Transcriptomic profile reveals gender-specific molecular mechanisms driving multiple sclerosis progression.

Abstract

Although the most common clinical presentation of multiple sclerosis (MS) is the so called Relapsing-Remitting MS (RRMS), the molecular mechanisms responsible for its progression are currently unknown. To tackle this problem, a whole-genome gene expression analysis has been performed on RRMS patients. The comparative analysis of the Affymetrix Human Gene 1.0 ST microarray data from peripheral blood leucocytes obtained from 25 patients in remission and relapse and 25 healthy subjects has revealed 174 genes altered in both remission and relapse, a high proportion of them showing what we have called "mirror pattern": they are upregulated in remission and downregulated in relapse or vice versa. The coexpression analysis of these genes has shown that they are organized in three female-specific and one male-specific modules. The interpretation of the modules of the coexpression network suggests that Epstein-Barr virus (EBV) reactivation of B cells happens in MS relapses; however, qPCR expression data of the viral genes supports that hypothesis only in female patients, reinforcing the notion that different molecular processes drive disease progression in females and males. Besides, we propose that the "primed" state showed by neutrophils in women is an endogenous control mechanism triggered to keep EBV reactivation under control through vitamin B12 physiology. Finally, our results also point towards an important sex-specific role of non-coding RNA in MS.