Multiple sclerosis. Current etiological concepts

Current Opinion in Neurology, 1994

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) leading to demyelination, axonal damage, and progressive neurologic disability. The development of MS is influenced by environmental factors, particularly the Epstein-Barr virus (EBV), and genetic factors, which include specific HLA types, particularly DRB1*1501-DQA1*0102-DQB1*0602, and a predisposition to autoimmunity in general. MS patients have increased circulating T-cell and antibody reactivity to myelin proteins and gangliosides. It is proposed that the role of EBV is to infect autoreactive B cells that then seed the CNS and promote the survival of autoreactive T cells there. It is also proposed that the clinical attacks of relapsing-remitting MS are orchestrated by myelinreactive T cells entering the white matter of the CNS from the blood, and that the progressive disability in primary and secondary progressive MS is caused by the action of autoantibodies produced in the CNS by meningeal lymphoid follicles with germinal centers.

Reviews in Medical Virology, 2000

Multiple sclerosis (MS) is a chronic, demyelinating disease of the CNS in which autoimmunity to myelin plays a role in pathogenesis. The epidemiology of MS indicates that it may be triggered by a virus infection before the age of adolescence, but attempts to associate a speci®c virus with MS have produced equivocal results. Many studies of the aetiology of MS have postulated that a persistent virus infection is involved, but transient virus infection may provide a plausible alternative mechanism that could explain many of the inconsistencies in MS research. The most studied animal model of MS is chronic relapsing experimental autoimmune encephalomyelitis (CREAE), which is induced in susceptible animals following injection of myelin components. While CREAE cannot provide information on the initiating factor for MS, it may mimic disease processes occurring after an initial trigger that may involve transient virus infection. The disease process may comprise separate triggering and relapse phases. The triggering phase may involve sensitisation to myelin antigens as a result of damage to oligodendrocytes or molecular mimicry. The relapse phase could be similar to CREAE, or alternatively relapses may be induced by further transient virus infections which may not involve infection of the CNS, but which may involve the recrudescence of anti-myelin autoimmunity. Although current vaccines have a high degree of biosafety, it is suggested that the measles-mumps-rubella vaccine in particular could be modi®ed to obviate any possibility of triggering anti-myelin autoimmunity.

Annals of the New York Academy of Sciences, 1984

Frontiers in Immunology

Current Allergy and Asthma Reports, 2007

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) leading to demyelination, axonal damage, and progressive neurologic disability. The development of MS is influenced by environmental factors, particularly the Epstein-Barr virus (EBV), and genetic factors, which include specific HLA types, particularly DRB1*1501-DQA1*0102-DQB1*0602, and a predisposition to autoimmunity in general. MS patients have increased circulating T-cell and antibody reactivity to myelin proteins and gangliosides. It is proposed that the role of EBV is to infect autoreactive B cells that then seed the CNS and promote the survival of autoreactive T cells there. It is also proposed that the clinical attacks of relapsing-remitting MS are orchestrated by myelinreactive T cells entering the white matter of the CNS from the blood, and that the progressive disability in primary and secondary progressive MS is caused by the action of autoantibodies produced in the CNS by meningeal lymphoid follicles with germinal centers.

Cerebrospinal Fluid Analysis in Multiple Sclerosis, 1996

Journal of Neuroimmunology, 1999

In the century and a half since multiple sclerosis MS was first recognized, the pathology of the condition has been defined with increasing detail. From the recognition and definition of MS as a clinical phenomenon, studies of the diseased brain tissue have progressed in a manner dependent on the science of the time. Through multiple generations, the increasingly detailed analysis of the MS lesion itself has lead to an increasingly sophisticated understanding of a complex, apparently diverse, immunopathological process. During this evolution, many hypotheses concerning the pathogenesis of MS have been overturned, and the interpretation of some clearly delineated gross and histological findings have been reversed. This review plots the progress and highlights current theories and emerging concepts regarding one of the most enigmatic of neurological diseases.

Acta Neurologica Belgica, 2007

Financial support: 'Nationaal fonds voor wetenschappelijk onderzoek Vlaanderen (FWO)'

Journal of autoimmune diseases, 2006

Epidemiological data suggest the notion that in Multiple Sclerosis (MS) is an acquired autoimmune disease and the cause may be an environmental factor(s), probably infectious, in genetically susceptible individuals. Several cases of viral induced demyelinatimg encephalomyelitis in human beings and in experimental models as well as the presence of IgG oligoclonal bands in the cerebrospinal fluid indicate that the infectious factor may be viral. However, the absence of a specific virus identification in MS central nervous system may hardly support this notion. On the other hand, the partial response of patients with MS to immunosuppressive and immunomodulatory therapy support the evidence of an autoimmune etiology for MS. However, the autoimmune hypothesis shares the same criticism with the infectious one in that no autoantigen(s) specific to and causative for MS has ever been identified. Nevertheless, the absence of identifiable infectious agent, especially viral does not rule out its presence at a certain time -point and the concomitant long term triggering of an autoimmune cascade of events thereafter. Several concepts have emerged in an attempt to explain the autoimmune mechanisms and ongoing neurodegeneration in MS on the basis of the infectious -viral hypothesis.

Journal of the Neurological Sciences, 2009

We tested the performance of MRZ-reaction, an intrathecal humoral immune response against-Measles (M), Rubella (R) and Varicella Zoster (Z) viruses, in multiple sclerosis (MS) diagnosis. The MRZ-reaction was significantly more positive in MS than in non-MS group with a specificity of 91.9%. In MS group, the RZ-profile was the most prevalent and the R-specific antibody-index was correlated to the number of oligoclonal bands (OCB) in CSF. Interestingly, the MRZ-reaction was detected in 53% of OCB-negative-MS patients. The MRZ-reaction seems to be a relevant CSF diagnostic marker of MS disease. The likely relation between its positivity and the vaccination status deserves to be investigated.

Clinical and Applied Immunology Reviews, 2005

Multiple sclerosis (MS) remains a leading cause of neurologic disability among young adults. Clinical manifestations of the disease result from immune-mediated demyelination of the central nervous system. Most patients experience new symptoms in a relapsing-remitting pattern, although the course is highly variable from person to person and even in the same individual over time. Recent neuropathological studies reveal that in addition to the surrounding myelin sheath, nerve axons themselves are targets of injury in MS lesions. Characterization of the inflammatory infiltrates present in MS brain and spinal cord tissue shows that active lesions can be segregated into 1 of 4 subtypes, with each individual having only a single pattern of involvement. Studies in animal models demonstrate that a number of myelin proteins can become immune system targets resulting in demyelination, and these models have also served to define multiple immunological mechanisms of disease. Translational studies using peripheral blood samples have characterized differences in the various myelin protein-reactive immune responses of MS patients and controls, and these investigations have validated some, but not all, of the disease mechanisms uncovered in animals. Adaptive and innate immunity both appear to contribute to disease pathogenesis within the target tissue of the central nervous system. Immunomodulatory therapies have been developed that partially arrest disease relapses and progression. Studies to dissect how these agents work have shed light on underlying disease

Journal of Experimental Medicine, 1973

Nature Reviews Neuroscience, 2002

Multiple sclerosis (MS) is one of the most common chronic and disabling disorders of the central nervous system (CNS), affecting 0.05-0.15% of Caucasians 1 . The disease usually begins in young adulthood and affects women more frequently than men. In 80-90% of cases, MS starts with a relapsing-remitting course (RR-MS). Over time, the number of relapses decreases, but most patients develop progressive neurological deficits that occur independently of relapses (the so-called secondary progressive phase). In 10-20% of patients, MS begins with a primary progressive course (PP-MS) without acute relapses. In general, the progression rate in RR-MS is comparable to that of PP-MS as soon as the patients enter the secondary progressive phase 2 . Imaging studies have revealed differences between RR-MS and PP-MS. In patients that suffer from RR-MS, acute CNS lesions with spontaneous resolution are frequently detected, even in the absence of clinical attacks 3 . These lesions are usually located in areas of white matter, and are often characterized by a disturbance of the blood-brain barrier, local oedema and demyelination -features that are compatible with an inflammatory process. By contrast, when progressing to the secondary phase and in patients with PP-MS, such inflammatory activity is much less conspicuous 3 . Global brain atrophy, however, is more dominant in the progressive stage and seems to correlate with disability 4,5 . These findings indicate that early in the disease, ongoing inflammatory activity is present in most patients and is responsible for the relapsing-remitting course, whereas a distinct process might be operative in the progressive phase of the disease, when inflammatory activity diminishes despite faster evolution of disability.

Mayo Clinic Proceedings, 1989

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 regard ing 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. PATHOLOGY Multiple sclerosis (MS) affects scattered areas of the central nervous system with a predilection for periventricular white matter, brainstem, spinal cord, and optic nerves. 1 The plaques are characterized by primary demyelination (destruction of myelin sheaths with preservation of axons) and death of oligodendro cytes (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. 2 This process is followed by extensive

Journal of Neuroimmunology, 1999

In the century and a half since multiple sclerosis MS was first recognized, the pathology of the condition has been defined with increasing detail. From the recognition and definition of MS as a clinical phenomenon, studies of the diseased brain tissue have progressed in a manner dependent on the science of the time. Through multiple generations, the increasingly detailed analysis of the MS lesion itself has lead to an increasingly sophisticated understanding of a complex, apparently diverse, immunopathological process. During this evolution, many hypotheses concerning the pathogenesis of MS have been overturned, and the interpretation of some clearly delineated gross and histological findings have been reversed. This review plots the progress and highlights current theories and emerging concepts regarding one of the most enigmatic of neurological diseases.