Clinical observations in human autoimmune diseases such as multiple sclerosis (MS) suggest a pivotal role of sex-related factors in the etiopathogenesis. These include a female preponderance in MS incidence and an increasing sex bias over time, a parent-of-origin effect in MS inheritance, and the protective effect of pregnancy on disease activity. The complex interplay of factors contributing to these clinical phenomena, however, is incompletely understood and may include sex hormones as well as genetic or epigenetic sex differences. While genetic and hormonal effects are impossible to study independently in humans, novel mouse models have started to unravel the cause-effect relationship between individual sex-related factors and autoimmunity. Here, we present the evidence for mechanisms underlying sex differences in the immune system and the central nervous system (CNS) and how these might help to explain some of the clinically observed sex differences in MS. A better understanding of the molecular underpinnings may ultimately help to devise sex-specific treatment strategies as well as highlight novel avenues for therapy in both sexes.
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