Better understanding of structure / function relationship of newly identified IgM Fc receptor
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 Fc receptors (FcRs). FcRs for switched antibodies (i.e., FcγRs, FcεRs, FcαR) are expressed by many different immune cells including myeloid cells and are extensively characterized as central mediators coupling innate and adaptive immune responses. Much of the knowledge gained 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, FcµR is selectively expressed by lymphocytes (B, T and NK cells in humans and only B cells in mice), suggesting distinct functions compared to other FcRs. FcµR may have a dual signaling ability: one through a potential as yet unidentified adaptor protein non-covalently associating with the FcµR ligand-binding chain and the other through its own Tyr/Ser residues in the cytoplasmic tail. FcµR binds pentameric IgM with a high avidity (~10 nM) in solution, 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 four different FcµR-deficient mice clearly indicate an important regulatory role of FcµR in development of autoreactive B cells and in production of autoantibodies. We propose a model how FcµR on B cells regulates autoreactive B cells developing in the bone marrow by cis engagement of FcµR and IgM B cell receptor via IgM-opsonized self-antigens. Understanding the mode of action of the FcμR may thus provide an insight in therapeutic options to ameliorate autoantibody-mediated rheumatic diseases.
Prof. Hiromi Kubagawa, MD
Eduardo Vieyra Olguin
Gupta, Sudhir, M.D., Ph.D., Professor, University of California at Irvine, Division of Basic and Clinical Immunology, USA
Honjo, Kazuhito, D.V.M., University of Alabama at Birmingham, Department of Medicine, USA
Kearney, John F., D.M.D, Ph.D., Professor, UAB, Department of Microbiology, USA
Vivarelli, Marina, M.D., Bombino Gesù Children’s Hospital-Scientific Institute, Division of Nephrology and Dialysis, Italy
Walter, Mark, R., Ph.D., Professor, UAB, Department of Microbiology, USA
Honjo, K., Y. Kubagawa, J. F. Kearney, and H. Kubagawa. 2015. Unique ligand-binding property of the human IgM Fc receptor. J. 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. J. Immunol. 194:4055-4057.
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. Hum. Immunol. 77:1194-1201.