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      Viral infections and multiple sclerosis

      review-article
      Drug Discovery Today. Disease Models
      Elsevier

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          Abstract

          The etiology and pathogenesis of MS is likely to involve multiple factors interacting with each other, and the role of infectious and viral agents is still under debate, however a consistent amount of studies suggests that some viruses are associated with the disease. The strongest documentation has come from the detection of viral nucleic acid or antigen or of an anti-viral antibody response in MS patients. A further step for the study of the mechanism viruses might be involved in can be made using in vitro and in vivo models. While in vitro models, based on glial and neural cell lines from various sources are widely used, in vivo animal models present challenges. Indeed neurotropic animal viruses are currently used to study demyelination in well-established models, but animal models of demyelination by human virus infection have only recently been developed, using animal gammaherpesviruses closely related to Epstein Barr virus (EBV), or using marmosets expressing the specific viral receptor for Human Herpesvirus 6 (HHV-6). The present review will illustrate the main potential mechanisms of MS pathogenesis possibly associated with viral infections and viruses currently used to study demyelination in animal models. Then the viruses most strongly linked with MS will be discussed, in the perspective that more than one virus might have a role, with varying degrees of interaction, contributing to MS heterogeneity.

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          Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein

          Structural similarity between viral T cell epitopes and self-peptides could lead to the induction of an autoaggressive T cell response. Based on the structural requirements for both MHC class 11 binding and TCR recognition of an immunodominant myelin basic protein (MBP) peptide, criteria for a data base search were developed in which the degeneracy of amino acid side chains required for MHC class 11 binding and the conservation of those required for T cell activation were considered. A panel of 129 peptides that matched the molecular mimicry motif was tested on seven MBP-specific T cell clones from multiple sclerosis patients. Seven viral and one bacterial peptide efficiently activated three of these clones. Only one peptide could have been identified as a molecular mimic by sequence alignment. The observation that a single T cell receptor can recognize quite distinct but structurally related peptides from multiple pathogens has important implications for understanding the pathogenesis of autoimmunity.
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            Is Open Access

            Multiple sclerosis: experimental models and reality

            One of the most frequent statements, provided in different variations in the introduction of experimental studies on multiple sclerosis (MS), is that “Multiple sclerosis is a demyelinating autoimmune disease and experimental autoimmune encephalomyelitis (EAE) is a suitable model to study its pathogenesis”. However, so far, no single experimental model covers the entire spectrum of the clinical, pathological, or immunological features of the disease. Many different models are available, which proved to be highly useful for studying different aspects of inflammation, demyelination, remyelination, and neurodegeneration in the central nervous system. However, the relevance of results from such models for MS pathogenesis has to be critically validated. Current EAE models are mainly based on inflammation, induced by auto-reactive CD4+ T-cells, and these models reflect important aspects of MS. However, pathological data and results from clinical trials in MS indicate that CD8+ T-cells and B-lymphocytes may play an important role in propagating inflammation and tissue damage in established MS. Viral models may reflect key features of MS-like inflammatory demyelination, but are difficult to use due to their very complex pathogenesis, involving direct virus-induced and immune-mediated mechanisms. Furthermore, evidence for a role of viruses in MS pathogenesis is indirect and limited, and an MS-specific virus infection has not been identified so far. Toxic models are highly useful to unravel mechanisms of de- and remyelination, but do not reflect other important aspects of MS pathology and pathogenesis. For all these reasons, it is important to select the right experimental model to answer specific questions in MS research.
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              Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis

              In the majority of patients multiple sclerosis starts with a relapsing remitting course (RRMS), which may at later times transform into secondary progressive disease (SPMS). In a minority of patients the relapsing remitting disease is skipped and the patients show progression from the onset (primary progressive MS, PPMS). Evidence obtained so far indicate major differences between RRMS and progressive MS, but no essential differences between SPMS and PPMS, with the exception of a lower incidence in the global load of focal white matter lesions and in particular in the presence of classical active plaques in PPMS. We suggest that in MS patients two types of inflammation occur, which develop in parallel but partially independent from each other. The first is the focal bulk invasion of T- and B-lymphocytes with profound blood brain barrier leakage, which predominately affects the white matter, and which gives rise to classical active demyelinated plaques. The other type of inflammation is a slow accumulation of T-cells and B-cells in the absence of major blood brain barrier damage in the connective tissue spaces of the brain, such as the meninges and the large perivascular Virchow Robin spaces, where they may form aggregates or in most severe cases structures in part resembling tertiary lymph follicles. This type of inflammation is associated with the formation of subpial demyelinated lesions in the cerebral and cerebellar cortex, with slow expansion of pre-existing lesions in the white matter and with diffuse neurodegeneration in the normal appearing white or gray matter. The first type of inflammation dominates in acute and relapsing MS. The second type of inflammation is already present in early stages of MS, but gradually increases with disease duration and patient age. It is suggested that CD8+ T-lymphocytes remain in the brain and spinal cord as tissue resident cells, which may focally propagate neuroinflammation, when they re-encounter their cognate antigen. B-lymphocytes may propagate demyelination and neurodegeneration, most likely by producing soluble neurotoxic factors. Whether lymphocytes within the brain tissue of MS lesions have also regulatory functions is presently unknown. Key open questions in MS research are the identification of the target antigen recognized by tissue resident CD8+ T-cells and B-cells and the molecular nature of the soluble inflammatory mediators, which may trigger tissue damage.
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                Author and article information

                Contributors
                Journal
                Drug Discov Today Dis Models
                Drug Discov Today Dis Models
                Drug Discovery Today. Disease Models
                Elsevier
                1740-6757
                1 March 2020
                1 March 2020
                :
                Affiliations
                [0005]Neurologia e Neurofisiologia Clinica, Azienda Ospedaliera Universitaria Senese I 53100 Siena, Italy
                Article
                S1740-6757(20)30005-0
                10.1016/j.ddmod.2020.02.003
                7102669
                32292487
                a8266eac-29c4-417f-97ee-26ccd593a489
                © 2020 Published by Elsevier Ltd.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

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