Abstract
Most natural IgM antibodies are encoded by germline Ig sequences and are produced in large quantities by both mice and humans in the absence of intentional immunization. Natural IgM are reactive with many conserved epitopes, including those shared by microorganisms and autoantigens. As a result, these antibodies play important roles in clearing intruding pathogens, as well as apoptotic/necrotic cells and otherwise damaged tissues. While natural IgM binds to target structures with low affinity due to a lack of significant selection by somatic hypermutation, its pentameric structure with 10 antigen-binding sites enables these antibodies to bind multivalent target antigens with high avidity. Opsonization of antigen complexed with IgM is mediated by cell surface Fc receptors. While the existence of Fc alpha/mu receptor has been known for some time, only recently has the Fc receptor specific for IgM (FCMR) been identified. In this review, we focus on our current understandings of how natural IgM and FCMR regulate the immune system and maintain homeostasis under physiological and pathological conditions.
Highlights
Studies of IgG antibodies produced in response to foreign antigens have provided a wealth of information about the mechanisms involved in generating a seemingly limitless array of antigen-binding specificities by diversification of their antigen-binding domains through somatic recombination and mutation
Because it is impossible to separate the effects of natural IgM from immune IgM when we evaluate the consequences of interactions between FCMR and an IgM molecule in non-immunized individuals; in this review, serum secreted IgM (sIgM) is taken to be synonymous to natural IgM
Injection of sIgM into Sμ−/− mice before immunization increased NP-specific IgG1 responses [25]. These results suggest that sIgM could augment TD humoral responses, but whether this was mediated by sIgM-mediated antigen processing/presentation, or FCMR-mediated signaling that renders B cells hyperresponsive to activation signals, or both, remains to be determined
Summary
Studies of IgG antibodies produced in response to foreign antigens have provided a wealth of information about the mechanisms involved in generating a seemingly limitless array of antigen-binding specificities by diversification of their antigen-binding domains through somatic recombination and mutation. The third function is attributed to sIgM-mediated clearance of tissue-breakdown molecules and binding to cell surface molecules on B and T cells to inhibit cell division and/or activation, thereby minimizing inflammation [16] This immunomodulatory role of sIgM has been confirmed by studies with two independently genetically engineered mouse strains lacking serum IgM (Sμ−/−) [24, 25]. These mice exhibit abnormal B cell development, impaired antibody responses, and enhanced production of autoantibodies (see below). This finding could explain why distinct knockout strains for the same gene often yield discrepant functional results
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