Gender-related genetic and biochemical differences: influence on susceptibility and course of multiple sclerosis

Multiple Sclerosis (MS) is a multifactorial disease. Women are more susceptible than men (female to male ratio of 2:1), yet have a slightly better prognosis than men even though inflammatory episodes are associated with greater subsequent disability. Although the biological background responsible of differences in susceptibility and course of MS between sexes is not fully understood, a number of observations suggests that a role is played by hormones, as well as by genetic and biochemical factors. Regarding hormones, it has been consistently reported that during pregnancy, when progesterone is continuously present, there are fewer relapses, and disability scores tend to be lower. In addition, during pregnancy, the number of CD8 suppressor T-cells is decreased and the ratio of CD4 helper to CD8 suppressor T-cells increased, indicating reduced disease activity. A different cytokine profile as well as a gender-specific effect of genetic variants between men and women have been observed. For instance, the chemokine CCL22, which expression in animal models of MS is correlated with clinical manifestations and development of inflammatory lesions, is increased in Cerebrospinal Fluid (CSF) from female, but not male, patients. The frequency of the AT haplotype in CCL22 encoding gene was shown to be significantly decreased in MS patients (P=0.017, OR: 0.49), but, stratifying patients according to gender, the observed association was even more pronounced in male patients compared with male controls (P=0.004, OR=0.18), whereas no significant differences were observed, in females. Other polymorphic variants in several genes related to inflammation, including Interferon-gamma, Brain Derived Neurothropic Factor (BDNF) and the glutathione S-transferase (GST) supergene family, are likely influence the risk to develop MS in a gender-related manner. These notions suggest that the role of inflammation differs between sexes, possibly mediated by immunomodulatory effects related to female sex hormones. In this chapter, current knowledge about genetic, biochemical and hormonal differences between male and female MS patients will be reviewed and discussed.