Editors' ChoiceAutoimmunity

Sex (steroids) is in the AIRE

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Science Translational Medicine  04 May 2016:
Vol. 8, Issue 337, pp. 337ec70
DOI: 10.1126/scitranslmed.aaf8771

Women are more susceptible to most autoimmune diseases, and although there is a clear role for hormonal factors and environmental interactions, molecular mechanisms for this effect have not been well defined. Recently, two groups have substantially advanced our understanding of this process by identifying how sex steroids regulate immune development.

T cells, which normally fight foreign pathogens, are educated in the thymus to avoid reactivity to self proteins. The curriculum for this education is partially regulated by a gene called AIRE (autoimmune regulator), which allows tissue-specific antigens to be expressed in the thymus and used for T cell selection. Dragin et al. and Zhu et al. independently determined that AIRE expression is lower in female human thymus than in male thymus. These differences were most pronounced during pubescence and during the mini-puberty of infancy, when sex steroids surge. Taking different approaches, Dragin and colleagues associated diminished AIRE expression with estrogen-induced gene methylation. Zhu and colleagues followed the finding of increased male AIRE expression by demonstrating that the androgen receptor binds the AIRE promoter and increases AIRE expression. In both studies, AIRE expression affected thymic expression of tissue-specific antigens. Last, using murine models of multiple sclerosis and thyroiditis, the groups found separately that altering sex steroid production (by castration or by manipulating the androgen or estrogen receptor system) influenced susceptibility to autoimmunity in an AIRE-dependent manner.

Overall, these field-advancing studies reveal sex-associated differences in the molecular regulation of immunity. These studies help explain the sex differences in disease risk and the relation of autoimmune disease to puberty. Understanding how this interaction may be monitored and modulated could suggest new hormone-based interventions to diminish autoimmune disease risk.

N. Dragin et al., Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J. Clin. Invest. 126, 1525–1537 (2016). [Full text]

M. -L. Zhu et al., Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat. Commun. 10.1038/ncomms11350 (2016).

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