Sex matters: mechanistic insights into sex-driven patterns of autoimmunity and implications for pharmacotherapy

Abstract

Autoimmune diseases (AiDs) affect up to 10% of the global population and exhibit striking differences between sexes. These disparities encompass prevalence, incidence, age at onset, disease severity and how patients respond to treatment. This review provides a comprehensive overview of the key biological mechanisms underlying sex-biased autoimmunity across multiple levels, including the immunomodulatory roles of sex hormones, sex-specific innate and adaptive immune responses, X-chromosome gene dosage and escape from inactivation as well as epigenetic regulation of immune pathways. In addition, we address how environmental and lifestyle factors, such as smoking, infections and the gut microbiome interact with sex-specific biology to shape autoimmune risk. Finally, we consider the pharmacological implications of sex differences, including variability in drug efficacy, safety and immune-related adverse events, further highlighting current gaps in sex stratified clinical research. Recognizing sex as a fundamental biological variable is essential for advancing the understanding of AiDs and for the development of more effective, tailored therapeutic strategies.