The importance of natural IgM: scavenger, protector and regulator

Key Points Natural IgM, a pentameric, polyreactive antibody, is mainly secreted by peritoneal B1 B cells and recognizes and binds self antigens such as phospholipids. The unique structure of natural IgM allows it to interact with many other components of the immune system, including members of the complement system, mannose-binding lectin and Fc receptor(s) for IgM. B cell survival and development in different compartments is differentially influenced by IgM. Natural IgM promotes the generation of mature B cells in the spleen but reduces the survival of peritoneal B cells. In the absence of secreted IgM, marginal zone B cell and peritoneal B1a B cell generation is favoured. Natural IgM has a key function in protecting against a range of viral, bacterial, fungal and parasitic infections. Its polyreactivity and high valency facilitates binding to pathogens, and enhances pathogen neutralization and agglutination. Natural IgM can therefore function to promote clearance and limit dissemination of pathogens and, with help from complement component C1q, boosts their engulfment by phagocytes and increases the presentation of pathogen-derived antigens. One key property of natural IgM is the promotion of the engulfment of apoptotic cells. The process of apoptotic cell clearance can lead to an anti-inflammatory environment in which B cells and macrophages increase their production of interleukin-10. Defects in apoptotic cell clearance and reduced serum IgM levels have been identified in patients with systemic lupus erythematosus. Therapies that target B cells to treat autoimmunity may lead to a reduction in serum IgM, thereby increasing the risk of infection and potentially promoting autoimmunity. Natural IgM has many roles in the immune system, from protection against infection to regulating autoimmunity. The authors discuss the pleiotropic properties of natural IgM, and the implications for B cell-targeted therapy. The existence of IgM has been known for more than a century, but its importance in immunity and autoimmunity continues to emerge. Studies of mice deficient in secreted IgM have provided unexpected insights into its role in several diverse processes, from B cell survival to atherosclerosis, as well as in autoimmunity and protection against infection. Among the various distinct properties that underlie the functions of IgM, two stand out: its polyreactivity and its ability to facilitate the removal of apoptotic cells. In addition, new B cell-targeted thera