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Nature and functions of autoantibodies

Nature Clinical Practice Rheumatology volume 4, pages 491–498 (2008)Cite this article

Abstract

Antibodies that react with self-molecules occur in healthy individuals and are referred to as natural antibodies or autoantibodies. Natural autoantibodies are mainly IgM, are encoded by unmutated V(D)J genes and display a moderate affinity for self-antigens. They provide a first line of defense against infections, probably serve housekeeping functions and contribute to the homeostasis of the immune system. By contrast, high-affinity, somatically mutated IgG autoantibodies reflect a pathologic process whereby homeostatic pathways related to cell clearance, antigen-receptor signaling or cell effector functions are disturbed. In some autoimmune disorders, autoantibodies might be present before disease onset, show remarkable specificity and serve as biomarkers providing an opportunity for diagnosis and therapeutic intervention. In organ-specific autoimmune diseases, such as myasthenia gravis or pemphigus, autoantibodies directly bind to and injure target organs. In systemic autoimmune diseases, autoantibodies react with free molecules, such as phospholipids, as well as cell surface and nucleoprotein antigens, forming pathogenic antigen–antibody (immune) complexes. These autoantibodies injure tissues and organs through engagement of FcγR activation of complement as well as internalization and activation of Toll-like receptors. Activation of intracellular Toll-like receptors in plasmacytoid dendritic cells leads to the production of type I interferon, whereas engagement of intracellular Toll-like receptors on antigen-presenting cells stimulates cell activation and the production of other inflammatory cytokines. Thus, immune complexes might perpetuate a positive feedback loop amplifying inflammatory responses.

Key Points

  • Natural antibodies or autoantibodies, particularly IgM, that react with self-molecules occur in normal individuals and display a moderate affinity but high avidity for self-antigens

  • High-affinity, somatically mutated, class-switched IgG autoantibodies reflect a pathologic process in which homeostatic pathways related to cell clearance, antigen-receptor signaling or cell effector functions are disturbed

  • The mechanisms involved in immune-complex-mediated tissue injury include engagement of FcγRs and activation of complement, as well as internalization and activation of Toll-like receptors

  • Autoantibodies might be detectable long before disease onset and serve as biomarkers enabling diagnosis and targeting of therapeutic intervention

  • In organ-specific autoimmune diseases, autoantibodies directly injure target organs; in systemic autoimmune diseases, they can also bind to different self-molecules and cause disease through the formation of immune complexes

  • Research is needed to clarify why certain antigens are targeted in different autoimmune diseases and how some antibodies activate, whereas others inhibit, immune responses

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Figure 1: Pathogenic autoantibodies cause inflammation and tissue injury.

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Author information

Authors and Affiliations

  1. K Elkon is a Professor of Medicine and Head of the Division of Rheumatology at the University of Washington School of Medicine, Seattle, WA, USA.,

    Keith Elkon

  2. P Casali is the Donald L Bren Professor of Medicine, Molecular Biology and Biochemistry, and Director of the Center for Immunology at the University of California, Irvine, CA, USA.,

    Paolo Casali

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  2. Paolo Casali
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Correspondence to Paolo Casali.

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Elkon, K., Casali, P. Nature and functions of autoantibodies. Nat Rev Rheumatol 4, 491–498 (2008). https://doi.org/10.1038/ncprheum0895

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