The conneXion between sex and immune responses

There are notable sex-based differences in immune responses to pathogens and self-antigens, with female individuals exhibiting increased susceptibility to various autoimmune diseases, and male individuals displaying preferential susceptibility to some viral, bacterial, parasitic and fungal infections. Although sex hormones clearly contribute to sex differences in immune cell composition and function, the presence of two X chromosomes in female individuals suggests that differential gene expression of numerous X chromosome-linked immune-related genes may also influence sex-biased innate and adaptive immune cell function in health and disease. Here, we review the sex differences in immune system composition and function, examining how hormones and genetics influence the immune system. We focus on the genetic and epigenetic contributions responsible for altered X chromosome-linked gene expression, and how this impacts sex-biased immune responses in the context of pathogen infection and systemic autoimmunity. Immune responses to pathogens and self-antigens show sex-based differences, with female individuals generally more susceptible to autoimmunity and male individuals more vulnerable to infections. In this Review, the authors explore the role of hormones and genetics in shaping immune responses, and discuss genetic and epigenetic contributions to altered X-linked gene expression that affect immune responses.