Multiple Sclerosis: Basic Concepts and Hypothesis
1989; Elsevier BV; Volume: 64; Issue: 5 Linguagem: Inglês
10.1016/s0025-6196(12)65563-3
ISSN1942-5546
Autores Tópico(s)Viral Infections and Immunology Research
ResumoMultiple sclerosis, an inflammatory disease of the central nervous system, is characterized by primary destruction of myelin. This review covers recent advances in neuropathology, immunogenetics, neuroimmunology, and neurovirology that have provided insights regarding its pathogenesis. Three hypotheses are discussed: (1) autoimmunity, (2) "bystander" demyelination, and (3) immune destruction of persistently infected oligodendrocytes. A paradigm for induction of primary demyelination is proposed in which immune cells recognize "foreign" antigens on the surface of oligodendrocytes in the context of major histocompatibility complex gene products. The final result of this scheme may be "dying-back gliopathy," the alteration being noted first in the most distal extension of the oligodendrocyte—that is, the myelin sheaths. Multiple sclerosis, an inflammatory disease of the central nervous system, is characterized by primary destruction of myelin. This review covers recent advances in neuropathology, immunogenetics, neuroimmunology, and neurovirology that have provided insights regarding its pathogenesis. Three hypotheses are discussed: (1) autoimmunity, (2) "bystander" demyelination, and (3) immune destruction of persistently infected oligodendrocytes. A paradigm for induction of primary demyelination is proposed in which immune cells recognize "foreign" antigens on the surface of oligodendrocytes in the context of major histocompatibility complex gene products. The final result of this scheme may be "dying-back gliopathy," the alteration being noted first in the most distal extension of the oligodendrocyte—that is, the myelin sheaths. Multiple sclerosis (MS) affects scattered areas of the central nervous system with a predilection for periventricular white matter, brainstem, spinal cord, and optic nerves.1Prineas JW The neuropathology of multiple sclerosis.in: Vinken PJ Bruyn GW Klawans HL Koetsier JC Handbook of Clinical Neurology. Vol 47: Demyelinating Diseases. Elsevier Science Publishing Company, New York1985: 213-257Google Scholar The plaques are characterized by primary demyelination (destruction of myelin sheaths with preservation of axons) and death of oligodendrocytes (myelin-producing cells) within the center of the lesion. During the early evolution of the plaque, perivascular inflammatory cells (lymphocytes, plasma cells, macrophages) invade the substance of the white matter and are thought to play a critical role in myelin destruction.2Prineas JW Wright RG Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis.Lab Invest. 1978; 38: 409-421PubMed Google Scholar This process is followed by extensive gliosis by astrocytes and aberrant attempts at remyelination with oligodendrocytes proliferating at the edges of the plaque.1Prineas JW The neuropathology of multiple sclerosis.in: Vinken PJ Bruyn GW Klawans HL Koetsier JC Handbook of Clinical Neurology. Vol 47: Demyelinating Diseases. Elsevier Science Publishing Company, New York1985: 213-257Google Scholar In addition, immunoglobulins are deposited within each plaque.3Prineas JW Graham JS Multiple sclerosis: capping of surface immunoglobulin G on macrophages engaged in myelin breakdown.Ann Neurol. 1981; 10: 149-158Crossref PubMed Scopus (234) Google Scholar Whether the principal effector cells that mediate demyelination are T cells or macrophages is unknown. Attempts to type the cells that infiltrate the brain in MS have yielded conflicting results.4Traugott U Reinherz EL Raine CS Multiple sclerosis: distribution of T cells, T cell subsets and Ia-positive macrophages in lesions of different ages.J Neuroimmunol. 1983; 4: 201-221Abstract Full Text PDF PubMed Scopus (287) Google Scholar, 5Booss J Esiri MM Tourtellotte WW Mason DY Immunohistological analysis of T lymphocyte subsets in the central nervous system in chronic progressive multiple sclerosis.J Neurol Sci. 1983; 62: 219-232Abstract Full Text PDF PubMed Scopus (245) Google Scholar, 6Traugott U Characterization and distribution of lymphocyte subpopulations in multiple sclerosis plaques versus autoimmune demyelinating lesions.Springer Semin Immunopathol. 1985; 8: 71-95PubMed Google Scholar, 7Hauser SL Bhan AK Gilles F Kemp M Kerr C Weiner HL Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions.Ann Neurol. 1986; 19: 578-587Crossref PubMed Scopus (323) Google Scholar Both CD8+ (cytotoxic/suppressor) T lymphocytes and CD4+ (helper/inducer) T lymphocytes surround the MS plaque. The relative proportions of T-cell subsets are controversial. Some investigators have found an excess of CD8+ cells in the perivascular cuffs at the edge of the lesion.7Hauser SL Bhan AK Gilles F Kemp M Kerr C Weiner HL Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions.Ann Neurol. 1986; 19: 578-587Crossref PubMed Scopus (323) Google Scholar Others have found an excess of CD4+ cells.4Traugott U Reinherz EL Raine CS Multiple sclerosis: distribution of T cells, T cell subsets and Ia-positive macrophages in lesions of different ages.J Neuroimmunol. 1983; 4: 201-221Abstract Full Text PDF PubMed Scopus (287) Google Scholar These discrepancies probably result from examination of the plaques at different stages of their evolution. Recent experiments have analyzed antigens of the major histocompatibility complex (MHC) in the brains of patients with MS.8Traugott U Multiple sclerosis: relevance of class I and class II MHC-expressing cells to lesion development.J Neuroimmunol. 1987; 16: 283-302Abstract Full Text PDF PubMed Scopus (165) Google Scholar The MHC is a set of closely linked genes that play a central role in the control of immune responses to self and foreign antigens. This function is of particular importance because CD4+ and CD8+ T cells recognize foreign antigen in the context of class II (HLA-DR, la) or class I (HLA-ABC) MHC gene products, respectively. The class II gene products, found primarily on macrophages and B cells, are important in presentation of antigen to T cells. Class I gene products are on the majority of cells in the body and are important in the generation of the cytotoxic response against viruses. The central nervous system is unique because MHC antigens normally are not present on neurons and glial cells.8Traugott U Multiple sclerosis: relevance of class I and class II MHC-expressing cells to lesion development.J Neuroimmunol. 1987; 16: 283-302Abstract Full Text PDF PubMed Scopus (165) Google Scholar In MS, however, class I and class II MHC-positive astrocytes are found with high frequency in active lesions. The class I-reactive glia are primarily associated with T-cell infiltrates, whereas class II-reactive astrocytes are found in many lesions, independently of the composition of inflammatory cells. Thus, class I and II MHC-positive astrocytes might play a role in local antigen presentation to T cells. In addition, the simultaneous presence of high numbers of class I MHC-positive astrocytes and CD8+ cells in acute lesions suggests the possibility that CD8+ cells play a role as cytotoxic T cells during early development of the lesion. The final consequence—that is, demyelination—in chronic active plaques may be attributable to several immunologic mechanisms, including receptor-mediated endocytosis by macrophages, cytotoxicity by T cells, or lymphokine release. One piece of evidence that provides an important clue to the pathogenesis of MS is the association between susceptibility and specific MHC haplotypes.9Oger JJF Arnason BGW Immunogenetics of multiple sclerosis.in: Panayi GS David CS Immunogenetics. Butterworths, Boston1984: 177-206Google Scholar Northern Caucasians with MS have an overrepresentation of the A3, B7, DR2, and Dw2 histocompatibility alleles with relative risks of 2 to 3 for the class I MHC alleles (A3, B7) and 4 to 5 for class II MHC alleles (DR2, Dw2). Because linkage disequilibria exist between these class I alleles and DR2, the possible increased representation of one group of alleles may merely reflect this phenomenon. The indefinite association between susceptibility and MHC haplotypes suggests that either more than one gene is involved or a strong environmental agent "breaks through" to disease in the absence of the MS susceptibility allele. The frequency of occurrence of A2, B12, DR7, and Dw7 is decreased in patients with MS.9Oger JJF Arnason BGW Immunogenetics of multiple sclerosis.in: Panayi GS David CS Immunogenetics. Butterworths, Boston1984: 177-206Google Scholar The data that pertain to this occurrence are in much better agreement, suggesting that some MHC alleles may protect against MS. Investigators have also reported that some MHC alleles (DR2) are associated with more progressive disease whereas others (DR3) are associated with more benign disease.10Duquette P Décary F Pleines J Boivin D Lamoureux G Cosgrove JBR Lapierre Y Clinical sub-groups of multiple sclerosis in relation to HLA: DR alleles as possible markers of disease progression.Can J Neurol Sci. 1985; 12: 106-110PubMed Google Scholar Studies in various populations (American blacks, Japanese, Arabs, Israeli Jews) have also shown an association with MHC but with different alleles in each case. The risk of MS developing among first-degree relatives of patients with MS is increased 15- to 20-fold over the risk in the general population.9Oger JJF Arnason BGW Immunogenetics of multiple sclerosis.in: Panayi GS David CS Immunogenetics. Butterworths, Boston1984: 177-206Google Scholar This finding may reflect either genetic factors or shared environmental agents. Attempts to analyze linkage between disease and HLA haplotypes in siblings affected by MS have substantiated a loose link between MS and MHC but do not permit conclusions about the mode of inheritance.11Stewart GJ McLeod JG Basten A Bashir HV HLA family studies and multiple sclerosis: a common gene, dominantly expressed.Hum Immunol. 1981; 3: 13-29Crossref PubMed Scopus (69) Google Scholar For more distant relatives, concordance for MS is lower but exceeds chance expectation. In contrast, for non-blood-relatives living together (for example, husband and wife), the concordance for MS is not increased above chance. Studies in twins have shown greater concordance between monozygotic twins than between dizygotic twins.12Bobowick AR Kurtzke JF Brody JA Hrubec Z Gillespie M Twin study of multiple sclerosis: an epidemiologic inquiry.Neurology. 1978; 28: 978-987Crossref PubMed Google Scholar, 13Williams A Eldridge R McFarland H Houff S Krebs H McFarlin D Multiple sclerosis in twins.Neurology. 1980; 30: 1139-1147Crossref PubMed Google Scholar, 14Ebers GC Bulman DE Sadovnick AD Paty DW Warren S Hader W Murray TJ Seland TP Duquette P Grey T Nelson R Nicolle M Brunet D A population-based study of multiple sclerosis in twins.N Engl J Med. 1986; 315: 1638-1642Crossref PubMed Scopus (518) Google Scholar, 15Kinnunen E Koskenvuo M Kaprio J Aho K Multiple sclerosis in a nationwide series of twins.Neurology. 1987; 37: 1627-1629Crossref PubMed Google Scholar Many monozygotic pairs, however, are discordant for MS, a strong argument that genetic influence is insufficient for the development of MS. Also, the severity and expression of the disease vary greatly between members of concordant pairs. Diseases that have been linked to the HLA complex have numerous similar features, including chronic course, inflammatory component, and weak genetic predisposition that does not obey mendelian genetics. One theory is that these disorders may have an autoimmune basis. The development of experimental autoimmune encephalomyelitis (EAE) as an animal model of MS has prompted investigation of the autoimmune basis of human demyelinating diseases.16Raine CS Traugott U Experimental autoimmune demyelination: chronic relapsing models and their therapeutic implications for multiple sclerosis.Ann NY Acad Sci. 1984; 436: 33-51Crossref PubMed Scopus (36) Google Scholar EAE can be induced by injection of central nervous system myelin or its components along with adjuvants. From the EAE model has evolved the concept that the primary target in MS may be myelin and not the oligodendrocyte.17Raine CS Experimental allergic encephalomyelitis and experimental allergic neuritis.in: Vinken PJ Bruyn GW Klawans HL Koetsier JC Handbook of Clinical Neurology. Vol 47: Demyelinating Diseases. Elsevier Science Publishing Company, New York1985: 429-466Google Scholar In addition, the disease can be transferred to naive animals with cells enriched for T lymphocytes reactive to the basic protein component of myelin.17Raine CS Experimental allergic encephalomyelitis and experimental allergic neuritis.in: Vinken PJ Bruyn GW Klawans HL Koetsier JC Handbook of Clinical Neurology. Vol 47: Demyelinating Diseases. Elsevier Science Publishing Company, New York1985: 429-466Google Scholar, 18Mokhtarian F McFarlin DE Raine CS Adoptive transfer of myelin basic protein-sensitized T cells produces chronic relapsing demyelinating disease in mice.Nature. 1984; 309: 356-358Crossref PubMed Scopus (318) Google Scholar, 19Sakai K Namikawa T Kunishita T Yamanouchi K Tabira T Studies of experimental allergic encephalomyelitis by using encephalitogenic T cell lines and clones in euthymic and athymic mice.J Immunol. 1986; 137: 1527-1531PubMed Google Scholar Therefore, attempts have been made to determine whether an immune response to normal myelin develops in patients with MS. To date, efforts to measure such a response in patients with MS have failed even though these responses can be detected in patients with postinfectious encephalomyelitis.20Hafler DA Benjamin DS Burks J Weiner HL Myelin basic protein and proteolipid protein reactivity of brain- and cerebrospinal fluid-derived T cell clones in multiple sclerosis and postinfectious encephalomyelitis.J Immunol. 1987; 139: 68-72PubMed Google Scholar Although certain immunologic abnormalities have been reported in MS, many of the findings are still controversial.21Bach MA Immunoregulatory T cells in multiple sclerosis: markers and functions.Springer Semin Immunopathol. 1985; 8: 45-56PubMed Google Scholar CD8+ lymphocytes apparently are decreased in the blood of patients with active MS and in those with a progressive course,22Paty DW Kastrukoff L Morgan N Hiob L Suppressor T-lymphocytes in multiple sclerosis: analysis of patients with acute relapsing and chronic progressive disease.Ann Neurol. 1983; 14: 445-449Crossref PubMed Scopus (61) Google Scholar, 23Hauser SL Reinherz EL Hoban CJ Schlossman SF Weiner HL Immunoregulatory T-cells and lymphocytotoxic antibodies in active multiple sclerosis: weekly analysis over a six-month period.Ann Neurol. 1983; 13: 418-425Crossref PubMed Scopus (72) Google Scholar, 24Kastrukoff LF Paty DW A serial study of peripheral blood T lymphocyte subsets in relapsing-remitting multiple sclerosis.Ann Neurol. 1984; 15: 250-256Crossref PubMed Scopus (42) Google Scholar, 25Hafler DA Fox DA Manning ME Schlossman SF Reinherz EL Weiner HL In vivo activated T lymphocytes in the peripheral blood and cerebrospinal fluid of patients with multiple sclerosis.N Engl J Med. 1985; 312: 1405-1411Crossref PubMed Scopus (273) Google Scholar a situation that leads to a relative increase in the CD4/CD8 ratio. Disease activity is not always associated with these T-cell changes, however. The data on T-cell subsets in the cerebrospinal fluid are more discordant.26Hauser SL Reinherz EL Hoban CJ Schlossman SF Weiner HL CSF cells in multiple sclerosis: monoclonal antibody analysis and relationship to peripheral blood T-cell subsets.Neurology. 1983; 33: 575-579Crossref PubMed Google Scholar, 27Hafler DA Buchsbaum M Johnson D Weiner HL Phenotypic and functional analysis of T cells cloned directly from the blood and cerebrospinal fluid of patients with multiple sclerosis.Ann Neurol. 1985; 18: 451-458Crossref PubMed Scopus (39) Google Scholar, 28Noronha A Richman DP Arnason BGW Multiple sclerosis: activated cells in cerebrospinal fluid in acute exacerbations.Ann Neurol. 1985; 18: 722-725Crossref PubMed Scopus (26) Google Scholar Some investigators have reported a corresponding decrease in CD8+ cells in the cerebrospinal fluid,28Noronha A Richman DP Arnason BGW Multiple sclerosis: activated cells in cerebrospinal fluid in acute exacerbations.Ann Neurol. 1985; 18: 722-725Crossref PubMed Scopus (26) Google Scholar whereas others have found no change.26Hauser SL Reinherz EL Hoban CJ Schlossman SF Weiner HL CSF cells in multiple sclerosis: monoclonal antibody analysis and relationship to peripheral blood T-cell subsets.Neurology. 1983; 33: 575-579Crossref PubMed Google Scholar, 27Hafler DA Buchsbaum M Johnson D Weiner HL Phenotypic and functional analysis of T cells cloned directly from the blood and cerebrospinal fluid of patients with multiple sclerosis.Ann Neurol. 1985; 18: 451-458Crossref PubMed Scopus (39) Google Scholar Some investigators have argued that the loss of CD8+ cells from the blood represents a disorder of immunoregulation.22Paty DW Kastrukoff L Morgan N Hiob L Suppressor T-lymphocytes in multiple sclerosis: analysis of patients with acute relapsing and chronic progressive disease.Ann Neurol. 1983; 14: 445-449Crossref PubMed Scopus (61) Google Scholar Others have suggested that the imbalance is the result of preferential sequestration of CD8+ cells in the central nervous system or lymphoid organs.25Hafler DA Fox DA Manning ME Schlossman SF Reinherz EL Weiner HL In vivo activated T lymphocytes in the peripheral blood and cerebrospinal fluid of patients with multiple sclerosis.N Engl J Med. 1985; 312: 1405-1411Crossref PubMed Scopus (273) Google Scholar Recent experiments suggest a decrease in the suppressor/inducer subset (CD4+, 2H4+) in serum of patients with progressive MS.29Morimoto C Hafler DA Weiner HL Letvin NL Hagan M Daley J Schlossman SF Selective loss of the suppressor-inducer T-cell subset in progressive multiple sclerosis: analysis with anti-2H4 monoclonal antibody.N Engl J Med. 1987; 316: 67-72Crossref PubMed Scopus (236) Google Scholar These suppressor/inducer cells are not found in the cerebrospinal fluid, an indication that the loss of such cells is not due to migration into the central nervous system. Suppressor T-cell function is also defective during active disease, as measured by concanavalin A-induced T-cell suppression30Antel JP Arnason BGW Medof ME Suppressor cell function in multiple sclerosis: correlation with clinical disease activity.Ann Neurol. 1979; 5: 338-342Crossref PubMed Scopus (229) Google Scholar, 31Antel JP Rosenkoetter M Reder A Oger JJ-F Arnason BGW Multiple sclerosis: relation of in vitro IgG secretion to T suppressor cell number and function.Neurology. 1984; 34: 1155-1160Crossref PubMed Google Scholar or by polyclonal IgG stimulation of peripheral blood mononuclear cells by pokeweed mitogen.32Goust J-M Hogan EL Arnaud P Abnormal regulation of IgG production in multiple sclerosis.Neurology. 1982; 32: 228-234Crossref PubMed Google Scholar Natural killer cell activity against tumor or virally infected targets may be decreased in MS,33Hauser SL Ault KA Levin MJ Garovoy MR Weiner HL Natural killer cell activity in multiple sclerosis.J Immunol. 1981; 127: 1114-1117PubMed Google Scholar but these results have not been confirmed.34Rice GPA Casali P Merigan TC Oldstone MBA Natural killer cell activity in patients with multiple sclerosis given α interferon.Ann Neurol. 1983; 14: 333-338Crossref PubMed Scopus (34) Google Scholar, 35Hirsch RL Johnson KP The effect of recombinant alpha2-interferon on defective natural killer cell activity in multiple sclerosis.Neurology. 1985; 35: 597-600Crossref PubMed Google Scholar Attempts to identify a single infectious agent as the cause of MS have been unsuccessful thus far.36Johnson RT Viral Infections of the Nervous System. Raven Press, New York1982Google Scholar Many infectious agents have been isolated in cultures of specimens from patients with MS, but the majority represent contaminants or noncausal agents. In addition, direct inoculation of brain material into primates, so successful in identifying a transferable agent in Creutzfeldt-Jakob disease, has been negative or inconclusive. The more sensitive technique of looking for "footprints" of virus infection in brain tissue by nucleic acid hybridization with radiolabeled DNA probes or RNA probes (riboprobes) complementary to viral genomes has suggested that some brains of subjects with MS harbor measles virus.37Haase AT Ventura P Gibbs Jr, CJ Tourtellotte WW Measles virus nucleotide sequences: detection by hybridization in situ.Science. 1981; 212: 672-675Crossref PubMed Scopus (107) Google Scholar The finding of measles virus genome in several control subjects without MS, however, suggested that viruses may reside in the nervous system without causing disease.37Haase AT Ventura P Gibbs Jr, CJ Tourtellotte WW Measles virus nucleotide sequences: detection by hybridization in situ.Science. 1981; 212: 672-675Crossref PubMed Scopus (107) Google Scholar Analysis of the cerebrospinal fluid of patients with MS shows increased IgG levels along with oligoclonal Ig bands.38Hershey LA Trotter JL The use and abuse of the cerebrospinal fluid IgG profile in the adult: a practical evaluation.Ann Neurol. 1980; 8: 426-434Crossref PubMed Scopus (88) Google Scholar, 39Miller JR Burke AM Bever CT Occurrence of oligoclonal bands in multiple sclerosis and other CNS diseases.Ann Neurol. 1983; 13: 53-58Crossref PubMed Scopus (68) Google Scholar, 40Vartdal F Vandvik B Norrby E Viral and bacterial antibody responses in multiple sclerosis.Ann Neurol. 1980; 8: 248-255Crossref PubMed Scopus (94) Google Scholar Attempts to identify the antigen to which the IgG is directed have been unsuccessful.40Vartdal F Vandvik B Norrby E Viral and bacterial antibody responses in multiple sclerosis.Ann Neurol. 1980; 8: 248-255Crossref PubMed Scopus (94) Google Scholar In serum samples from patients with MS, titers of antibody to measles virus are increased.40Vartdal F Vandvik B Norrby E Viral and bacterial antibody responses in multiple sclerosis.Ann Neurol. 1980; 8: 248-255Crossref PubMed Scopus (94) Google Scholar, 41Adams JM Imagawa DT Measles antibodies in multiple sclerosis.Proc Soc Exp Biol Med. 1962; 111: 562-566Crossref PubMed Scopus (245) Google Scholar In many patients with MS, however, antibody titers to two or more viruses are increased in the cerebrospinal fluid. In diseases that are known to be caused by a virus (subacute sclerosing panencephalitis [measles] and mumps meningitis), IgG and oligoclonal bands in the cerebrospinal fluid are directed almost exclusively against the infectious agent.42Vandvik B Norrby E Oligoclonal IgG antibody response in the central nervous system to different measles virus antigens in subacute sclerosing panencephalitis.Proc Natl Acad Sci USA. 1973; 70: 1060-1063Crossref PubMed Scopus (132) Google Scholar, 43Link H Laurenzi MA Frydén A Viral antibodies in oligoclonal and polyclonal IgG synthesized within the central nervous system over the course of mumps meningitis.J Neuroimmunol. 1981; 1: 287-298Abstract Full Text PDF PubMed Scopus (25) Google Scholar Because this is not the case with MS, some investigators have suggested that, in MS, the IgG in the central nervous system is "nonsense antibody" that represents a dysfunction in immune regulation. The alternative hypothesis is that the humoral immune response is to an unrecognized infectious agent that is the cause of MS. Two approaches to distinguish whether antibody is "nonsense" or "sense" have been used: analysis of banding patterns of IgG eluted from different MS plaques in the same patient44Mattson DH Roos RP Arnason BGW Isoelectric focusing of IgG eluted from multiple sclerosis and subacute sclerosing panencephalitis brains.Nature. 1980; 287: 335-337Crossref PubMed Scopus (118) Google Scholar and study of idiotypes (combining sites of antibody molecules) of the oligoclonal IgG in cerebrospinal fluid from multiple patients.45Gerhard W Taylor A Wroblewska Z Sandberg-Wollheim M Koprowski H Analysis of a predominant immunoglobulin population in the cerebrospinal fluid of a multiple sclerosis patient by means of an anti-idiotypic hybridoma antibody.Proc Natl Acad Sci USA. 1981; 78: 3225-3229Crossref PubMed Scopus (16) Google Scholar, 46Gerhard W Taylor A Sandberg-Wollheim M Koprowski H Longitudinal analysis of three intrathecally produced immunoglobulin subpopulations in an MS patient.J Immunol. 1985; 134: 1555-1560PubMed Google Scholar The first approach showed that each MS plaque may have unique IgG banding patterns. The second approach showed that anti-idiotypic antisera raised against cerebrospinal fluid IgG fail to cross-react with cerebrospinal fluid from other patients with MS. These results are consistent with the possibility that the antibody is, indeed, a "nonsense antibody." An important impetus to continuation of the search for a viral cause for MS has come from study of several naturally occurring model diseases in animals in which viruses cause demyelination.47Dal Canto MC Rabinowitz SG Experimental models of virus-induced demyelination of the central nervous system.Ann Neurol. 1982; 11: 109-127Crossref PubMed Scopus (143) Google Scholar These diseases include canine distemper virus (paramyxovirus) in dogs,48McCullough B Krakowka S Koestner A Experimental canine distemper virus-induced demyelination.Lab Invest. 1974; 31: 216-222PubMed Google Scholar visna virus (nononcogenic retrovirus) in sheep,49Haase AT Pathogenesis of lentivirus infections.Nature. 1986; 322: 130-136Crossref PubMed Scopus (408) Google Scholar JHM virus (coronavirus) in mice50Lampert PW Sims JK Kniazeff AJ Mechanism of demyelination in JHM virus encephalomyelitis: electron microscopic studies.Acta Neuropathol (Berl). 1973; 24: 76-85Crossref PubMed Scopus (196) Google Scholar and rats,51Watanabe R Wege H ter Meulen V Adoptive transfer of EAE-like lesions from rats with coronavirus-induced demyelinating encephalomyelitis.Nature. 1983; 305: 150-153Crossref PubMed Scopus (178) Google Scholar Semliki Forest virus (togavirus) in mice,52Suckling AJ Pathak S Jagelman S Webb HE Virus-associated demyelination: a model using avirulent Semliki Forest virus infection of mice.J Neurol Sci. 1978; 39: 147-154Abstract Full Text PDF PubMed Scopus (45) Google Scholar and Theiler's virus (picornavirus) in mice.53Lipton HL Theiler's virus infection in mice: an unusual biphasic disease process leading to demyelination.Infect Immun. 1975; 11: 1147-1155PubMed Google Scholar The mechanisms of the demyelination in these viral models are beginning to be understood. For example, in JHM virus infection in mice the demyelination seems to be the result of direct cytopathic injury of oligodendrocytes, the myelin-producing cells.50Lampert PW Sims JK Kniazeff AJ Mechanism of demyelination in JHM virus encephalomyelitis: electron microscopic studies.Acta Neuropathol (Berl). 1973; 24: 76-85Crossref PubMed Scopus (196) Google Scholar In contrast, in rats the demyelination by JHM may be a consequence of autoimmune mechanisms by which sensitized T cells recognize myelin antigens.51Watanabe R Wege H ter Meulen V Adoptive transfer of EAE-like lesions from rats with coronavirus-induced demyelinating encephalomyelitis.Nature. 1983; 305: 150-153Crossref PubMed Scopus (178) Google Scholar In visna virus, macrophages that are persistently infected are actively involved in the demyelinating process.53Lipton HL Theiler's virus infection in mice: an unusual biphasic disease process leading to demyelination.Infect Immun. 1975; 11: 1147-1155PubMed Google Scholar With infection by Theiler's virus, viral antigens have been detected on the inner and outer glial loops of oligodendrocytes such that an immune response seems to be directed against viral or "novel" antigens on the surface of these glial cells.54Rodriguez M Oleszak E Leibowitz J Theiler's murine encephalomyelitis: a model of demyelination and persistence of virus.CRC Crit Rev Immunol. 1987; 7: 325-365Google Scholar, 55Rodriguez M Leibowitz JL Lampert PW Persistent infection of oligodendrocytes in Theiler's virus-induced encephalomyelitis.Ann Neurol. 1983; 13: 426-433Crossref PubMed Scopus (227) Google Scholar, 56Rodriguez M Pease LR David CS Immune-mediated injury of virus-infected oligodendrocytes: a model of multiple sclerosis.Immunol Today. 1986; 7: 359-363Abstract Full Text PDF Scopus (53) Google Scholar These experiments emphasize that viruses from different "families" may induce primary demyelination, probably by unique mechanisms.44Mattson DH Roos RP Arnason BGW Isoelectric focusing of IgG eluted from multiple sclerosis and subacute sclerosing panencephalitis brains.Nature. 1980; 287: 335-337Crossref PubMed Scopus (118) Google Scholar The recent discovery, in Japan57Osame M Matsumoto M Usuku K Izumo S Ijichi N Amitani H Tara M Igata A Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemialike cells.Ann Neurol. 1987; 21: 117-122Crossref PubMed Scopus (597) Google Scholar and in the Caribbean,58Vernant JC Maurs L Gessain A Barin F Gout O Delaporte JM Sanhadji K Buisson G de-Thé G Endemic tropical spastic paraparesis associated with human T-lymphotropic virus type I: a clinical and seroepidemiological study of 25 cases.Ann Neurol. 1987; 21: 123-130Crossref PubMed Scopus (233) Google Scholar that chronic progressive myelopathy may be the result of persistent infection with human T-lymphotropic virus type I (HTLV-I) has stimulated speculation that viruses may be implicated in MS. Koprowski and associates59Koprowski H DeFreitas EC Harper ME Sandberg-Wollheim M Sheremata WA Robert-Guroff M Saxinger CW Feinberg MB Wong-Staal F Gallo RC Multiple sclerosis and human T-cell lymphotropic retroviruses.Nature. 1985; 318: 154-160Crossref PubMed Scopus (299) Google Scholar reported that serum and spinal fluid samples from patients with MS in Sweden and in Key West, Florida, contained antibodies reactive with viral protein (p24) of HTLV-I. Others have failed to detect any antibody to HTLV-I, II, or III in patients with MS.60Karpas A Kämpf U Sidèn à Koch M Poser S Lack of evidence for involvement of known human retroviruses in multiple sclerosis (letter to the editor).Nature. 1986; 322: 177-178Crossref PubMed Scopus (73) Google Scholar, 61Hauser SL Aubert C Burks JS Kerr C Lyon-Caen O de The G Brahic M Analysis of human T-lymphotropic virus sequences in multiple sclerosis tissue (letter to the editor).Nature. 1986; 322: 176-177Crossref PubMed Scopus (89) Google Scholar In Japan, however, investigators62Ohta M Ohta K Mori F Nishitani H Saida T Sera from patients with multiple sclerosis react with human T cell lymphotropic virus-I gag proteins but not env proteins—Western blotting analysis.J Immunol. 1986; 137: 3440-3443PubMed Google Scholar found that 11 of 46 patients with MS reacted to purified HTLV-I proteins by Western blot analysis. The discrepancies in the results may be due to differences in sensitivity of various methods. Recently, Reddy and associates63Reddy EP Sandberg-Wollheim M Mettus RV Ray PE DeFreitas E Koprowski H Amplification and molecular cloning of HTLV-I sequences from DNA of multiple sclerosis patients.Science. 1989; 243: 529-533Crossref PubMed Scopus (147) Google Scholar amplified and molecularly cloned HTLV-I sequences from DNA of lymphocytes from patients with MS. Confirmation of these results by other investigators will be necessary before a firm statement can be made about its role in pathogenesis. Several hypotheses have been proposed to explain the clinical and experimental features of this demyelinating disorder, three of which will be discussed. They are relevant to the possibility of an immune-mediated demyelination triggered by viral infection. The most widely considered hypothesis is that MS is the result of an immune reaction directed against self myelin antigens.64Arnason BGW Relevance of experimental allergic encephalomyelitis to multiple sclerosis.Neurol Clin. August 1983; 1: 765-782PubMed Google Scholar T cells are thought to enter the central nervous system through endothelial cells and to react with normal white matter. The myelin antigens may be presented to helper T cells (CD4+) by endothelial cells65McCarron RM Kempski O Spatz M McFarlin DE Presentation of myelin basic protein by murine cerebral vascular endothelial cells.J Immunol. 1985; 134: 3100-3103PubMed Google Scholar or astrocytes,66Hofman FM von Hanwehr RI Dinarello CA Mizel SB Hinton D Merrill JE Immunoregulatory molecules and IL 2 receptors identified in multiple sclerosis brain.J Immunol. 1986; 136: 3239-3245PubMed Google Scholar which are known to carry class II MHC antigens in MS lesions. As a result of T-cell activation, lymphokines and macrophages could mediate myelin destruction.3Prineas JW Graham JS Multiple sclerosis: capping of surface immunoglobulin G on macrophages engaged in myelin breakdown.Ann Neurol. 1981; 10: 149-158Crossref PubMed Scopus (234) Google Scholar This hypothesis is supported by elegant experiments, using EAE, that demonstrated that T-cell clones (CD4+) sensitized to myelin proteins can mediate demyelination in the central nervous system.18Mokhtarian F McFarlin DE Raine CS Adoptive transfer of myelin basic protein-sensitized T cells produces chronic relapsing demyelinating disease in mice.Nature. 1984; 309: 356-358Crossref PubMed Scopus (318) Google Scholar, 19Sakai K Namikawa T Kunishita T Yamanouchi K Tabira T Studies of experimental allergic encephalomyelitis by using encephalitogenic T cell lines and clones in euthymic and athymic mice.J Immunol. 1986; 137: 1527-1531PubMed Google Scholar In addition, the linkage of the disease with class II MHC gene products (DR2) is further evidence that this mechanism may be important. A series of crucial experiments by Hafler and associates20Hafler DA Benjamin DS Burks J Weiner HL Myelin basic protein and proteolipid protein reactivity of brain- and cerebrospinal fluid-derived T cell clones in multiple sclerosis and postinfectious encephalomyelitis.J Immunol. 1987; 139: 68-72PubMed Google Scholar on T-cell clones isolated from the cerebrospinal fluid of patients with MS, however, failed to identify a single clone that was reactive for myelin antigens despite the ongoing demyelination. In contrast, myelin-reactive clones were demonstrated in patients with postinfectious encephalomyelitis. One important hypothesis being considered is that in MS the myelin is an "innocent bystander" that is destroyed as a consequence of an immune response occurring within the nervous system.47Dal Canto MC Rabinowitz SG Experimental models of virus-induced demyelination of the central nervous system.Ann Neurol. 1982; 11: 109-127Crossref PubMed Scopus (143) Google Scholar This hypothesis may help explain why different viruses can induce demyelination in the nervous system of rodents and why different "etiologic" agents have been isolated from MS-involved brains. The scenario would be that viruses or other infectious agents frequently invade the central nervous system. During the defense against this infection, T lymphocytes and macrophages are recruited to the lesion. Subsequently, in the process of clearance of virus by T cells, myelin is destroyed nonspecifically by lymphokines or neutral proteases released by activated macrophages. Experiments by Wisniewski and Bloom67Wisniewski HM Bloom BR Primary demyelination as a nonspecific consequence of a cell-mediated immune reaction.J Exp Med. 1975; 141: 346-359Crossref PubMed Scopus (173) Google Scholar support this hypothesis by demonstrating that animals previously sensitized to purified protein derivative (PPD) of tuberculin will undergo demyelination if challenged by this antigen in the nervous system. In addition, myelin basic protein can be degraded by neutral proteases in vitro.68Cammer W Bloom BR Norton WT Gordon S Degradation of basic protein in myelin by neutral proteases secreted by stimulated macrophages: a possible mechanism of inflammatory demyelination.Proc Natl Acad Sci USA. 1978; 75: 1554-1558Crossref PubMed Scopus (239) Google Scholar The concept of bystander demyelination, however, is not supported by the observation that demyelination is a rare consequence of an immune response to viral or fungal encephalitides. If bystander demyelination were more prominent, then demyelination would occur each time the immune system interacts with viruses that infect the central nervous system (that is, measles, mumps, and herpes). It may be argued, however, that genetic factors control whether specific lymphokines that could induce demyelination are released. On the basis of the paradigm of demyelination in mice induced by Theiler's virus, Rodriguez and colleagues56Rodriguez M Pease LR David CS Immune-mediated injury of virus-infected oligodendrocytes: a model of multiple sclerosis.Immunol Today. 1986; 7: 359-363Abstract Full Text PDF Scopus (53) Google Scholar proposed that the demyelination in MS may be the result of immune-mediated destruction of virus-infected oligodendrocytes. This hypothesis would incorporate epidemiologic data (exogenous agent) and a contribution of immunogenetics to pathogenesis. Immunogenetic data in MS implicate that specific genes within the MHC protect against the development of MS. Genes may play a role in host resistance against the exogenous agent that is acquired early in life. In resistant hosts, viral antigens would be recognized in the context of class I or class II MHC gene products, and viral replication would be limited as a consequence of a protective immune response. Virus would be cleared from the central nervous system without long-term sequelae. In susceptible hosts, absence of specific MHC gene products may result in failure of clearance of the virus; thus, the virus persists in glial cells. During the course of infection, the virus could infect oligodendrocytes in a manner such that novel antigens are present on the surface of these cells (Fig. 1). These novel antigens may be virus antigens or "up-regulated" normal host antigens that are seen as foreign in the context of specific MHC alleles. The virus itself may be capable of inducing demyelination by interfering with the function of the myelin-producing cell. The current evidence suggests, however, that immune cells must also play a role in demyelination because immunosuppression seems to have a favorable effect on the course of MS. The presence of a novel antigen on an oligodendrocyte or on myelin could result in immunoglobulin-directed killing (injury by complement, antibody-dependent cell-mediated cytotoxicity, or activation of macrophages). Processed viral antigens may be recognized by CD8+ cells (class I-restricted cytotoxic T cells) or CD4+ cells (class II-restricted cytotoxic T cells), which could be effectors in demyelination. The final result would be injury to the myelin-producing cell or to the myelin sheath. This result may occur as a dying-back gliopathy,69Ludwin SK Johnson ES Evidence for a "dying-back" gliopathy in demyelinating disease.Ann Neurol. 1981; 9: 301-305Crossref PubMed Scopus (102) Google Scholar, 70Rodriguez M Virus-induced demyelination in mice: "dying back" of oligodendrocytes.Mayo Clin Proc. 1985; 60: 433-438Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar the alteration being noted first in the most distal extension of the oligodendrocytes (that is, the glial loops and myelin sheaths) and interfering with the differential function of the oligodendrocyte (that is, the maintenance of myelin). The evidence suggests that an exogenous agent (that is, a virus) may be important in triggering demyelination in MS. If multiple exogenous agents are able to induce this pathologic process, however, then identifying the offending agent may prove to be difficult. If common pathogens can produce demyelination, then distinguishing these etiologic agents from the viruses that "normally" reside in the central nervous system may be impossible. Alternatively, attempts to interfere specifically with various arms of the immune response by use of monoclonal antibody therapy may be beneficial without the requirement of knowing the causative agent. The scheme proposed in Figure 1 may provide the basis for designing specific immunotherapy to interfere with demyelination.
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