Multiple sclerosis (MS) is a demyelinating disease of the brain and spinal cord that displays striking sex dichotomies, which closely interacts with aging. As the main underlying mechanism in MS is likely to gradually switch from inflammation to neurodegeneration with aging, the transition from the relapsing phase to the progressive phase often occurs during the fifth decade. Incidence of the relapse-onset form of MS favors women, at a ratio of about 3:1 with higher inflammatory activity, early in the disease course. However, men have, on average, a higher rate of disability accumulation with a greater propensity to developing progressive forms of the disease with aging. Similarly, in imaging, women are likely to have more T2 and enhancing lesions, whereas men show more structural atrophy of the central nervous system in MS.

Studies in mouse and man have pinpointed interesting sex-specific differences in the T cell response in MS and other autoimmune disorders. IFNy+ CD4+ T helper 1 (Th1) responses are exacerbated in females; by contrast, there is emerging evidence that Th17 responses are increased in men. In the mouse, elegant genetic models that segregate sex hormones and chromosomes, as well as X chromosome copy number, have helped identify new cellular and molecular mechanisms that may explain sex-dependent differences in MS.

Despite the current data on human and animal studies, there are many open questions on sex-specific issues targeting multiple aspects of MS including pathophysiology, natural history and management, that we hope can be addressed in this Research Topic.

These question include, but are not limited to:

• Sex-dependent dichotomies in the use of diagnostic and prognostic biomarkers in CNS neuroimmune disorders
• Sex dichotomies in MS diagnosis (e.g. sensitivity and specificity of diagnostic criteria in women vs men)
• Sex differences in treatment responses in MS
• How sex regulates the interaction of different immune cell types
• Sex-dependent processes in compartmentalized immunity in the meninges and perivascular place
• The molecular interplay of sex hormonal and chromosomal factors in regulating pathogenesis in CNS autoimmunity.

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Frontiers in Neurology

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