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Modulation of autoimmune rheumatic diseases by oestrogen and progesterone

Key Points

  • Sexual dimorphism in the risk and expression of human autoimmune rheumatic diseases involves the immunomodulatory effects of postpubertal levels of sex steroid hormones

  • Oestrogen increases the risk of SLE in genetically susceptible women by increasing type 1 interferon production and favouring the survival of B cells that produce pathogenic IgG autoantibodies

  • Progesterone might reduce the risk of SLE in genetically predisposed women by countering these oestrogen effects—thus, the balance between oestrogen and progesterone might influence the risk of SLE

  • Pregnancy-induced amelioration of rheumatoid arthritis probably involves anti-inflammatory and tolerogenic effects of high circulating levels of progesterone, oestrogen and cortisol

  • Research into mechanisms of sex-steroid-related immunomodulation is expected to uncover novel therapeutic targets in autoimmune rheumatic conditions and to improve understanding of sexual dimorphism in risk of other diseases

Abstract

Sexual dimorphism is evident in the risk and expression of several human autoimmune diseases. Differences in disease manifestations observed between sexes are likely to involve immunomodulation by sex steroids, nonhormonal factors encoded by genes on the X and Y chromosomes, and immunological phenomena unique to pregnancy. In systemic lupus erythematosus (SLE), and perhaps other autoantibody-mediated diseases, oestrogen seems to increase the risk of disease in genetically predisposed women by targeting key immune pathways, including the type 1 interferon (IFN) response, differentiation of CD4+ T helper cells and survival of autoreactive B cells. By contrast, progesterone seems to reduce the risk of SLE by counteracting the effects of oestrogen on some of these same pathways, which suggests that the balance between oestrogen and progesterone can determine disease expression. In this Review we focus on the roles of the sex steroid hormones oestrogen and progesterone in modulating the risk and expression of SLE and rheumatoid arthritis. Intensive research in this area promises to identify novel therapeutic strategies and improve understanding of the immunological requirements and complications of pregnancy, and is expected to define the mechanisms behind sexual dimorphism in autoimmunity, immunity and other aspects of human health—a newly announced directive of the NIH.

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Figure 1: Effects of oestrogen and progesterone on the risk of systemic lupus erythematosus in women.
Figure 2: Potential contributions of oestrogen and progesterone to amelioration of rheumatoid arthritis in pregnant women.
Figure 3: Potential mechanisms through which oestrogen and progesterone might modulate the loss of immune tolerance and regulate the production of pathogenic IgG autoantibodies in systemic lupus erythematosus.
Figure 4: Potential mechanisms through which high levels of oestrogen and progesterone during pregnancy reduce disease activity in rheumatoid arthritis.

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Acknowledgements

The authors thank J. L. Nelson, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA and M. Wener, University of Washington, Seattle, WA, USA for their thoughtful comments during the writing of this Review. Research work in G.H.'s laboratory has been supported by NIH grant AI101564 and the Robert F. and Betty Snead Fund for Innovation in Lupus Research. Research work in D.C.'s laboratory has been supported by grants AI066261 and AI089775 from the NIH and a Veterans Administration Merit Award (5 I01 BX001133).

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Both authors contributed equally to researching data for the article, providing a substantial contribution to discussions of the content, writing the article, and to the review and/or editing of the manuscript before submission.

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Correspondence to Grant C. Hughes.

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Hughes, G., Choubey, D. Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat Rev Rheumatol 10, 740–751 (2014). https://doi.org/10.1038/nrrheum.2014.144

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