Peripheral blood gene expression signature mirrors central nervous system disease: The model of multiple sclerosis

Abstract

Global gene expression analysis using cDNA microarrays has proven to be a sensitive method to gain insight into molecular pathways mediating multiple sclerosis (MS) activity and to develop and refine the molecular taxonomy of the disease. This method was applied as a tool to investigate molecular heterogeneity of MS related gene transcripts in the aim of distinguishing between transcripts that trigger disease activity and account for direct genotype–phenotype correlation, and those whose expression is altered as a downstream effect of other genes. This review summarizes the current state of gene expression microarray applications for the study of MS, and specifically emphasizes the results of gene expression studies using peripheral blood mononuclear cells (PBMC) that were shown to be useful for better understanding of disease related pathways, monitoring of therapeutic responses to various drugs and prediction of clinical outcome. In the long run it is expected that the information provided by cDNA microarrays experiments will allow the determination of key molecular players involved in MS pathogenesis, and lead to better management of the disease using targeted treatments that will prevent its progression.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease affecting the central nervous system (CNS). MS affects mainly young adults with a peak onset between 20 and 40 years of age. The alterations in the immune system initiated by a loss of immunological tolerance to self-antigens, lead to the development of autoreactive phenomena that can be detected in the peripheral blood. Pathologically, the disease is characterized by perivascular infiltration of monocytes and lymphocytes mainly CD4+ T-cells within the brain and spinal cord that lead to myelin destruction [1]. In MS, peripheral blood mononuclear cells (PBMC) are involved in disease pathogenesis and induce active demyelination. Autoreactive activated T-cells invade the blood–brain barrier and initiate an inflammatory response that leads to myelin destruction and significant neurological disability [2], [3]. Gene expression microarray technology is a new tool for comprehensive evaluation of thousands of genes transcripts simultaneously [4]. In recent years, microarray technology has been used for comprehensive analysis to classify diseases, identify effects of different stimuli or treatments in vivo or in vitro, single out genes that may play a role in a specific disease or in a specific biologic process and was shown as a potent technology also to distinguish transcriptional patterns and complex networks that underlie such processes.

The technology is based on hybridization of mRNA to high-density array of immobilized target sequences. Each sequence corresponds to a specific gene of interest. The labeled pool of sample mRNA is subsequently hybridized to the array and the fluorescence at each spot on the array is quantitatively measured in correspondence to the expression level of each particular gene [5].