Secreted IgM and Its Receptors in Health and Disease PDF Download

Author: Trang Thi Thuy Nguyen
Publisher:
ISBN: 9780355150360
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Languages : en
Pages :

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Book Description
The immunoglobulin (Ig) isotype IgM is present on the surface of all developing B lymphocytes, as membrane-bound antigen-receptor (BCR). Like all Ig, it is present also in secreted form (sIgM). sIgM is generated by activated B cells following foreign antigen exposure, such as following infections, as well as spontaneously by the B-1 cell subset as “natural” sIgM, via stimulation by self-antigens. The absence of sIgM was shown previously to diminish the ability of a host to control infections with various bacterial and viral pathogens. This appeared to be due at least in part to an effect of sIgM on IgG response enhancement. Furthermore, selective deficiency of sIgM in humans and mice has been associated with antibody-mediated autoimmunity. Thus, sIgM has multiple immune-regulatory and immune-defense functions, but the mechanisms underlying these different functions are incompletely understood. The objective of this dissertation was to explore how sIgM and its receptors regulate B cell immunity. In Chapter 2, I outline studies that characterized the B cell developmental changes in mice lacking all sIgM ([mu]s[superscript –/–]). The data demonstrated that the absence of sIgM resulted in altered B cell selection during bone marrow B cell development. The resulting changes in the BCR repertoire caused the accumulation of autoreactive B cells and autoantibodies in these mice. The absence of sIgM affected all subsets of B cells. It increased marginal zone B cells and decreased follicular B cells as well as body cavity B-1 cells, and resulted in the appearance of a large population of CD5+ anergic B cells. A causal relationship between the absence of natural sIgM and these developmental defects was established by demonstrating that polyclonal IgM rescued B cell development and returned autoantibody levels to near normal. Thus, sIgM deficiency causes primary autoimmune disease by altering B cell development and selection. Chapter 3 explores how sIgM-deficiency reduces IgG responses. Adoptive transfer systems were used to distinguish effects of sIgM on B cell development and B cell activation. The studies showed that development of sIgM-deficient B cells in a sIgM-sufficient environment did not rescue normal anti-viral IgG responses to influenza virus infection and suggested a direct effect of sIgM on B cell activation. Complement receptor and Fc[alpha]/[mu]R interaction with sIgM were shown to be unlikely responsible. Instead, B cell-specific deletion of the Fc[mu]R resulted in similar reductions in virus-specific serum IgG titers as seen in [mu]s[superscript -/-] mice, as well as strongly reduced hemagglutination inhibition titers, and passive protective capacity of immune sera. Reduced IgG responses correlated with reduced antigen-specific B cell numbers early after infection and reduced short- and long-lived plasma cells and memory B cells. Provision of sIgM rescued plasma cell differentiation in [mu]s[superscript –/–] B cells, but not Fc[mu]R[superscript –/–] mice. The data identify sIgM-Fc[mu]R direct interaction on B cells as a non-redundant signal required for full B cell activation and differentiation after influenza virus infection.Chapter 4 determines how the interaction of IgM and Fc[mu]R affects B cell development and peripheral B cell homeostasis. Transfection experiments, STED microscopy and proximal ligation assays demonstrated that the Fc[mu]R receptor interacted with IgM in two distinct B cell compartments: The cell surface and the trans-Golgi network. Expression in the trans-Golgi network in developing immature B cells constrained mIgM, i.e. BCR transport and surface expression. By controlling the levels of IgM-BCR expression, the Fc[mu]R regulated the peripheral B cell pool size, the development of natural IgM-secreting B-1 cells, and prevented the formation of spontaneous germinal centers, and IgG autoantibody producing B cells. Thus, the Fc[mu]R is a critical regulator of B cell homeostasis and late B cell development.