Autoimmune diseases are more common in women: insights into sex and gender differences in autoimmunity

Autoimmune diseases (ADs) comprise a heterogeneous group of disorders characterised by a breakdown of immune tolerance and chronic immune-mediated tissue damage. Their onset and progression result from a complex interplay between genetic susceptibility, hormonal influences, immune regulatory mechanisms, and environmental exposures collectively referred to as the exposome. A striking feature of ADs is their pronounced sexual dimorphism, with a markedly higher prevalence in women for most conditions, alongside sex-specific differences in clinical presentation, severity, and prognosis. This review provides a comprehensive overview of the genetic and environmental determinants contributing to autoimmunity, with particular emphasis on how sex- and gender-related factors shape immune tolerance and disease susceptibility. We discuss central and peripheral tolerance mechanisms, the role of key regulators such as AIRE and FOXP3, sex chromosome-linked effects including X-chromosome inactivation, and the immunomodulatory impact of sex hormones across different life stages. Furthermore, we examine how environmental exposures, infections, and geographic variability interact with genetic background and sex-specific immune regulation to influence autoimmune disease risk. By integrating biological sex and gender-related factors within the framework of immune tolerance and the exposome, this review highlights the need for a sex-aware and personalised approach to understanding, diagnosing, and treating ADs.