Genetic Determinants of Antibody Levels in Cerebrospinal Fluid in Multiple Sclerosis: Possible Links to Endogenous Retroviruses.

Alexander Emmer,Martin Staege,Malte Kornhuber,Christine Brütting

doi:10.3390/ijms19030786

Abstract

The pathogenesis of multiple sclerosis (MS) has not been clarified. In addition to environmental factors; genetic determinants have been implicated in the pathogenesis of MS. Furthermore, endogenous retroviruses (ERV) might play a role in MS. The presence of oligoclonal immunoglobulin in cerebrospinal fluid (CSF) is a typical feature of MS. Recently, genetic polymorphisms in loci on human chromosomes 6, 14 and 18 have been identified as major determinants of CSF antibody levels in MS. The functional relevance of these single nucleotide polymorphisms (SNPs) remains unclear and none of them is located in an open reading frame. In previous studies, we identified ERV sequences in the vicinity of MS associated SNPs. Here, we describe the identification of ERV sequences in the neighborhood of SNPs associated with CSF antibody levels. All of the identified SNPs are located in the vicinity of ERV sequences. One of these sequences has very high homology to a sequence derived from the so-called MS-associated retrovirus (MSRV). Another cluster of three ERV sequences from the immunoglobulin heavy chain locus has retained the typical organization of retroviral genomes. These observations might shed new light on a possible association between ERVs and MS pathogenesis.

Highlights

Another cluster of three endogenous retrovirus (ERV) sequences from the immunoglobulin heavy chain locus has retained the typical organization of retroviral genomes
Multiple sclerosis (MS) is a disease that is characterized by central nervous system demyelination with concomitant destruction of neurons
The functional relevance of these single nucleotide polymorphisms (SNPs) remains unclear and none of them is located in an open reading frame

Summary

Introduction

Multiple sclerosis (MS) is a disease that is characterized by central nervous system demyelination with concomitant destruction of neurons. During the course of MS, an activation of the immune system takes place and inflammation plays a major role in disease activity. The presence of oligoclonal immunoglobulin in the cerebrospinal fluid (CSF) is a typical feature of MS and so-called oligoclonal bands (OCBs), as detected by isoelectric focusing, are of diagnostic importance in MS [1]. The pathogenesis of MS OCB is still unresolved. OCBs have been reported in the CSF of patients with different viral diseases like e.g., in human immunodeficiency virus (HIV) infected individuals [2,3,4]. Genetic polymorphisms in loci on human chromosomes 6, 14 and 18 have been identified as major determinants of CSF antibody levels in MS [5]. We have put forward the hypothesis that inflammation in MS, including humoral parts, could be driven by one or more endogenous retrovirus (ERV) elements [6]

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