Abstract
Immunoglobulin (Ig) M is the first antibody isotype produced during an immune response and is critical for host defense against infections. Recent studies have revealed that IgM also plays an important role in immune regulation and immunological tolerance. Mice lacking secretory IgM not only exhibit impaired production of antigen-specific IgG and are more susceptible to bacterial and viral infections, but also produce autoantibodies and are prone to develop autoimmune diseases. For many years, IgM has been thought to function predominantly by binding to antigen and activating complement (C′) system. It is now clear that IgM can also elicit its function through the IgM Fc receptor (FcμR). In this chapter, we will review the role of FcμR in B cell development, maturation, survival and activation, antibody production, host defense against bacterial and viral infections, and B cell tolerance. We will also discuss the relative contribution of IgM-C′ and IgM-FcμR pathways in humoral immune responses. Finally, we will discuss the possible involvement of FcμR in human chronic lymphocytic leukemia.
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References
Baker N, Ehrenstein MR (2002) Cutting edge: selection of B lymphocyte subsets is regulated by natural IgM. J Immunol 169(12):6686–6690
Boyden SV (1966) Natural antibodies and the immune response. Adv Immunol 5:1–28
Brenner D, Brustle A, Lin GH, Lang PA, Duncan GS, Knobbe-Thomsen CB et al (2014) Toso controls encephalitogenic immune responses by dendritic cells and regulatory T cells. Proc Natl Acad Sci USA 111(3):1060–1065. https://doi.org/10.1073/pnas.1323166111
Burns GF, Cawley JC, Barker CR (1979) Characterization of the receptor for IgM present on human B lymphocytes. Immunology 36(3):569–577
Carroll MC (2008) Complement and humoral immunity. Vaccine 26 Suppl 8:I28–I33. https://doi.org/10.1016/j.vaccine.2008.11.022
Choi SC, Wang H, Tian L, Murakami Y, Shin DM, Borrego F et al (2013) Mouse IgM Fc receptor, FCMR, promotes B cell development and modulates antigen-driven immune responses. J Immunol 190(3):987–996. https://doi.org/10.4049/jimmunol.1202227
Daëron M (2014) Fc receptors as adaptive immunoreceptors. Curr Top Microbiol Immunol 382:131–164. https://doi.org/10.1007/978-3-319-07911-0_7
Dharmadhikari G, Muhle M, Schulthess FT, Laue S, Oberholzer J, Pattou F et al (2012) TOSO promotes beta-cell proliferation and protects from apoptosis. Mol Metab 1(1–2):70–78. https://doi.org/10.1016/j.molmet.2012.08.006
Ding Z, Bergman A, Rutemark C, Ouchida R, Ohno H, Wang JY et al (2013) Complement-activating IgM enhances the humoral but not the T cell immune response in mice. PLoS One 8(11):e81299. https://doi.org/10.1371/journal.pone.0081299
Dorner T, Radbruch A (2007) Antibodies and B cell memory in viral immunity. Immunity 27(3):384–392. https://doi.org/10.1016/j.immuni.2007.09.002
Ehrenstein MR, Notley CA (2010) The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol 10(11):778–786. https://doi.org/10.1038/nri2849
Engels N, Konig LM, Heemann C, Lutz J, Tsubata T, Griep S et al (2009) Recruitment of the cytoplasmic adaptor Grb2 to surface IgG and IgE provides antigen receptor-intrinsic costimulation to class-switched B cells. Nat Immunol 10(9):1018–1025. https://doi.org/10.1038/ni.1764
Engels N, Wienands J (2011) The signaling tool box for tyrosine-based costimulation of lymphocytes. Curr Opin Immunol 23(3):324–329. https://doi.org/10.1016/j.coi.2011.01.005
Faitschuk E, Hombach AA, Frenzel LP, Wendtner CM, Abken H (2016) Chimeric antigen receptor T cells targeting Fc mu receptor selectively eliminate CLL cells while sparing healthy B cells. Blood 128(13):1711–1722. https://doi.org/10.1182/blood-2016-01-692046
Fellah JS, Wiles MV, Charlemagne J, Schwager J (1992) Evolution of vertebrate IgM: complete amino acid sequence of the constant region of Ambystoma mexicanum mu chain deduced from cDNA sequence. Eur J Immunol 22(10):2595–2601. https://doi.org/10.1002/eji.1830221019
Ferrarini M, Hoffman T, Fu SM, Winchester R, Kunkel HG (1977) Receptors for IgM on certain human B lymphocytes. J Immunol 119(4):1525–1529
Hancer VS, Diz-Kucukkaya R, Aktan M (2012) Overexpression of Fc mu receptor (FCMR, TOSO) gene in chronic lymphocytic leukemia patients. Med Oncol 29(2):1068–1072. https://doi.org/10.1007/s12032-011-9821-3
Heyman B, Pilström L, Shulman MJ (1988) Complement activation is required for IgM-mediated enhancement of the antibody response. J Exp Med 167(6):1999–2004. https://doi.org/10.1084/jem.167.6.1999
Hitoshi Y, Lorens J, Kitada SI, Fisher J, LaBarge M, Ring HZ et al (1998) Toso, a cell surface, specific regulator of Fas-induced apoptosis in T cells. Immunity 8(4):461–471
Honda S, Sato K, Totsuka N, Fujiyama S, Fujimoto M, Miyake K et al (2016) Marginal zone B cells exacerbate endotoxic shock via interleukin-6 secretion induced by Fcalpha/muR-coupled TLR4 signalling. Nat Commun 7:11498. https://doi.org/10.1038/ncomms11498
Honjo K, Kubagawa Y, Jones DM, Dizon B, Zhu Z, Ohno H et al (2012a) Altered Ig levels and antibody responses in mice deficient for the Fc receptor for IgM (FcmuR). Proc Natl Acad Sci USA 109(39):15882–15887. https://doi.org/10.1073/pnas.1206567109
Honjo K, Kubagawa Y, Kubagawa H (2012b) Is Toso an antiapoptotic protein or an Fc receptor for IgM? Blood 119(7):1789–1790. https://doi.org/10.1182/blood-2011-09-380782
Honjo K, Kubagawa Y, Kearney JF, Kubagawa H (2015) Unique ligand-binding property of the human IgM Fc receptor. J Immunol 194(4):1975–1982. https://doi.org/10.4049/jimmunol.1401866
Honjo K, Kubagawa Y, Suzuki Y, Takagi M, Ohno H, Bucy RP et al (2014) Enhanced auto-antibody production and Mott cell formation in FcmuR-deficient autoimmune mice. Int Immunol 26(12):659–672. https://doi.org/10.1093/intimm/dxu070
Ikuta K, Takami M, Kim CW, Honjo T, Miyoshi T, Tagaya Y et al (1987) Human lymphocyte Fc receptor for IgE: sequence homology of its cloned cDNA with animal lectins. Proc Natl Acad Sci USA 84(3):819–823
Kaetzel CS, Robinson JK, Chintalacharuvu KR, Vaerman JP, Lamm ME (1991) The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA. Proc Natl Acad Sci USA 88(19):8796–8800
Kikutani H, Inui S, Sato R, Barsumian EL, Owaki H, Yamasaki K et al (1986) Molecular structure of human lymphocyte receptor for immunoglobulin E. Cell 47(5):657–665
Kinet JP (1989) Antibody-cell interactions: Fc receptors. Cell 57(3):351–354
Kubagawa H, Kubagawa Y, Jones D, Nasti TH, Walter MR, Honjo K (2014a) The old but new IgM Fc receptor (FcmuR). Curr Top Microbiol Immunol 382:3–28. https://doi.org/10.1007/978-3-319-07911-0_1
Kubagawa H, Oka S, Kubagawa Y, Torii I, Takayama E, Kang DW et al (2014b) The long elusive IgM Fc receptor, FcmuR. J Clin Immunol 34(Suppl 1):S35–S45. https://doi.org/10.1007/s10875-014-0022-7
Kubagawa H, Oka S, Kubagawa Y, Torii I, Takayama E, Kang DW et al (2009) Identity of the elusive IgM Fc receptor (FcmuR) in humans. J Exp Med 206(12):2779–2793. https://doi.org/10.1084/jem.20091107
Kubagawa H, Skopnik CM, Zimmermann J, Durek P, Chang HD, Yoo E et al (2017) Authentic IgM Fc Receptor (FcmuR). Curr Top Microbiol Immunol 408:25–45. https://doi.org/10.1007/82_2017_23
Lamon EW, Andersson B, Whitten HD, Hurst MM, Ghanta V (1976) IgM complex receptors on subpopulations of murine lymphocytes. J Immunol 116(5):1199–1203
Lang KS, Lang PA, Meryk A, Pandyra AA, Boucher LM, Pozdeev VI et al (2013) Involvement of Toso in activation of monocytes, macrophages, and granulocytes. Proc Natl Acad Sci USA 110(7):2593–2598. https://doi.org/10.1073/pnas.1222264110
Lang PA, Meryk A, Pandyra AA, Brenner D, Brustle A, Xu HC et al (2015) Toso regulates differentiation and activation of inflammatory dendritic cells during persistence-prone virus infection. Cell Death Differ 22(1):164–173. https://doi.org/10.1038/cdd.2014.138
Lapke N, Tartz S, Lee KH, Jacobs T (2015) The application of anti-Toso antibody enhances CD8(+) T cell responses in experimental malaria vaccination and disease. Vaccine 33(48):6763–6770. https://doi.org/10.1016/j.vaccine.2015.10.065
Li FJ, Kubagawa Y, McCollum MK, Wilson L, Motohashi T, Bertoli LF et al (2011) Enhanced levels of both the membrane-bound and soluble forms of IgM Fc receptor (FcmuR) in patients with chronic lymphocytic leukemia. Blood 118(18):4902–4909. https://doi.org/10.1182/blood-2011-04-350793
Liu J, Zhu H, Qian J, Xiong E, Zhang L, Wang YQ et al (2018) Fcmicro receptor promotes the survival and activation of marginal zone B cells and protects mice against bacterial sepsis. Front Immunol 9:160. https://doi.org/10.3389/fimmu.2018.00160
Liu J, Wang Y, Xiong E, Hong R, Lu Q, Ohno H et al (2019) Role of the IgM Fc receptor in immunity and tolerance. Front Immunol 10:529. https://doi.org/10.3389/fimmu.2019.00529
Ludin C, Hofstetter H, Sarfati M, Levy CA, Suter U, Alaimo D et al (1987) Cloning and expression of the cDNA coding for a human lymphocyte IgE receptor. EMBO J 6(1):109–114
Moretta L, Ferrarini M, Durante ML, Mingari MC (1975) Expression of a receptor for IgM by human T cells in vitro. Eur J Immunol 5(8):565–569. https://doi.org/10.1002/eji.1830050812
Mostov KE (1994) Transepithelial transport of immunoglobulins. Annu Rev Immunol 12:63–84. https://doi.org/10.1146/annurev.iy.12.040194.000431
Nguyen TT, Klasener K, Zurn C, Castillo PA, Brust-Mascher I, Imai DM et al (2017a) The IgM receptor FcmuR limits tonic BCR signaling by regulating expression of the IgM BCR. Nat Immunol 18(3):321–333. https://doi.org/10.1038/ni.3677
Nguyen TTT, Graf BA, Randall TD, Baumgarth N (2017b) sIgM-FcmuR interactions regulate early B cell activation and plasma cell development after influenza virus infection. J Immunol 199(5):1635–1646. https://doi.org/10.4049/jimmunol.1700560
Nguyen XH, Lang PA, Lang KS, Adam D, Fattakhova G, Foger N et al (2011) Toso regulates the balance between apoptotic and nonapoptotic death receptor signaling by facilitating RIP1 ubiquitination. Blood 118(3):598–608. https://doi.org/10.1182/blood-2010-10-313643
Notley CA, Baker N, Ehrenstein MR (2010) Secreted IgM enhances B cell receptor signaling and promotes splenic but impairs peritoneal B cell survival. J Immunol 184(7):3386–3393. https://doi.org/10.4049/jimmunol.0902640
Ouchida R, Lu Q, Liu J, Li Y, Chu Y, Tsubata T et al (2015) FcmuR interacts and cooperates with the B cell receptor to promote B cell survival. J Immunol 194(7):3096–3101. https://doi.org/10.4049/jimmunol.1402352
Ouchida R, Mori H, Hase K, Takatsu H, Kurosaki T, Tokuhisa T et al (2012a) Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses. Proc Natl Acad Sci USA 109(40):E2699–E2706. https://doi.org/10.1073/pnas.1210706109
Ouchida R, Mori H, Hase K, Takatsu H, Kurosaki T, Tokuhisa T, Ohno H, Wang J-Y (2012b) Critical role of the IgM Fc receptor in IgM homeostasis, B cell survival and humoral immune responses. Proc Natl Acad Sci USA 109:15989–15990 (Author Summary)
Ouchida R, Mori H, Ohno H, Wang JY (2013) FcmuR (Toso/Faim3) is not an inhibitor of Fas-mediated cell death in mouse T and B cells. Blood 121(12):2368–2370. https://doi.org/10.1182/blood-2012-12-470906
Pallasch CP, Schulz A, Kutsch N, Schwamb J, Hagist S, Kashkar H et al (2008) Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease. Blood 112(10):4213–4219. https://doi.org/10.1182/blood-2008-05-157255
Pichler WJ, Knapp W (1977) Receptors for IgM-coated erythrocytes on chronic lymphatic leukemia cells. J Immunol 118(3):1010–1015
Proto-Siqueira R, Panepucci RA, Careta FP, Lee A, Clear A, Morris K et al (2008) SAGE analysis demonstrates increased expression of TOSO contributing to Fas-mediated resistance in CLL. Blood 112(2):394–397. https://doi.org/10.1182/blood-2007-11-124065
Rutemark C, Alicot E, Bergman A, Ma M, Getahun A, Ellmerich S et al (2011) Requirement for complement in antibody responses is not explained by the classic pathway activator IgM. Proc Natl Acad Sci USA 108(43):E934–E942. https://doi.org/10.1073/pnas.1109831108
Schneeman TA, Bruno ME, Schjerven H, Johansen FE, Chady L, Kaetzel CS (2005) Regulation of the polymeric Ig receptor by signaling through TLRs 3 and 4: linking innate and adaptive immune responses. J Immunol 175(1):376–384
Shibuya A, Honda S (2006) Molecular and functional characteristics of the Fcalpha/muR, a novel Fc receptor for IgM and IgA. Springer Semin Immunopathol 28(4):377–382. https://doi.org/10.1007/s00281-006-0050-3
Shibuya A, Honda S (2015) Immune regulation by Fcalpha/mu receptor (CD351) on marginal zone B cells and follicular dendritic cells. Immunol Rev 268(1):288–295. https://doi.org/10.1111/imr.12345
Shibuya A, Honda SI, Shibuya K (2017) A pro-inflammatory role of Fcalpha/muR on marginal zone B cells in sepsis. Int Immunol 29(11):519–524. https://doi.org/10.1093/intimm/dxx059
Shibuya A, Sakamoto N, Shimizu Y, Shibuya K, Osawa M, Hiroyama T et al (2000) Fc alpha/mu receptor mediates endocytosis of IgM-coated microbes. Nat Immunol 1(5):441–446. https://doi.org/10.1038/80886
Shima H, Takatsu H, Fukuda S, Ohmae M, Hase K, Kubagawa H et al (2010) Identification of TOSO/FAIM3 as an Fc receptor for IgM. Int Immunol 22(3):149–156. https://doi.org/10.1093/intimm/dxp121
Sörman A, Heyman B (2017) Specific IgM and regulation of antibody responses. Curr Top Microbiol Immunol 408:67–87. https://doi.org/10.1007/82_2017_24
Stadtmueller BM, Huey-Tubman KE, Lopez CJ, Yang Z, Hubbell WL, Bjorkman PJ (2016) The structure and dynamics of secretory component and its interactions with polymeric immunoglobulins. Elife 5. https://doi.org/10.7554/eLife.10640
Turula H, Wobus CE (2018) The role of the polymeric immunoglobulin receptor and secretory immunoglobulins during mucosal infection and immunity. Viruses 10(5). https://doi.org/10.3390/v10050237
Vire B, David A, Wiestner A (2011) TOSO, the Fcmicro receptor, is highly expressed on chronic lymphocytic leukemia B cells, internalizes upon IgM binding, shuttles to the lysosome, and is downregulated in response to TLR activation. J Immunol 187(8):4040–4050. https://doi.org/10.4049/jimmunol.1100532
Wang H, Coligan JE, Morse HC 3rd (2016) Emerging functions of natural IgM and its Fc receptor FCMR in immune homeostasis. Front Immunol 7:99. https://doi.org/10.3389/fimmu.2016.00099
Yi S, Yu Z, Zhou K, Wang Y, An G, Li Z et al (2011) TOSO is overexpressed and correlated with disease progression in Chinese patients with chronic lymphocytic leukemia. Leuk Lymphoma 52(1):72–78. https://doi.org/10.3109/10428194.2010.531411
Yu J, Duong VHH, Westphal K, Westphal A, Suwandi A, Grassl GA et al (2018) Surface receptor Toso controls B cell-mediated regulation of T cell immunity. J Clin Invest 128(5):1820–1836. https://doi.org/10.1172/jci97280
Acknowledgements
We thank Lumin Zhang for secretarial assistance and the members in Wang lab for helpful suggestions. This work was supported by the Major Research Plan of the National Natural Science Foundation of China (91942302 to J.Y.W.), the National Key R & D Plan of the Ministry of Science and Technology (SQ2019YFE0100600 to J.Y.W.), the National Natural Science Foundation of China (81571529 and 31870898 to J.Y.W), Projects of International Cooperation and Exchanges NSFC (81811540035 to J.Y.W.), a grant-in-aid for scientific research (C) from Japan Society for the Promotion of Science (17K08878 to J.Y.W), China Postdoctoral Science Foundation Grant (2018M641929 to J.L.), and National Natural Science Foundation for Young Scholar (81901594 to J.L.).
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Liu, J., Wang, Y., Min, Q., Xiong, E., Heyman, B., Wang, JY. (2020). Regulation of Humoral Immune Responses and B Cell Tolerance by the IgM Fc Receptor (FcμR). In: Wang, JY. (eds) B Cells in Immunity and Tolerance. Advances in Experimental Medicine and Biology, vol 1254. Springer, Singapore. https://doi.org/10.1007/978-981-15-3532-1_7
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