The Essential Role of Epstein-Barr Virus in the Pathogenesis of Multiple Sclerosis

Pender, Michael P.

doi:10.1177/1073858410381531

Cited by 128 publications

(132 citation statements)

References 111 publications

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“…In the LPS lesion, the demyelination results from the focal administration of a bacterial toxin, but although some have suggested that MS may arise from bacterial activity,31 there is no reason from our data to believe that other mechanisms that result in similar activation of the innate immune system, such as Epstein–Barr virus infection,32 would not also cause demyelination. If so, the precise identity of the infective agent may be less important than its ability in a particular person to induce a local environment toxic to oligodendrocytes, such as one characterized by hypoxia, nitric oxide, and superoxide.…”

Section: Discussionmentioning

confidence: 69%

Cause and prevention of demyelination in a model multiple sclerosis lesion

Desai

Davies

Tachrount³

et al. 2016

Annals of Neurology

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ObjectiveDemyelination is a cardinal feature of multiple sclerosis, but it remains unclear why new lesions form, and whether they can be prevented. Neuropathological evidence suggests that demyelination can occur in the relative absence of lymphocytes, and with distinctive characteristics suggestive of a tissue energy deficit. The objective was to examine an experimental model of the early multiple sclerosis lesion and identify pathogenic mechanisms and opportunities for therapy.MethodsDemyelinating lesions were induced in the rat spinal dorsal column by microinjection of lipopolysaccharide, and examined immunohistochemically at different stages of development. The efficacy of treatment with inspired oxygen for 2 days following lesion induction was evaluated.ResultsDemyelinating lesions were not centered on the injection site, but rather formed 1 week later at the white–gray matter border, preferentially including the ventral dorsal column watershed. Lesion formation was preceded by a transient early period of hypoxia and increased production of superoxide and nitric oxide. Oligodendrocyte numbers decreased at the site shortly afterward, prior to demyelination. Lesions formed at a site of inherent susceptibility to hypoxia, as revealed by exposure of naive animals to a hypoxic environment. Notably, raising the inspired oxygen (80%, normobaric) during the hypoxic period significantly reduced or prevented the demyelination.InterpretationDemyelination characteristic of at least some early multiple sclerosis lesions can arise at a vascular watershed following activation of innate immune mechanisms that provoke hypoxia, and superoxide and nitric oxide formation, all of which can compromise cellular energy sufficiency. Demyelination can be reduced or eliminated by increasing inspired oxygen to alleviate the transient hypoxia. Ann Neurol 2016;79:591–604

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Section: Discussionmentioning

confidence: 69%

Cause and prevention of demyelination in a model multiple sclerosis lesion

Desai

Davies

Tachrount³

et al. 2016

Annals of Neurology

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“…Production of antigen-specific IgG antibodies in response to infection can be associated with the development of self-and polyreactive antibodies (12)(13)(14)(15). In addition, 23% of circulating IgG-positive memory B cells normally express polyreactive antibodies, most of which arise by somatic mutations (5).…”

Section: Resultsmentioning

confidence: 99%

Differential regulation of self-reactivity discriminates between IgG⁺human circulating memory B cells and bone marrow plasma cells

Scheid

Mouquet

Köfer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Long-term humoral immunity is maintained by the formation of high-affinity class-switched memory B cells and long-lived antibody-secreting plasma cells. In healthy humans, a substantial fraction of IgG-positive memory B cells express self-reactive and polyreactive IgG antibodies that frequently develop by somatic mutations. Whether self-and polyreactive IgG-secreting B cells are also tolerated in the long-lived plasma cell pool is not known. To address this question, we cloned and expressed the Ig genes from 177 IgG-producing bone marrow plasma cells of four healthy donors. All antibodies were highly mutated but the frequency of self-and polyreactive IgG antibodies was significantly lower than that found in circulating memory B cells. The data suggest that in contrast to the development of memory B cells, entry into the bone marrow plasma cell compartment requires previously unappreciated selective regulation by mechanisms that limit the production of self-and polyreactive serum IgG antibodies. N ewly developing self-reactive B cells are efficiently counterselected at two tolerance checkpoints before becoming circulating naive B cells (1, 2). Antigen-mediated activation of naive B cells in the presence of T-cell help induces germinal centers and the development of memory B cells and long-lived bone marrow plasma cells that express high affinity, isotype class-switched antibodies (3, 4). Surprisingly, compared with naive B cells, circulating IgG-positive memory B cells are significantly enriched for self-reactive and polyreactive antibodies (5). These antibodies develop in the germinal center from nonself-reactive or polyreactive precursors by somatic mutations and appear in the serum of healthy humans in low amounts (6). Whether cells producing self-reactive and polyreactive IgG can enter the bone marrow plasma cell compartment has not been determined.To address this question, we produced recombinant monoclonal antibodies from isolated IgG-secreting plasma cells from bone marrow of four healthy donors (HDs) and compared the Ig gene features and antibody reactivity profiles to historic data obtained from IgG-positive memory B cells (5, 7). Ig gene sequence analysis showed that bone marrow plasma cells carry significantly higher numbers of somatic mutations than circulating memory B cells and that the two compartments differ in their Ig light (IgL) chain variable (V) gene use and IgG isotype subclass distribution. Further, the frequency of polyreactive and self-reactive IgG-positive antibodies was significantly lower in bone marrow plasma cells than in the memory B-cell compartment. In summary, the data suggest that entry into the bone marrow plasma cell compartment is selective for B cells producing highly mutated antibodies that are not self-or polyreactive.

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“…The resulting cellular detritus are captured and processed by APC and presented to autoreactive CD8-T lymphocytes who display an autoimmune reaction. In this manner, the pro-inflammatory cytokines and chemokines secreted during the infection mediate the damage, becoming activators of the T CD8 cells specific for viral antigen and autoreactive inductors of the autoimmune process [Pender: 2011]. In this case the activation and differentiation of T CD8 cells occurs in an unspecific way Becher et al , Haahr & Hollsberg, 2006. On the other hand, the CNS antiviral polyspecific immune response in MS, has become a potential tool to evidence chronic autoimmune response in these patients Cohrs, 2007.…”

Section: Viral Persistence and Activation Mediated By Inflammatory Cymentioning

confidence: 99%

Glial and Axonal Pathology in Multiple Sclerosis

Robinson-Agramonte¹,

González‐Quevedo²,

Gonçalves³

2012

Recent Advances in Immunology to Target Cancer, Inflammation and Infections

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The Essential Role of Epstein-Barr Virus in the Pathogenesis of Multiple Sclerosis

Cited by 128 publications

References 111 publications

Cause and prevention of demyelination in a model multiple sclerosis lesion

Cause and prevention of demyelination in a model multiple sclerosis lesion

Differential regulation of self-reactivity discriminates between IgG⁺human circulating memory B cells and bone marrow plasma cells

Glial and Axonal Pathology in Multiple Sclerosis

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The Essential Role of Epstein-Barr Virus in the Pathogenesis of Multiple Sclerosis

Cited by 128 publications

References 111 publications

Cause and prevention of demyelination in a model multiple sclerosis lesion

Cause and prevention of demyelination in a model multiple sclerosis lesion

Differential regulation of self-reactivity discriminates between IgG+human circulating memory B cells and bone marrow plasma cells

Glial and Axonal Pathology in Multiple Sclerosis

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Differential regulation of self-reactivity discriminates between IgG⁺human circulating memory B cells and bone marrow plasma cells