Journal Article

Cumulative Roles for Epstein-Barr Virus, Human Endogenous Retroviruses, and Human Herpes Virus-6 in Driving an Inflammatory Cascade Underlying MS Pathogenesis

Karimi, Abbas, Meier, Ute-Christiane, Middeldorp, Jaap Michiel, Cipian, Richard Christopher, Ramasamy, Ranjan

2021

Overview

Roles for viral infections and aberrant immune responses in driving localized neuroinflammation and neurodegeneration in multiple sclerosis (MS) are the focus of intense research. Epstein-Barr virus (EBV), as a persistent and frequently reactivating virus with major immunogenic influences and a near 100% epidemiological association with MS, is considered to play a leading role in MS pathogenesis, triggering localized inflammation near or within the central nervous system (CNS). This triggering may occur directly via viral products (RNA and protein) and/or indirectly via antigenic mimicry involving B-cells, T-cells and cytokine-activated astrocytes and microglia cells damaging the myelin sheath of neurons. The genetic MS-risk factor HLA-DR2b (DRB1*1501β, DRA1*0101α) may contribute to aberrant EBV antigen-presentation and anti-EBV reactivity but also to mimicry-induced autoimmune responses characteristic of MS. A central role is proposed for inflammatory EBER1, EBV-miRNA and LMP1 containing exosomes secreted by viable reactivating EBV+ B-cells and repetitive release of EBNA1-DNA complexes from apoptotic EBV+ B-cells, forming reactive immune complexes with EBNA1-IgG and complement. This may be accompanied by cytokine- or EBV-induced expression of human endogenous retrovirus-W/-K (HERV-W/-K) elements and possibly by activation of human herpesvirus-6A (HHV-6A) in early-stage CNS lesions, each contributing to an inflammatory cascade causing the relapsing-remitting neuro-inflammatory and/or progressive features characteristic of MS. Elimination of EBV-carrying B-cells by antibody- and EBV-specific T-cell therapy may hold the promise of reducing EBV activity in the CNS, thereby limiting CNS inflammation, MS symptoms and possibly reversing disease. Other approaches targeting HHV-6 and HERV-W and limiting inflammatory kinase-signaling to treat MS are also being tested with promising results. This article presents an overview of the evidence that EBV, HHV-6, and HERV-W may have a pathogenic role in initiating and promoting MS and possible approaches to mitigate development of the disease.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Antibodies / Antibodies, Viral - immunology / Antigen presentation / Antigen-Antibody Complex - immunology / Antigen-antibody complexes / Antigens / Apoptosis / Astrocytes / Autoimmunity / B-Lymphocytes - immunology / Blood-Brain Barrier / Brain - virology / Cell therapy / Cells / Central nervous system / Coinfection / Cytokines / Cytomegalovirus / DNA methylation / DNA, Viral - immunology / Drb1 protein / Endogenous Retroviruses - pathogenicity / Endogenous Retroviruses - physiology / Epidemiology / Epstein-Barr virus / Epstein-Barr Virus Nuclear Antigens - genetics / Epstein-Barr Virus Nuclear Antigens - immunology / Exosomes / Gene expression / Gene Products, env - physiology / Genetic Predisposition to Disease / Genomes / Health risk assessment / Herpes viruses / Herpesviridae Infections - complications / Herpesviridae Infections - immunology / Herpesviridae Infections - virology / Herpesvirus 4, Human - immunology / Herpesvirus 4, Human - pathogenicity / Herpesvirus 6, Human - immunology / Herpesvirus 6, Human - pathogenicity / human endogenous retrovirus-W / human herpesvirus-6 / Humans / Immune response / Immunogenicity / Immunoglobulin G / Immunology / Infections / Inflammation / inflammatory cascade / Lymph Nodes - virology / Lymphocytes / Lymphocytes B / Lymphocytes T / Magnetic resonance imaging / Memory / Microglia / MicroRNAs / Mimicry / miRNA / Models, Immunological / Molecular Mimicry / Multiple sclerosis / Multiple Sclerosis - etiology / Multiple Sclerosis - immunology / Multiple Sclerosis - therapy / Multiple Sclerosis - virology / Myelin / Myelin Sheath - immunology / Myelin Sheath - pathology / Neurodegeneration / Neuroinflammatory Diseases - etiology / Neuroinflammatory Diseases - virology / Pathogenesis / Pregnancy Proteins - physiology / Proteins / Risk factors / Transcriptional Activation / Virus Activation / Virus Latency / Young adults