## 3 Role of Sex Hormones and Chromosomes
At higher concentrations, E2 exerts mainly anti-inflammatory effects by inhibiting the production and signaling of pro-inflammatory cytokines, such as TNF-\(\alpha\), IL-1, and IL-6, as well as inhibiting NK cell activation, and by inducing expression of anti-inflammatory cytokines, such as IL-4 and IL-10, favoring a Th2 phenotype and transforming growth factor \(\beta\) (TGF-\(\beta\)) expression, and activating Treg cells [17; 22]. However, at lower concentrations (equivalent to pre-ovulatory menstrual cycle levels), E2 stimulates TNF-\(\alpha\), IFN-\(\gamma\), IL-1 production, and NK cell activity, probably promoting a pro-inflammatory environment. Moreover, EBV infection, the environmental factor more strongly associated with MS risk, is influenced by ESR expression and the host's sex. In a recent paper, the risk of MS was increased 32-fold in individuals after an EBV infection, and levels of serum neurofilaments, a marker of neurodegeneration, increased after EBV seroconversion [23]. Although both males and females are equally susceptible to EBV, they present different responses to the virus. In people with MS, there is a clear interaction between MS risk genes and EBV latency III infection, with a definite gender effect [24]. EBNA2 expression is negatively correlated with ESR2 in female lymphoblastoid cell lines, but it is not in males. LMP1 is negatively correlated with ESR2 in both males and females, and the EBV DNA copy number was positively correlated with ESR2 expression in females [24]. Finally, polymorphism in the estrogen receptor binding site has been implicated in the different susceptibility to autoimmunity observed between males and females [20]. Progesterone is another hormone considered immune-modulatory. Progesterone favors Treg cell differentiation and promotes the down-regulation of pro-inflammatory cytokines production and Th2 differentiation with a contemporary downregulation of activation molecules (i.e., CD80, CD86, and MHC-II) [25]. Progesterone can also modulate the remyelination process by increasing the rate of myelin synthesis [26]. A positive correlation between the progesterone and estrogen peak and attenuated clinical activity has been described during the last trimester of pregnancy [26]. Conversely, an increased risk of relapse is typical of the postpartum period when progesterone and estrogen levels dramatically decrease [26]. Androgens are protective against the development of autoimmune diseases of the CNS (Figure 1). It has been demonstrated that androgens upregulate the autoimmune regulator (Aire), thus increasing its thymus expression and enhancing the tolerance mechanism [27]. As outlined above, evidence of a direct effect of sex steroids on the immune system can explain part, but not all, of the sex bias observed in MS incidence and clinical course. A role for sex chromosome has been less well-studied in both MS and experimental autoimmune encephalomyelitisitis (EAE). The four core genotypes (FCG) mice have been used to study the role of sex chromosomes without the confounding factor of sex hormones. Chromosome influence has been hypothesized to be correlated to different parental imprinting. In a study by [PERSON] and collaborators, they found that maternal imprinting determined a lower methylation and, thus, higher expression of the Foxp3 gene on the X chromosome. This effect is more protective on the XY progeny compared to the XX progeny [14]. Finally, recent reports on the influence of the gut microbiota on gender-based autoimmunity suggest that both bacteria and sex hormones can interact to regulate the immune response and the development of the disease in genetically susceptible individuals.