc receptor (FcμR) in humans

Kubagawa, Hiromi; Oka, Satoshi; Kubagawa, Yoshiki; Torii, Ikuko; Takayama, Eiji; Kang, Dong‐Won; Gartland, G. Larry; Bertoli, Luigi F.; Mori, Hiromi; Takatsu, Hiroyuki; Kitamura, Toshio; Ohno, Hiroshi; Wang, Jing

doi:10.1084/jem.20091107

Cited by 193 publications

(374 citation statements)

References 55 publications

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“…When considering this, it is surprising that the Ab response elicited by N. gonorrhoeae is poor compared with other mucosal infections and does not elicit a classical immunologic memory response that would otherwise protect upon subsequent exposure (7). B cells are APCs and express many pattern recognition molecules capable of detecting bacterial-derived products (20,(41)(42)(43)(44). Although this suggests that B cells should recognize all bacteria equally, our results unexpectedly reveal that N. gonorrhoeae has a specific tropism for the IgM memory subset of human B cells that elicits both their proliferation and a potent but broadly reactive T cell-independent Ig response.…”

Section: Discussioncontrasting

confidence: 39%

Vigorous Response of Human Innate Functioning IgM Memory B Cells upon Infection by Neisseria gonorrhoeae

Ostrowski

Gray-Owen

2012

The Journal of Immunology

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Neisseria gonorrhoeae, the cause of the sexually transmitted infection gonorrhea, elicits low levels of specific Ig that decline rapidly after the bacteria are cleared. Reinfection with the same serovar can occur, and prior gonococcal infection does not alter the Ig response upon subsequent exposure, suggesting that protective immunity is not induced. The mucosal Ig response apparent during gonorrhea does not correlate with that observed systemically, leading to a suggestion that it is locally generated. In considering whether N. gonorrhoeae directly influences B cells, we observed that gonococcal infection prolonged viability of primary human B cells in vitro and elicited robust activation and vigorous proliferative responses in the absence of T cells. Furthermore, we observed the specific expansion of IgD+CD27+ B cells in response to gonococcal infection. These cells are innate in function, conferring protection against diverse microbes by producing low-affinity, broadly reactive IgM without inducing classical immunologic memory. Although gonococcal infection of B cells produced small amounts of gonococcal-specific IgM, IgM specific for irrelevant Ags were also produced, suggesting a broad, polyspecific Ig response. The gonococci were effectively bound and engulfed by B cells. TLR9-inhibitory CpGs blocked B cell responses, indicating that intracellular bacterial degradation allows for innate immune detection within the phagolysosome. To our knowledge, this is the first report of a bacterial pathogen having specific affinity for the human IgM memory B cells, driving their potent activation and polyclonal Ig response. This unfocused T-independent response explains the localized Ig response that occurs, despite an absence of immunologic memory elicited during gonorrhea.

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Section: Discussioncontrasting

confidence: 39%

Vigorous Response of Human Innate Functioning IgM Memory B Cells upon Infection by Neisseria gonorrhoeae

Ostrowski

Gray-Owen

2012

The Journal of Immunology

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“…Although we cannot formally exclude the possibility that FcμR is expressed by a minor population of certain cell types and/or tissues, the available data indicate that FcμR predominantly regulates B-cell function in mice. In humans, FcμR was found to be expressed by B cells, T cells, and natural killer cells (16), and it is possible that human FcμR may have additional functions not present in mice. In fact, FcμR has been suggested to regulate Fas-mediated apoptosis in human T and B cells (23,24).…”

Section: Discussionmentioning

confidence: 99%

“…We would propose that this mechanism ensures that FcμR only functions in antigen-stimulated B cells, allowing it to enhance the activation of antigenspecific B cells. The cytoplasmic tail of FcμR contains potential phosphorylation motifs for protein kinase C and casein kinase C, as well as several conserved tyrosine residues (16). It remains to be elucidated how FcμR-mediated signals cooperate with BCRderived signals to promote B-cell survival.…”

Section: (Unpaired T Test) (D)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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107

154

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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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“…However, a direct interplay of the IgM RF with a receptor that could strengthen the interaction of cells with IgM RF-containing IC had not been excluded. To rule this out, and because it had not previously been reported, we investigated whether our in vitro M-CSF-generated macrophages expressed the recently identified hematopoietic receptors for IgM Fc, that is, the receptor Fca/mR recognizing both IgA and IgM, and the strictly IgM-specific receptor FcmR (41,42). Our analyses used validated mAbs (41,49).…”

Section: Discussionmentioning

confidence: 99%

IgM and IgA Rheumatoid Factors Purified from Rheumatoid Arthritis Sera Boost the Fc Receptor– and Complement-Dependent Effector Functions of the Disease-Specific Anti–Citrullinated Protein Autoantibodies

Anquetil

Clavel

Offer

et al. 2015

The Journal of Immunology

106

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Rheumatoid factors (RF) and the disease-specific anti–citrullinated protein autoantibodies (ACPA) coexist in the joints of rheumatoid arthritis (RA) patients where they probably contribute to synovitis. We investigated the influence of IgM and IgA RF on the FcR- and complement-dependent effects of ACPA immune complexes (ACPA-IC). When stimulated by ACPA-IC formed in the presence of IgM RF or IgA RF fractions purified from RA serum pools, M-CSF–generated macrophages skewed their cytokine response toward inflammation, with increases in the TNF-α/IL-10 ratio and in IL-6 and IL-8 secretion, and decreases in the IL-1Ra/IL-1β ratio. In the IgM RF-mediated amplification of the inflammatory response of macrophages, the participation of an IgM receptor was excluded, notably by showing that they did not express any established receptor for IgM. Rather, this amplification depended on the IgM RF-mediated recruitment of more IgG into the ACPA-IC. However, the macrophages expressed FcαRI and blocking its interaction with IgA inhibited the IgA RF-mediated amplification of TNF-α secretion induced by ACPA-IC, showing its major implication in the effects of RF of the IgA class. LPS further amplified the TNF-α response of macrophages to RF-containing ACPA-IC. Lastly, the presence of IgM or IgA RF increased the capacity of ACPA-IC to activate the complement cascade. Therefore, specifically using autoantibodies from RA patients, the strong FcR-mediated or complement-dependent pathogenic potential of IC including both ACPA and IgM or IgA RF was established. Simultaneous FcR triggering by these RF-containing ACPA-IC and TLR4 ligation possibly makes a major contribution to RA synovitis.

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Identity of the elusive IgM Fc receptor (FcμR) in humans

Cited by 193 publications

References 55 publications

Vigorous Response of Human Innate Functioning IgM Memory B Cells upon Infection by Neisseria gonorrhoeae

Vigorous Response of Human Innate Functioning IgM Memory B Cells upon Infection by Neisseria gonorrhoeae

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

IgM and IgA Rheumatoid Factors Purified from Rheumatoid Arthritis Sera Boost the Fc Receptor– and Complement-Dependent Effector Functions of the Disease-Specific Anti–Citrullinated Protein Autoantibodies

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