Gender and the Sex Hormone Estradiol Affect Multiple Sclerosis Risk Gene Expression in Epstein-Barr Virus-Infected B Cells

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.

Construction of Immune-Related ceRNA Network in Dilated Cardiomyopathy: Based on Sex Differences

“…Both the sexes have the same seroprevalence of EBV. Nonetheless, EBV antibody titers in females are generally higher than those in males ( Keane et al, 2021 ). Gender and sex hormone estradiol have been demonstrated to alter EBV latency III functions and regulate multiple sclerosis (MS) risk genes differently among both sexes ( Keane et al, 2021 ).…”

“…Nonetheless, EBV antibody titers in females are generally higher than those in males ( Keane et al, 2021 ). Gender and sex hormone estradiol have been demonstrated to alter EBV latency III functions and regulate multiple sclerosis (MS) risk genes differently among both sexes ( Keane et al, 2021 ). However, whether gender and sex hormones affect EBV infection in the myocardium of DCM patients still warrants further research.…”

The interaction between Epstein–Barr virus and multiple sclerosis genetic risk loci: insights into disease pathogenesis and therapeutic opportunities

“…There is also evidence of gender differences in the interaction between EBV and the MS genetic risk factors. Using a large LCL gene expression data set, it was shown that two of the MS risk loci, TRAF3 / RCOR1 and TBX6 (that had earlier displayed allele dependent binding of EBNA2 ), showed sex differences in their associations with gene expression 88 . The expression level of TRAF3 also showed a female‐biased correlation with expression of the oestrogen receptor 2 ( ESR2 ) gene.…”

“…Using a large LCL gene expression data set, it was shown that two of the MS risk loci, TRAF3 / RCOR1 and TBX6 (that had earlier displayed allele dependent binding of EBNA2 ), showed sex differences in their associations with gene expression. 88 The expression level of TRAF3 also showed a female‐biased correlation with expression of the oestrogen receptor 2 ( ESR2 ) gene. The authors also found that CD40 and ZC3HAV1 demonstrated a male‐biased response to oestradiol treatment of LCLs.…”

Sex, aging and immunity in multiple sclerosis and experimental autoimmune encephalomyelitis: An intriguing interaction

“…Epidemiological evidence has recently identified EBV infection as a trigger of MS ( 17 ). Interestingly, the expression levels of genetic risk loci linked with MS were shown to differ between males and females, possibly due to epigenetic modifications ( 18 ). Furthermore, in EBV-infected B cells in vitro , the expression levels of estradiol receptors were shown to correlate with EBV infection traits, such as EBV latency III genes, thus providing evidence toward the sex-associated pathways of pathogenicity in MS and EBV-related pathology ( 18 ).…”