The importance of natural IgM: scavenger, protector and regulator

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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.

Abstract

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 therapies for the treatment of autoimmunity have been shown to cause a reduction in serum IgM, potentially disrupting the functions of this immunoregulatory molecule and increasing susceptibility to infection.

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Figure 1: Schematic depiction of IgM structure.
Figure 2: IgM directs apoptotic cells to macrophages through the recruitment of C1q and MBL.
Figure 3: The influence of natural IgM on self antigen engagement by the B cell receptor.
Figure 4: Natural IgM modifies B cell survival through modulation of B cell receptor signalling.

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Acknowledgements

We are grateful to F. Mackay and J. Brown for their comments. We apologize to all of our colleagues whose work could not be cited directly, owing to space constraints. This work has been supported by grants from Arthritis Research UK, The Wellcome Trust and the Medical Research Council.

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Correspondence to Michael R. Ehrenstein.

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Glossary

Follicular dendritic cells

Specialized non-haematopoietic stromal cells that reside in the lymphoid follicles and germinal centres. These cells have long dendrites and carry intact antigens on their surface. They are crucial for the optimal selection of B cells that produce antigen-binding antibodies.

T cell-independent antibody responses

Antibody responses to polymeric antigens, such as polysaccharides and lipids, that do not require T cell help.

B1 B cells

IgMhiIgDlowMAC1+B220lowCD23 cells that are the main population of B cells found in the peritoneal and pleural cavities. Their precursors develop in the fetal liver and omentum. In adult mice, the B1 B cell population is maintained at a constant size, owing to the self-renewing capacity of these cells. B1 B cells recognize self components, as well as common bacterial antigens, and secrete antibodies that tend to have low affinity and broad specificity. B1 B cells can be divided into at least two subsets, B1a and B1b, based on their expression of CD5. This description of B1 B cells is based on studies in mice; human B1 B cells have been less well characterized.

Caecal ligation and puncture

An experimental model of peritonitis in rodents, in which the caecum is ligated and then punctured, thereby forming a small hole. This leads to leakage of intestinal bacteria into the peritoneal cavity and subsequent peritoneal infection.

Lyme disease

A disease caused by the bacterium Borrelia burgdorferi or other Borrelia spp. that is transmitted to humans via the bites of infected blacklegged ticks. Symptoms can include skin rash, fever, fatigue, headache, muscle pain, stiff neck and swelling of the knee and other large joints. Most cases can be successfully treated with antibiotics.

Agglutination

Clumping of antigens in the presence of antibodies.

Erythrocyte rosetting

Red blood cells forming clumps around a cell; in malaria, non-infected erythrocytes rosette around infected red blood cells.

Intravenous immunoglobulin

Immunoglobulin (mainly IgG) that is pooled from a large number of individuals. It is used as a replacement in patients who have been depleted of immunoglobulins and for the treatment of patients with immunomodulatory disorders.

Immune complexes

Complexes of antigens bound to antibodies and, sometimes, components of the complement system. The levels of immune complexes are increased in many autoimmune disorders, in which they become deposited in tissues and cause tissue damage.

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Ehrenstein, M., Notley, C. The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol 10, 778–786 (2010) doi:10.1038/nri2849

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