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DNA-damaging autoantibodies and cancer: the lupus butterfly theory

Nature Reviews Rheumatology volume 12, pages 429–434 (2016)Cite this article

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Abstract

Autoantibodies reactive against host DNA are detectable in the circulation of most people with systemic lupus erythematosus (SLE). The long-held view that antibodies cannot penetrate live cells has been disproved. A subset of lupus autoantibodies penetrate cells, translocate to nuclei, and inhibit DNA repair or directly damages DNA. The result of these effects depends on the microenvironment and genetic traits of the cell. Some DNA-damaging antibodies alone have little impact on normal cells, but in the presence of other conditions, such as pre-existing DNA-repair defects, can become highly toxic. These findings raise new questions about autoimmunity and DNA damage, and reveal opportunities for new targeted therapies against malignancies particularly vulnerable to DNA damage. In this Perspectives article, we review the known associations between SLE, DNA damage and cancer, and propose a theory for the effects of DNA-damaging autoantibodies on SLE pathophysiology and cancer risk.

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Figure 1: Chronic inflammation and DNA damage in people with SLE.
Figure 2: Cell-penetrating autoantibodies.
Figure 3: Nuclear-penetrating autoantibodies and synthetic lethality.

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Acknowledgements

A.E.C. is the Arthritis Society Chair in Rheumatic Diseases at the University of Calgary, Calgary, Alberta, Canada. D.A.I. is supported by a Biomedical Centre award to University College Hospital and University College London. R.R.-G. is supported by National Institutes of Health (NIH) awards R03CA173822 and P60 AR066464. J.E.H. is supported by the Department of Therapeutic Radiology at Yale School of Medicine and a Yale Center for Clinical Investigation CTSA Scholar Award. This publication was made possible by CTSA Grant Number UL1 TR000142 from the National Center for Advancing Translational Science (NCATS), components of the NIH, and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.

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Authors and Affiliations

  1. Philip W. Noble and James E. Hansen are at the Department of Therapeutic Radiology, Yale School of Medicine, 15 York Street, New Haven, Connecticut 06520, USA.,

    Philip W. Noble & James E. Hansen

  2. Sasha Bernatsky is at the Department of Medicine, Divisions of Rheumatology and Clinical Epidemiology, McGill University, 687 Avenue des Pins Quest, Montreal, Quebec H3A 1A1, Canada.,

    Sasha Bernatsky

  3. Ann E. Clarke is at the Division of Rheumatology, Department of Medicine, Cumming School of Medicine, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada.,

    Ann E. Clarke

  4. Department of Medicine, David A. Isenberg is at the Centre for Rheumatology, Rayne Building, 5 University Street, University College London, London WC1E 6JF, UK.,

    David A. Isenberg

  5. Rosalind Ramsey-Goldman is at the Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 East Huron Street, Chicago, Illinois 60611, USA.,

    Rosalind Ramsey-Goldman

  6. James E. Hansen is at the Yale Cancer Center, Yale School of Medicine, 15 York Street, New Haven, Connecticut 06520, USA.,

    James E. Hansen

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Noble, P., Bernatsky, S., Clarke, A. et al. DNA-damaging autoantibodies and cancer: the lupus butterfly theory. Nat Rev Rheumatol 12, 429–434 (2016). https://doi.org/10.1038/nrrheum.2016.23

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