Abstract
Multiple Sclerosis (MS) is a complex immune-mediated disease of the central nervous system. Treatment is based on immunomodulation, including specifically targeting B cells. B cells are the main host for the Epstein-Barr Virus (EBV), which has been described as necessary for MS development. Over 200 genetic loci have been identified as increasing susceptibility to MS. Many MS risk genes have altered expression in EBV infected B cells, dependent on the risk genotype, and are themselves regulated by the EBV transcription factor EBNA2. Females are 2-3 times more likely to develop MS than males. We investigated if MS risk loci might mediate the gender imbalance in MS. From a large public dataset, we identified gender-specific associations with EBV traits, and MS risk SNP/gene pairs with gender differences in their associations with gene expression. Some of these genes also showed gender differences in correlation of gene expression level with Estrogen Receptor 2. To test if estrogens may drive these gender specific differences, we cultured EBV infected B cells (lymphoblastoid cell lines, LCLs), in medium depleted of serum to remove the effects of sex hormones as well as the estrogenic effect of phenol red, and then supplemented with estrogen (100 nM estradiol). Estradiol treatment altered MS risk gene expression, LCL proliferation rate, EBV DNA copy number and EBNA2 expression in a sex-dependent manner. Together, these data indicate that there are estrogen-mediated gender-specific differences in MS risk gene expression and EBV functions. This may in turn contribute to gender differences in host response to EBV and to MS susceptibility.
Highlights
Multiple Sclerosis (MS) is an autoimmune disorder in which the myelin sheath of neurons in the central nervous system is damaged by immune cells [1]
To determine if any MS risk SNPs are sex-biased eQTLs, we interrogated the eQTL effect of MS risk SNPs from the GEUVADIS dataset, based on three sets, which consisted of lymphoblastoid cell lines (LCLs) of both genders together, male LCLs and female LCLs (Figure 1A)
In this study we investigated if there were gender differences in the interaction of MS risk genes with Epstein-Barr virus (EBV) latency III infection, and if these differences were affected by estradiol, to assess if the differences might underpin the increased susceptibility of females to MS
Summary
Multiple Sclerosis (MS) is an autoimmune disorder in which the myelin sheath of neurons in the central nervous system is damaged by immune cells [1]. It is a complex disorder involving a strong genetic component and a number of highly implicated environmental factors. Epstein-Barr virus (EBV), lack of sun exposure, vitamin D deficiency, and smoking are all environmental factors with different degrees of evidence [3]. All of these environmental risk factors have effects on the immune system [3]
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