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

Haritz Irizar,Álvaro Prada,Javier Olascoaga,Maider Muñoz-Culla,Lucia Sepúlveda,Adolfo López De Munain,Tamara Castillo-Triviño,David Otaegui,Matías Sáenz-Cuesta,Gorka Zamora-López,Francisco J Esteban

doi:10.1371/journal.pone.0090482

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.

Highlights

The most common clinical presentation of multiple sclerosis (MS) is the so called RelapsingRemitting MS (RRMS), the molecular mechanisms responsible for its progression are currently unknown
The primed state of neutrophils is part of the endogenous mechanisms aimed to keep under control the reactivation of Epstein-Barr virus (EBV) infection in the B cells; and its when control mechanisms fail that reactivation of EBV infection in B lymphocytes happens, triggering the chain of events leading to the pathogenic inflammatory response
The whole-genome gene expression analysis of peripheral blood leukocytes has allowed the observation that the genes that are differentially expressed in the two main phases of relapsingremitting multiple sclerosis, relapse and remission, show a behavior that gives rise to a pattern we have called ‘‘mirror pattern’’: if a gene is upregulated in remission is downregulated in relapse and vice versa

Summary

Introduction

The most common clinical presentation of multiple sclerosis (MS) is the so called RelapsingRemitting MS (RRMS), the molecular mechanisms responsible for its progression are currently unknown. The most common clinical presentation of the disease (in 85– 90% of the cases) is the so called Relapsing-Remitting MS (RRMS) In this form of the disease patients suffer from episodes of acute onset of neurological symptoms that typically last from 48 hours to several weeks called relapses followed by longer periods of clinical stability. This transient nature of neurological symptoms is explained by subsiding inflammation, remyelination of axons and the plasticity of the nervous system. The recovery of neurological ability after a relapse happens mostly due to remyelination of the lesions caused by the immunological attack

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