Transcriptional activity of endogenous retroviruses in multiple sclerosis: a sign of deficient chromatin-mediated silencing.

Abstract

Multiple sclerosis (MS) is an immunemediated disease of the CNS associated with inflammation, demyelination and axon destruction [1]. While MS may take different clinical courses from one patient to the other, it is frequently characterized by a fluctuating disease activity, where flareups of the neurological disabilities are followed by phases of remission. The precise etiology of MS is mysterious, but it is generally described as the consequence of environmental factors on individuals with genetic predispositions. Damage to the CNS is mediated by CD4 T cells together with other immune effector cells including CD8 T cells, NK cells, γ-δ T cells, B cells and monocytes. Several of these cell populations display increased expression of proinflammatory cytokines including TNF-α, IL-6 and IL-1 that play an important role in the activation of the T-cell population attacking the myelin sheath. In phases of relapse, accumulation of proinflammatory cytokines is further increased [2]. Thus, it seems that in the patients, several hematopoietic cells types fail to keep transcription of proinflammatory genes in check, maintaining excessively high basal expression of these genes and possibly over-reacting on proinflammatory external stimuli. Interestingly, MS is also associated with extensive transcriptional activity of pericentromeric and/or interspersed repeats. This has generated clear interest for the potential role of repeats in the onset of this disease. In particular, human endogenous retro viruses (HERVs) have been considered as a potential threat. These repeats are vestigial retroviral genomes inserted in the human DNA that in many cases retain intact promoter activity, encode proteins and in some cases are sufficiently complete to engender secreted capsids. HERV virions are present in blood samples from more than two-thirds of MS patients – particularly in patients with active MS [3], with increased HERV antigen expression on MS patient B cells and monocytes [4]. Multiple studies have focused on the potentially pathogenic effect of HERVs, examining their impact on the expression of host genes adjacent to their cite of insertion, or the immunogenicity of HERV encoded Transcriptional activity of endogenous retroviruses in multiple sclerosis: a sign of deficient chromatin-mediated silencing