Why women’s immune systems are more prone to attacking themselves

Autoimmune diseases occur when the immune system attacks the body’s own tissues. The fact that women are disproportionately affected is well established, but the underlying mechanism has not been fully explained. The researchers examined T cell receptors (TCRs), the proteins that allow immune cells to distinguish self from non-self, in thymus tissue from male and female organ donors. The thymus is the organ where T cells mature and learn tolerance.

The key finding: female effector T cells had significantly more TCRs targeting self-antigens associated with autoimmunity. At the same time, female regulatory T cells (Tregs), which suppress immune responses, had fewer of these TCRs. This imbalance may help explain why the immune system in women is more likely to attack the body’s own tissues.

Thymic selection as a possible mechanism

The difference was specific to TCRs directed at self-antigens linked to autoimmunity, not those targeting cancer cells or viruses. The researchers suggest that lower expression of AIRE, a regulator that helps the thymus develop tolerance to self-antigens, in females may influence how these receptors are selected during maturation.

Implications for ageing and disease

Autoimmune diseases become more common with age, making them relevant to longevity research. Chronic autoimmune activity contributes to inflammaging, the low-grade inflammation associated with accelerated biological ageing. Understanding the origin of this sex difference, already present at the T cell maturation stage, raises new questions about prevention and early intervention.

The study, published in eLife, is based on tissue analysis from donors and describes an association. How this sex difference in practice shapes autoimmune risk requires further investigation.

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Search terms to explore further: T cell receptor thymic selection sex differences, AIRE autoimmunity regulatory T cells, inflammaging autoimmune disease ageing