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Microbial infections and multiple sclerosis Ryuji KUBOTA 1 , Shuji IZUMO 1 1Division of Molecular Pathology, Center for Chronic Viral Diseases, Kagoshima University Keyword: 多発性硬化症 , ウイルス , molecular mimicry , bystander activation pp.503-515
Published Date 2006/8/10
DOI https://doi.org/10.11477/mf.1431100159
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Multiple sclerosis(MS)is an inflammatory demyelinating disease of the central nervous system(CNS). It has been postulated that microbial infections or autoimmune process may contribute to the pathogenesis of MS. A large body of evidences from epidemiology including geographical distribution, immigrants, homozygous twins, and preceding viral infections before MS exacerbation, and animal models for virus-induced demyelination indicates that microbial infections are associated with initiation and exacerbation of MS. It has been reported that many viruses such as Epstein-Barr virus, human herpesvirus 6, and measles virus may be associated with the disease, however, despite extensive efforts for seeking a single causative agent for MS, it has not been known. This indicates that multiple microbes, not a single agent, may contribute to the pathogenesis of MS. The possible mechanisms in which viral infections cause the disease include molecular mimicry, bystander activation with or without epitope spreading, and persistent viral infection in the CNS. In the molecular mimicry model, T cells recognize both foreign antigens and self antigens. Peripheral T cells recognize viral antigens after viral infection, some of which migrate into the CNS and cross-recognize autoantigens on antigen-presenting cells(APC)in the CNS, resulting in the tissue damage. Antigen recognition by T cell receptor(TCR)is highly degenerate, in which a single TCR can recognize a huge number of different antigens with various affinities, even if there is no amino acid homology among antigens. Furthermore, T cells originally have a potential to recognize autoantigens, because T cells, which recognize autoantigens with weak affinity, are positively selected in the thymus. Therefore it is not surprising that CNS autoantigen-specific T cells can be detected in the peripheral blood not only from MS patients but also from healthy individuals. These findings strongly support the view that molecular mimicry is considered to be a common phenomenon. However, it is not known whether the mechanism of molecular mimicry is sufficient for the pre-existing autoreactive T cells becoming autoaggressive ones which can induce the disease. In the bystander activation model, which is representative in a demyelinating disease by Theiler’s murine encephalomyelitis virus(TMEV), viral infection to the CNS resident cells causes tissue damage, resulting in epitope spreading of cryptic CNS antigens. CNS APC expressing the released autoantigens sufficiently stimulates the pre-existing autoreactive T cells;thereafter the T cells become autoaggressive to attack the CNS. This model requires some virus to infect the CNS resident cells. The mechanisms of molecular mimicry and bystander activation may not be exclusive for the pathogenesis of MS. In the persistent viral infection model, e. g. TMEV infection, the virus infects CNS resident cells such as oligodendrocytes and destroys the infected cells, resulting in demyelination. HTLV-Ⅰ-associated myelopathy(HAM)is an inflammatory human disease associated with retrovirus infection and resembles the primary progressive form of MS. In HAM, HTLV-Ⅰ-infected CD4+T cells and HTLV-Ⅰ-specific CD8+cytotoxic T cells are increased in the periphery and accumulated in the CNS, causing the immune response to induce the CNS damage. This is bystander activation by non-autoantigen specific, virus specific T cells, which does not need viral infection to the CNS resident cells. So far, it is not known whether autoimmune process can be involved in HAM. It is necessary to do further studies on autoreactive T cells of HAM. The development of immunology will improve our better understanding of MS and will help to establish more effective therapy for the disease.


Copyright © 2006, Igaku-Shoin Ltd. All rights reserved.

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電子版ISSN 1882-1243 印刷版ISSN 0001-8724 医学書院

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