Abstract
We review how polyreactive natural IgM autoantibodies (IgM-NAA) protect the host from invading micro-organisms and host neo-antigens that are constantly being produced by oxidation mechanisms and cell apoptosis. Second, we discuss how IgM-NAA and IgM anti-leukocyte antibodies (IgM-ALA) inhibits autoimmune inflammation by anti-idiotypic mechanisms, enhancing removal of apoptotic cells, masking neo-antigens, and regulating the function of dendritic cells (DC) and effector cells. Third, we review how natural IgM prevents autoimmune disorders arising from pathogenic IgG autoantibodies, triggered by genetic mechanisms (e.g., SLE) or micro-organisms, as well as by autoreactive B and T cells that have escaped tolerance mechanisms. Studies in IgM knockout mice have clearly demonstrated that regulatory B and T cells require IgM to effectively regulate inflammation mediated by innate, adaptive, and autoimmune mechanisms. It is, therefore, not surprising why the host positively selects such autoreactive B1 cells that generate IgM-NAA, which are also evolutionarily conserved. Fourth, we show that IgM-ALA levels and their repertoire can vary in normal humans and disease states and this variation may partly explain the observed differences in the inflammatory response after infection, ischemic injury, or after a transplant. We also show how protective IgM-NAA can be rendered pathogenic under non-physiological conditions. We also review IgG-NAA that are more abundant than IgM-NAA in plasma. However, we need to understand if the (Fab)2 region of IgG-NAA has physiological relevance in non-disease states, as in plasma, their functional activity is blocked by IgM-NAA having anti-idiotypic activity. Some IgG-NAA are produced by B2 cells that have escaped tolerance mechanisms and we show how such pathogenic IgG-NAA are regulated to prevent autoimmune disease. The Fc region of IgG-NAA can influence inflammation and B cell function in vivo by binding to activating and inhibitory FcγR. IgM-NAA has therapeutic potential. Polyclonal IgM infusions can be used to abrogate on-going inflammation. Additionally, inflammation arising after ischemic kidney injury, e.g., during high-risk elective cardiac surgery or after allograft transplantation, can be prevented by pre-emptively infusing polyclonal IgM or DC pretreated ex vivo with IgM or by increasing in vivo IgM with a vaccine approach. Cell therapy is appealing as less IgM will be required.
Highlights
The study of natural IgM autoantibodies (IgM-NAA) has given us a good insight on how nature, by creating polyreactive pentavalent antibodies, has accomplished a difficult task of trying to protect the host from both diverse foreign pathogens and from diverse self neo-antigens that are constantly produced within the host
We showed that polyclonal murine IgM, but not IgM pre-adsorbed with activated splenic leukocytes, bound to recombinant soluble CD40 and PD1 but not PDL-1, CD40L, and CD80, indicating, that IgM anti-leukocyte antibodies (IgM-ALA) has binding specificity to certain dendritic cells (DC) receptors, just as we observed with human T cell receptors where IgM bound to CD4, CD3, and CD2 but not to CD8 [39]
A single dose (150 μg) of normal purified polyclonal IgM was administered intravenously to wild-type C57BL6 (WT-B6) mice to increase baseline circulating IgM by about 30–50% and to determine if increasing IgM would protect these WT-B6 from severe renal ischemia (32 min clamp time). These studies clearly indicated that increasing circulating IgM levels protected mice from severe renal ischemia reperfusion injury (IRI) (Figure 9C). We determined that this protection was mediated by IgM-ALA as administering similar quantity of polyclonal IgM pre-adsorbed with activated splenic leukocytes to remove IgM-ALA failed to protect these WT-B6 mice from severe renal IRI (Figure 9C)
Summary
We review how natural IgM prevents autoimmune disorders arising from pathogenic IgG autoantibodies, triggered by genetic mechanisms (e.g., SLE) or micro-organisms, as well as by autoreactive B and T cells that have escaped tolerance mechanisms. Studies in IgM knockout mice have clearly demonstrated that regulatory B and T cells require IgM to effectively regulate inflammation mediated by innate, adaptive, and autoimmune mechanisms. It is, not surprising why the host positively selects such autoreactive B1 cells that generate IgM-NAA, which are evolutionarily conserved. We need to understand if the (Fab) region of IgG-NAA has physiological relevance in non-disease states, as in plasma, their functional activity is blocked by IgM-NAA having anti-idiotypic activity.
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