Baker, N.D.V.; (2005) The role of serum IGM in immunity and autoimmunity. Doctoral thesis , University of London.

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Abstract

Natural IgM has a wide range of actions in the immune system, is the first class of antibody to be produced, provides immediate defence against infection and assists subsequent development of the immune response. IgM is a potent complement activator, because of its pentameric structure and can have stable interactions with polymeric antigens. Here I investigated the effects of serum IgM deficiency on B cell development. Mice lacking serum IgM (Su-) have an expansion in marginal zone (MZ) B cells with a corresponding reduction in follicular (FO) B cells. This expansion in MZ B cells is further accentuated in response to T-independent antigens. I have found that the increase in MZ/FO B cell ratio (and the expansion of peritoneal B1 cells) is fully reversed by administration of polyclonal, but not monoclonal, IgM. Natural IgM, by virtue of its polyreactivity, may enhance antigen driven signalling through the B cell receptor (BCR) and promote the formation of FO B cells. Conversely, in the absence of serum IgM, BCR signalling is reduced and MZ B cells are preferentially formed. In the absence of serum IgM, splenic follicular B cells have a shortened life span whereas peritoneal B1 B cells have a longer life span. However proliferation, and calcium mobilisation in response to BCR crosslinking in vitro is normal. These results demonstrate that natural IgM regulates the selection of B lymphocyte subsets in the periphery. It was previously shown that S i mice have an increased propensity for developing IgG autoantibodies. In order to determine whether serum IgM deficiency accelerates autoimmunity, Su- mice were intercrossed into C57Black/6/pr mutant mice, which develop mild autoimmunity and lymphadenopathy. It was found that splenic marginal zone B cell numbers were further increased in the Ipr serum IgM deficient (S i-lpr) mice. This increase in MZ B cells is associated with more severe lymphadenopathy, but not with worsening autoimmunity. Furthermore, the autoimmunity observed in these mice does not appear to be as a direct consequence of MZ B cell expansion.

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