Review Article | Published:

Protective autoantibodies in the rheumatic diseases: lessons for therapy

Nature Reviews Rheumatology volume 9, pages 291300 (2013) | Download Citation

Abstract

The adaptive immune system augments host defenses against diverse infectious threats, yet also carries intertwined risks for the development of autoimmune disease. The immune system incorporates homeostatic pathways for essential housekeeping functions that involve recognition of oxidation-modified endogenous molecules. Now, the properties of a physiological class of natural autoantibodies, which seem to modulate the severity or even prevent the onset of autoimmune disease, are beginning to be defined. Whereas disease-associated IgG autoantibodies to nuclear antigens and citrulline-modified self-proteins have been shown to activate innate pattern recognition receptors leading to increased cell death and tissue injury, a class of IgM autoantibodies to oxidation-associated neo-antigens can oppose these pathogenic effects. These naturally arising regulatory IgM autoantibodies enhance the capacity for the phagocytic clearance of host cells affected by programmed death pathways. These antibodies can also suppress key signalling pathways in the innate immune system involved in the control and resolution of inflammatory responses to Toll-like receptor agonists and disease-associated IgG autoantibodies.

Key points

  • Innate immune effects, responsible for recognition and disposal of damaged and apoptotic cells, accomplish intertwined goals of regulation of inflammatory responses and reinforcement of immunologic tolerance

  • Naturally arising IgM antibodies (NAbs) to oxidation-associated neo-epitopes are present from birth; levels can be increased by exposure to apoptotic cells

  • Autoreactive NAbs enhance phagocytic clearance of apoptotic cells and have the capacity to block inflammatory responses induced by Toll-like receptor ligands and autoantibody-containing immune complexes

  • Regulatory properties of NAbs to apoptotic cells are associated with blocked activation of mitogen-activated protein kinases; functional properties are linked to recruitment of early complement factors, C1q and MBL

  • In experimental models, IgM NAbs to apoptotic cells inhibit the development of inflammatory arthritis and atherosclerosis

  • In patients with rheumatic diseases, spontaneously higher levels of NAbs correlate with fewer cardiovascular events

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Acknowledgements

Our work has been supported by grants from the NIH; R01AI090118, R01 AI068063 and ARRA supplement, R01AI090118, and from the ACR REF Within Our Reach campaign, the Alliance for Lupus Research, the Arthritis Foundation, and the P. Robert Majumder Charitable Trust.

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  1. Laboratory of B-Cell Immunobiology, Departments of Medicine and Pathology, NYU School of Medicine, Alexandria Center, Room 804, 450 East 29th Street, New York, NY 10016, USA

    • Gregg J. Silverman
    • , Jaya Vas
    •  & Caroline Grönwall

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G. J. Silverman and J. Vas researched data for the article; G. J. Silverman and C. Grönwall wrote the article and made substantial contributions to review and/or editing of the article before submission. All authors made substantial contributions to discussing the content of this article.

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The authors declare no competing financial interests.

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Correspondence to Gregg J. Silverman.

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https://doi.org/10.1038/nrrheum.2013.30

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