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Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator

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  • Meng-Lei Zhu

    (School of Medicine, University of North Carolina at Chapel Hill
    School of Medicine, University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill)

  • Pearl Bakhru

    (School of Medicine, University of North Carolina at Chapel Hill
    School of Medicine, University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill)

  • Bridget Conley

    (School of Medicine, University of North Carolina at Chapel Hill
    School of Medicine, University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill)

  • Jennifer S. Nelson

    (School of Medicine, University of North Carolina at Chapel Hill)

  • Meghan Free

    (School of Medicine, University of North Carolina at Chapel Hill)

  • Aaron Martin

    (School of Medicine, University of North Carolina at Chapel Hill)

  • Joshua Starmer

    (University of North Carolina at Chapel Hill)

  • Elizabeth M. Wilson

    (School of Medicine, University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
    School of Medicine, University of North Carolina at Chapel Hill)

  • Maureen A. Su

    (School of Medicine, University of North Carolina at Chapel Hill
    School of Medicine, University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill)

Abstract

Male gender is protective against multiple sclerosis and other T-cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well understood. Autoimmune regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared with females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity.

Suggested Citation

  • Meng-Lei Zhu & Pearl Bakhru & Bridget Conley & Jennifer S. Nelson & Meghan Free & Aaron Martin & Joshua Starmer & Elizabeth M. Wilson & Maureen A. Su, 2016. "Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
  • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11350
    DOI: 10.1038/ncomms11350
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    Cited by:

    1. Jean Lee & Leonid A. Yurkovetskiy & Derek Reiman & Lara Frommer & Zoe Strong & Anthony Chang & George J. Kahaly & Aly A. Khan & Alexander V. Chervonsky, 2024. "Androgens contribute to sex bias of autoimmunity in mice by T cell-intrinsic regulation of Ptpn22 phosphatase expression," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Amina Zahaf & Abdelmoumen Kassoussi & Tom Hutteau-Hamel & Amine Mellouk & Corentine Marie & Lida Zoupi & Foteini Tsouki & Claudia Mattern & Pierre Bobé & Michael Schumacher & Anna Williams & Carlos Pa, 2023. "Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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