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Front Immunol ; 12: 757302, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790199

RESUMO

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*1501ß, 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.


Assuntos
Retrovirus Endógenos/patogenicidade , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 6/patogenicidade , Esclerose Múltipla/etiologia , Doenças Neuroinflamatórias/virologia , Anticorpos Antivirais/imunologia , Complexo Antígeno-Anticorpo/imunologia , Autoimunidade , Linfócitos B/imunologia , Barreira Hematoencefálica , Encéfalo/virologia , Coinfecção , DNA Viral/imunologia , Retrovirus Endógenos/fisiologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Produtos do Gene env/fisiologia , Predisposição Genética para Doença , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 6/imunologia , Humanos , Linfonodos/virologia , Modelos Imunológicos , Mimetismo Molecular , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Esclerose Múltipla/virologia , Bainha de Mielina/imunologia , Bainha de Mielina/patologia , Doenças Neuroinflamatórias/etiologia , Proteínas da Gravidez/fisiologia , Ativação Transcricional , Ativação Viral , Latência Viral
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