Natural IgM and the Development of B Cell-Mediated Autoimmune Diseases

Abstract

Most serum immunoglobulin M (IgM) is “natural IgM,” which is produced apparently spontaneously by a distinct subset of B cells requiring no exogenous antigenic or microbial stimuli. Natural IgM is an evolutionarily conserved molecule and reacts with a variety of epitopes expressed on both self- and non-self antigens. It has long been understood that secreted (s) IgM contributes to the removal of altered self-antigens, such as apoptotic and dying cells. As we outline in this review, it is thought that this sIgM housekeeping function removes potential triggers of autoresponse induction. However, we recently demonstrated an unexpected and distinct role for sIgM in the control of autoreactive B cells: the regulation of bone marrow B cell development. The absence of sIgM blocked pro- to pre- B-cell transition and greatly altered the BCR repertoire of the developing B cells and the peripheral B-cell pools in genetically engineered mice. This finding strongly suggests that IgM is critical for B-cell central tolerance induction. Given that treatment of sIgM-deficient mice with polyclonal IgM corrected these developmental defects, therapeutic application of IgM could be of clinical relevance in the treatment of some B-cell–mediated autoimmune diseases.

Secreted IgM: New tricks for an old molecule

“…Using Ig‐allotype‐disparate B cells, we were able to differentiate sIgM binding from IgM–BCR surface expression and showed constitutive binding of sIgM onto the cell surface of B cells in vivo, which was reduced in the absence of the FcµR . Studies in transfected HeLa cells, as well as primary mouse B cells, showed that sIgM binding to surface‐expressed FcµR caused the rapid internalization and degradation of the complex through the endocytic pathway, a process that in CLL was shown to depend on the state of FcµR glycosylation . Interestingly, some sIgM uptake was shown to occur also in the absence of the FcµR, suggesting that not all sIgM internalization is mediated by the FcµR .…”

“…The polymeric immunoglobulin receptor (pIgR) is a highly conserved glycosylated receptor of about 81 kDa that is expressed principally by mucosal epithelial cells. The receptor binds both, dimeric IgA as well as pentameric sIgM via recognition of the J‐chain . The main function of the pIgR appears to be linked to the transepithelial transport of dimeric IgA, generated by plasma cells in the mucosal lamina propria, across the epithelial cell layer.…”

“…Studies in transfected HeLa cells, as well as primary mouse B cells, showed that sIgM binding to surface‐expressed FcµR caused the rapid internalization and degradation of the complex through the endocytic pathway, a process that in CLL was shown to depend on the state of FcµR glycosylation . Interestingly, some sIgM uptake was shown to occur also in the absence of the FcµR, suggesting that not all sIgM internalization is mediated by the FcµR . Recent studies showed rapid FcµR‐mediated sIgM internalization by human CD4 T cells .…”

“…Complement receptors 1 and 2 (CD35/CD21) are primarily expressed on B cells and on follicular dendritic cells (FDCs). 114,115 Complement receptor engagement has been shown to be critically involved in the induction of maximal antibody responses following immunization (reviewed in Ref. 116).…”

The five dimensions of B cell tolerance

“…Normal individuals produce F I G U R E 2 Tolerance by clonal deletion in ABO-incompatible transplantation. 39 43,44 IgM autoantibodies control complement activation, do not mediate cytolysis at 37°C and scavenge C3 and C4 complement components. The figure depicts an example.…”