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Better understanding of structure / function relationship of newly identified IgM Fc receptor (FcµR)

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Humoral Immune Regulation

Antibody, a key player in humoral immunity, has dual binding activities: to antigens via its amino terminal variable regions, called Fab, and to effector molecules via its carboxyl terminal constant region, called Fc. One of the effector molecules is a family of cell surface Fc receptors (FcRs). FcRs for switched antibodies (i.e., IgG, IgA, IgE) are expressed by many different immune cells and are extensively characterized as central mediators coupling innate and adaptive immune responses. Much of the knowledge gained on these FcRs has now been translated to clinical practice. By contrast, the effector function of FcR for IgM, the first antibody appearing in phylogeny, ontogeny and immune responses, has begun to be explored, since it was identified by us in 2009.

Unlike other FcRs, IgM FcR (or FcµR) is selectively expressed by lymphocytes. In humans, both bone marrow-derived (B) and thymus-derived (T) lymphocytes and to a lesser extent, natural killer (NK) lymphocytes express FcµR on their cell surface, whereas in mice, only B lymphocytes do. The lymphocyte-restricted distribution of FcµR suggests its distinct functions compared to other FcRs. FcµR may have dual signaling abilities: one through a potential, as yet unidentified, adaptor protein that non-covalently associates with the FcµR ligand-binding chain and the other through its own tyrosine and serine residues in the relatively long cytoplasmic tail of the ligand-binding chain. FcµR binds pentameric IgM ligands with high avidity in solution (trans interaction), but more efficiently binds IgM when it is attached to a membrane component via the Fab region on the same cell surface (cis engagement).

The findings from mice deficient for FcµR gene indicate its important regulatory role in development of self-reactive B cells and in production of autoantibodies as seen in patients with autoimmune or rheumatic diseases. Understanding the mode of action of the FcμR may thus provide an insight in therapeutic options to ameliorate autoantibody-mediated rheumatic diseases.

Keywords

Natural IgM
IgM Fc receptor
B cell
Tolerance
Autoantibody

Humoral Immune Regulation Prof. Dr. Hiromi Kubagawa Phone +49 (0)30 28460-782 Hiromi.Kubagawa@drfz.de more
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Prof. Hiromi Kubagawa, MD

Master students
Khlowd Al-Qaisi
Pedram Mahmoudi Aliabadi

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  • Baumgarth, Nicole, Ph.D., Professor, Center for Comparative Medicine, University of California Davis, CA, USA
  • Cooper, Max D., M.D., Professor, Department of Pathology, Medical School of Emory University, Atlanta, GA, USA
  • Kearney, John F., D.M.D, Ph.D., Professor, Department of Microbiology, School of Medicine, University of Alabama at Birmingham, AL, USA
  • Lee, Keyeong-Hee, Ph.D., Professor, Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany
  • Melchers, Fritz, Ph.D., Professor, Deutsches Rheuma-Forschungszentrum, Berlin, Germany
  • Radbruch, Andreas, Ph.D., Director and Professor, Deutsches Rheuma-Forschungszentrum, Berlin, Germany
  • Sutton, Brian, Professor, Randall Centre for Cell and Molecular Biophysics, King’s College, London, UK
  • Wang, Ji-Yang, Ph.D., Professor, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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  • Kubagawa, H., K. Honjo, N. Ohkura, S. Sakaguchi, A. Radbruch, F. Melchers, and P.K. Jani. 2019. Functional roles of the IgM Fc receptor in the immune system. Immunol. 10:945.
  • Liu, J., H. Zhu, J. Qian, E. Xiong, L. Zhang, Y. Q. Wang, Y. Chu, H. Kubagawa, T. Tsubata, and J. Y. Wang. 2018. Fcµ receptor promotes the survival and activation of marginal zone B cells and protects mice against bacterial sepsis. Immunol. 9:160.
  • Kubagawa, H., C. M. Skopnik, J. Zimmermann, P. Durek, H. D. Chang, E. Yoo, L. F. Bertoli, K. Honjo, and A. Radbruch. 2017. Authentic IgM Fc receptor (FcµR). Top. Microbiol. Immunol. 408:25-45.
  • Gupta, S., S. Agrawal, S. Gollapudi, and H. Kubagawa. 2016. FcμR in human B cell subsets in primary selective IgM deficiency, and regulation of FcμR and production of natural IgM antibodies by IGIV. Immunol. 77:1194-1201.
  • Honjo, K., Y. Kubagawa, J. F. Kearney, and H. Kubagawa. 2015. Unique ligand-binding property of the human IgM Fc receptor. Immunol. 194:1975-1982.
  • Kubagawa, H., M. C. Carroll, C. O. Jacob, K. S. Lang, K. H. Lee, T. Mak, M. McAndrews, H. C. Morse, G. P. Nolan, H. Ohno, G. H. Richter, R. Seal, J. Y. Wang, A. Wiestner, and J. E. Coligan. 2015. Nomenclature of Toso, Fas apoptosis inhibitory molecule 3, and IgM FcR. Immunol. 194:4055-4057.
  • Kubagawa, Y., K. Honjo, D. W. Kang, and H. Kubagawa. 2014. Monoclonal antibodies specific for human IgM Fc receptor inhibit ligand-binding activity. Antib. Immunodiag. Immunother. 33:393-400.
  • Honjo, K., Y. Kubagawa, Y. Suzuki, M. Takagi, H. Ohno, R. P. Bucy, S. Izui, and H. Kubagawa. 2014. Enhanced auto-antibody production and Mott cell formation in FcµR-deficient autoimmune mice. Immunol. 26:659-672.
  • Kubagawa, H., Y. Kubagawa, D. Jones, T. H. Nasti, M. R. Walter, and K. Honjo. 2014. The old but new IgM Fc receptor (FcµR). Top. Microbiol. Immunol. 382:3-28.
  • Kubagawa, H., S. Oka, Y. Kubagawa, I. Torii, E. Takayama, D. W. Kang, D. Jones, N. Nishida, T. Miyawaki, L. F. Bertoli, S. K. Sanders, and K. Honjo. 2014. The long elusive IgM Fc receptor; FcµR. Clin. Immunol. 34:S35-S45.
  • Honjo, K., Y. Kubagawa, D. M. Jones, B. Dizon, Z. Zhu, Hiroshi Ohno, S. Izui, J. F. Kearney, and H. Kubagawa. 2012. Altered Ig levels and antibody responses in mice deficient for the Fc receptor for IgM (FcµR). Natl. Acad. Sci. USA 109:15882-15887.
  • Li, F. J., Y. Kubagawa, M. K. McCollum, L. Wilson, T. Motohashi, L. F. Bertoli, J. C. Barton, S. Barnes, R. S. Davis, and H. Kubagawa. 2011. Enhanced levels of both the membrane-bound and soluble forms of IgM Fc receptor (FcµR) in patients with chronic lymphocytic leukemia. Blood 118:4902-4909.
  • Kubagawa, H., S. Oka, Y. Kubagawa, I. Torii, E. Takayama, D. W. Kang, G. L. Gartland, L. F. Bertoli, H. Mori, H. Takatsu, T. Kitamura, H. Ohno, and J. Y. Wang. 2009. Identity of the elusive IgM Fc receptor (FcµR) in humans. Exp. Med. 206:2779-2793.
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