[Autoimmune disease predisposition: Aire « protects » men]

Area of Science:

• Immunology
• Endocrinology
• Genetics

Background:

• Autoimmune diseases affect 5-8% of the population, characterized by immune system deregulation.
• The thymus educates T cells via central tolerance, involving thymic epithelial cells (TEC) and tissue-specific antigens (TSA).
• Women exhibit higher susceptibility to most autoimmune diseases compared to men.

Purpose of the Study:

• To investigate sex-associated differences in thymic transcriptome and their link to autoimmune disease susceptibility.
• To explore the relationship between gender, hormones, and the autoimmune regulator (AIRE) in central tolerance.

Main Methods:

• Comparative analysis of thymic transcriptome in women and men.
• Study of human and murine cell models to analyze gender, hormone, and AIRE interactions.
• Investigation of epigenetic modifications, including DNA methylation, within the AIRE promoter.

Main Results:

• Sex-associated differences in TSA expression controlled by AIRE were identified.
• AIRE expression was found to be lower in women than in men post-puberty.
• Estrogen was shown to decrease thymic AIRE expression through epigenetic modifications, specifically increased methylation of the AIRE promoter.

Conclusions:

• Reduced central tolerance effectiveness in women post-puberty may lead to increased autoreactive lymphocytes and higher autoimmune disease risk.
• Estrogen's impact on AIRE expression via epigenetic mechanisms contributes to sex-based differences in autoimmune susceptibility.
• Environmental estrogen-like compounds may influence the rising incidence of autoimmune diseases.