Transcriptomic Profile Reveals Gender-Specific Molecular Mechanisms Driving Multiple Sclerosis Progression

Abstract

BackgroundAlthough 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.ResultsThe 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.ConclusionsThe 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.

Sex-dependent factors encoded in the immune compartment dictate relapsing or progressive phenotype in demyelinating disease

“…In addition, when comparing female with male transgenic immune cells, various pathway involved in negative regulation of T cell-mediated immunity were upregulated in female transgenic cells. These results are in line with a comparative analysis of leukocytes isolated from RRMS patients in remission or during relapse, where a sex-specific coexpression of genes was found (27).…”

Sex-Based Differences in Multiple Sclerosis (MS): Part II: Rising Incidence of Multiple Sclerosis in Women and the Vulnerability of Men to Progression of this Disease

“…Interestingly, this spike in mononucleosis cases in girls preceded agewise the increase in the female to male sex ratio of MS, suggesting an association between increased mononucleosis and MS in girls (Ramagopalan et al 2013a). Finally, a recent microarray study that compared gene expression by peripheral blood mononuclear cells of men and women with RRMS during relapse and remission identified a gene signature that suggests that EBV reactivation occurs in women, but not in men during MS relapses (Irizar et al 2014). Together, these studies provide some indications of a possible interaction between EBV infection and infectious mononucleosis and the more robust adaptive immune response that occurs in females.…”

Interleukin-17A Levels Vary in Relapsing-Remitting Multiple Sclerosis Patients in Association with Their Age, Treatment and the Time of Evolution of the Disease

“…There is a female preponderance in MS [4] and a defining feature comprises its fluctuating disease activity, with the occurrence of clinical relapses separated by periods of clinical stability (remissions) [5]. These latter stages can be prolonged for years, and gender appears to play a critical role in MS development, progression and response to treatment [6]. More than 80% of patients express a relapsing-remitting form of MS (RRMS), characterized by exacerbations of partially or nearly completely reversible neurological disability.…”