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Viruses and multiple sclerosis
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4.
5.
6.
7.
heat shock protein on oligodendroglia in older lesions. MHC II expression predominates in the active lesion and occurs on invading and resident macrophages and on astrocytes, but not on endothelial cells. Oligodendrocyte proliferation and CNS remyelination are common in active lesions. In chronic lesions, HSP-65 occurs in proliferated oligodendrocytes. Adhesion molecules and cytokines (e.g. TNF) associated with their upregulation are expressed in active lesions. These may have a role in cellular traffic to the CNS. Interactions between hypertrophic astrocytes and proliferating oligodendrocytes occur particularly in active lesions and involve expression of immature oligodendrocyte markers. These interactions are believed to reflect a protective rather than a phagocytic event and are not specific for MS (Supported by NMSS RG 1001-G-7 and NIH NS 08952 and NS 11920).
Immunogenetic studies in multiple sclerosis
Dale E. McFarlin (NINDS, Bethesda, MD, USA) Studies of MS in families, particularly twins, as well as ethnic populations, have provided strong evidence of genetic contributions to the pathogenesis of the disease. The findings indicate that multiple genes are involved and that MS is not purely genetic. In parallel, advances in the understanding of antigen recognition by T cells have established that the MHC and TcR molecules operate jointly in regulation of cellular immune reactivity. These advances have been applied to the modification and prevention of experimental allergic encephalomyelitis. Currently, there is considerable enthusiasm for attempting similar approaches in MS. At least three major questions remain: 1. To what extent can concepts developed in highly inbred rodents be extrapolated to outbred humans with MS?
2. Against what antigen(s) is immune reactivity directed in MS? 3. Do multiple immune responses contribute to the pathogenesis of MS in the overall patient population? Genes in addition to MHC and TcR may be related to the pathogenesis of MS. These include genes on the human 6th chromosome that code from proteins involved in antigen processing and the transport of MHC molecules to the cell surface. Considerable research is also being directed at genetic elements that regulate transcription. For example, regulation of MHC expression varies among different cells in the CNS and preliminary findings indicate that this reflects differences in transcription. Both the expression of class II MHC molecules and the production of cytokines such as tumor necrosis factor, also encoded on human chromosome 6, vary among different rat strains and correlate with susceptibility to EAE. These findings may be due to differences in transcription. Genes on other chromosomes may also be important. For example, recent studies on nonobese diabetic mice have provided evidence that genes outside the MHC complex are related to this spontaneously occurring autoimmune disease. The data indicate that these genes may encode the IL-1 receptor, and molecules that may be involved in homing of lymphocytes to the pancreas. Collectively, the findings imply that multiple gene influences may contribute to the pathogenesis of MS.
Viruses and multiple sclerosis
Richard T. Johnson (Johns Hopkins University School of Medicine, Baltimore, MD, USA) The role of viruses in the pathogenesis of multiple sclerosis (MS) remains unclear. A viral etiology was postulated over 100 years ago and studies of slow viral infections in the past three decades have rekindled speculation. Evidence for viruses as initiating factors in the disease comes from three areas of investigation. (1) Epidemiological studies have shown that, in addition to genetic factors, MS appears to be related to some
178
environmental exposure(s) in childhood. Furthermore, in several isolated populations clustering of cases has suggested "outbreaks" of the disease. (2) Studies of animals and of other human demyelinating diseases have shown that viruses can cause diseases with long incubation periods, and can cause myelin destruction by a variety of different mechanisms. Studies have also documented that viruses can initiate autoimmune responses to myelin proteins in susceptible hosts. (3) Studies in patients with MS have consistently shown abnormal immune responses particularly to viral antigens and have shown the intrathecal antibody synthesis to a variety of viruses, most notably measles. In prospective epidemiological studies exacerbations of disease have been temporally associated with symptoms of viral infections. Three human demyelinating diseases have been defined in which viral infectious agents are known. These include progressive multifocal leukoencephalopathy (PML), post-infectious encephalomyelitis, and human immunodeficiency virus encephalopathy and myelopathy. In each case, the virus is of a different family and in each case, the pathogenesis of the demyelination appears different. In PML, an opportunistic infection of the immunosuppressed, direct lytic infection of oligodendrocytes leads to multiple areas of central nervous system demyelination. The selective vulnerability of cells maintaining myelin provides the simplest method of causation of human demyelinating disease. The other diseases have not proved as straightforward. Post-infectious encephalomyelitis is a perivenular demyelinating disease that occurs as an unusual complication of a variety of viral infections, most prominently measles. Measles was the first human immunodeficiency syndrome ever described and studies of this immunodeficiency have shown that there is a leukopenia and at the same time there is a remarkable activation of cells, including the findings that the lymphocytes of 15% of the cases of measles and 47% of cases who develop encephalomyelitis proliferate in the presence of myelin basic protein. Virus is seldom isolated from the nervous system, intrathecal antibody synthesis does not occur, interferon is not
elevated in spinal fluid and viral proteins and viral RNA are not detectable by immunocytochemistry and by in situ hybridization in brains of patients dying with encephalomyelitis. Thus, the demyelinating disease does not appear to be caused by the selective vulnerability of any cell in the nervous system, but by infection of lymphoid cells, leading to the activation of lymphocytes including, in some patients, populations that are reactive against myelin basic protein and possibly other myelin constituents. These activated cells may selectively home to the nervous system, causing an autoimmune encephalitis after the virus has been cleared from lymphoid organs. Acquired immunodeficiency syndrome (AIDS) was not recognized until the summer of 1981. In 1985, however, it became evident that there was direct infection of the CNS and demyelination has been documented in both the brain and spinal cords in addition to a generalized myelin pallor. The pathogenesis of these myelin changes is unknown. Virus is present in both brain and spinal cord, but it has been found entirely, if not exclusively, in macrophages and microglial cells. By analogy to Visna, the prototype virus of the same lentivirus family, it is suggested that myelin destruction is mediated by cytokines released by infected macrophages or lymphocytes. In search for a virus in multiple sclerosis, there are lessons to be learned from these three diseases. Although the mechanisms of pathogenesis in progressive multifocal leukoencephalopathy is straightforward, historically it was necessary first to identify the virus by electron microscopy and then devise new cell culture methods by which to isolate a previously unknown virus. In post-infectious encephalomyelitis, the causative virus is only known because of the very characteristic clinical picture that predates the encephalomyelitis. At the time of the encephalomyelitis, the virus is no longer present and there is no evidence of direct infection of the nervous system. The demyelination of the nervous system during the course of AIDS shows unique morphological changes related to a new disease due to a new virus. The virus is present in the nervous system, but is present in the wrong cells. There appear to be intermediate mediators of demyelination.
4.
5.
6.
7.
heat shock protein on oligodendroglia in older lesions. MHC II expression predominates in the active lesion and occurs on invading and resident macrophages and on astrocytes, but not on endothelial cells. Oligodendrocyte proliferation and CNS remyelination are common in active lesions. In chronic lesions, HSP-65 occurs in proliferated oligodendrocytes. Adhesion molecules and cytokines (e.g. TNF) associated with their upregulation are expressed in active lesions. These may have a role in cellular traffic to the CNS. Interactions between hypertrophic astrocytes and proliferating oligodendrocytes occur particularly in active lesions and involve expression of immature oligodendrocyte markers. These interactions are believed to reflect a protective rather than a phagocytic event and are not specific for MS (Supported by NMSS RG 1001-G-7 and NIH NS 08952 and NS 11920).
Immunogenetic studies in multiple sclerosis
Dale E. McFarlin (NINDS, Bethesda, MD, USA) Studies of MS in families, particularly twins, as well as ethnic populations, have provided strong evidence of genetic contributions to the pathogenesis of the disease. The findings indicate that multiple genes are involved and that MS is not purely genetic. In parallel, advances in the understanding of antigen recognition by T cells have established that the MHC and TcR molecules operate jointly in regulation of cellular immune reactivity. These advances have been applied to the modification and prevention of experimental allergic encephalomyelitis. Currently, there is considerable enthusiasm for attempting similar approaches in MS. At least three major questions remain: 1. To what extent can concepts developed in highly inbred rodents be extrapolated to outbred humans with MS?
2. Against what antigen(s) is immune reactivity directed in MS? 3. Do multiple immune responses contribute to the pathogenesis of MS in the overall patient population? Genes in addition to MHC and TcR may be related to the pathogenesis of MS. These include genes on the human 6th chromosome that code from proteins involved in antigen processing and the transport of MHC molecules to the cell surface. Considerable research is also being directed at genetic elements that regulate transcription. For example, regulation of MHC expression varies among different cells in the CNS and preliminary findings indicate that this reflects differences in transcription. Both the expression of class II MHC molecules and the production of cytokines such as tumor necrosis factor, also encoded on human chromosome 6, vary among different rat strains and correlate with susceptibility to EAE. These findings may be due to differences in transcription. Genes on other chromosomes may also be important. For example, recent studies on nonobese diabetic mice have provided evidence that genes outside the MHC complex are related to this spontaneously occurring autoimmune disease. The data indicate that these genes may encode the IL-1 receptor, and molecules that may be involved in homing of lymphocytes to the pancreas. Collectively, the findings imply that multiple gene influences may contribute to the pathogenesis of MS.
Viruses and multiple sclerosis
Richard T. Johnson (Johns Hopkins University School of Medicine, Baltimore, MD, USA) The role of viruses in the pathogenesis of multiple sclerosis (MS) remains unclear. A viral etiology was postulated over 100 years ago and studies of slow viral infections in the past three decades have rekindled speculation. Evidence for viruses as initiating factors in the disease comes from three areas of investigation. (1) Epidemiological studies have shown that, in addition to genetic factors, MS appears to be related to some
178
environmental exposure(s) in childhood. Furthermore, in several isolated populations clustering of cases has suggested "outbreaks" of the disease. (2) Studies of animals and of other human demyelinating diseases have shown that viruses can cause diseases with long incubation periods, and can cause myelin destruction by a variety of different mechanisms. Studies have also documented that viruses can initiate autoimmune responses to myelin proteins in susceptible hosts. (3) Studies in patients with MS have consistently shown abnormal immune responses particularly to viral antigens and have shown the intrathecal antibody synthesis to a variety of viruses, most notably measles. In prospective epidemiological studies exacerbations of disease have been temporally associated with symptoms of viral infections. Three human demyelinating diseases have been defined in which viral infectious agents are known. These include progressive multifocal leukoencephalopathy (PML), post-infectious encephalomyelitis, and human immunodeficiency virus encephalopathy and myelopathy. In each case, the virus is of a different family and in each case, the pathogenesis of the demyelination appears different. In PML, an opportunistic infection of the immunosuppressed, direct lytic infection of oligodendrocytes leads to multiple areas of central nervous system demyelination. The selective vulnerability of cells maintaining myelin provides the simplest method of causation of human demyelinating disease. The other diseases have not proved as straightforward. Post-infectious encephalomyelitis is a perivenular demyelinating disease that occurs as an unusual complication of a variety of viral infections, most prominently measles. Measles was the first human immunodeficiency syndrome ever described and studies of this immunodeficiency have shown that there is a leukopenia and at the same time there is a remarkable activation of cells, including the findings that the lymphocytes of 15% of the cases of measles and 47% of cases who develop encephalomyelitis proliferate in the presence of myelin basic protein. Virus is seldom isolated from the nervous system, intrathecal antibody synthesis does not occur, interferon is not
elevated in spinal fluid and viral proteins and viral RNA are not detectable by immunocytochemistry and by in situ hybridization in brains of patients dying with encephalomyelitis. Thus, the demyelinating disease does not appear to be caused by the selective vulnerability of any cell in the nervous system, but by infection of lymphoid cells, leading to the activation of lymphocytes including, in some patients, populations that are reactive against myelin basic protein and possibly other myelin constituents. These activated cells may selectively home to the nervous system, causing an autoimmune encephalitis after the virus has been cleared from lymphoid organs. Acquired immunodeficiency syndrome (AIDS) was not recognized until the summer of 1981. In 1985, however, it became evident that there was direct infection of the CNS and demyelination has been documented in both the brain and spinal cords in addition to a generalized myelin pallor. The pathogenesis of these myelin changes is unknown. Virus is present in both brain and spinal cord, but it has been found entirely, if not exclusively, in macrophages and microglial cells. By analogy to Visna, the prototype virus of the same lentivirus family, it is suggested that myelin destruction is mediated by cytokines released by infected macrophages or lymphocytes. In search for a virus in multiple sclerosis, there are lessons to be learned from these three diseases. Although the mechanisms of pathogenesis in progressive multifocal leukoencephalopathy is straightforward, historically it was necessary first to identify the virus by electron microscopy and then devise new cell culture methods by which to isolate a previously unknown virus. In post-infectious encephalomyelitis, the causative virus is only known because of the very characteristic clinical picture that predates the encephalomyelitis. At the time of the encephalomyelitis, the virus is no longer present and there is no evidence of direct infection of the nervous system. The demyelination of the nervous system during the course of AIDS shows unique morphological changes related to a new disease due to a new virus. The virus is present in the nervous system, but is present in the wrong cells. There appear to be intermediate mediators of demyelination.