Neuropathology of multiple sclerosis-new concepts

Multiple sclerosis is a chronic inflammatory disease of the central nervous system with profound heterogeneity in clinical course, neuroradiological presentation and response to therapy. The pathological analysis of 235 actively demyelinating lesions coming from three centers revealed different structural and immunological features suggesting that different pathogenetic mechanisms are involved in lesion formation. On the basis of the presence or absence of immunoglobulin and complement deposition, myelin protein loss and the patterns of oligodendrocyte degeneration beside a T cell- and macrophage-dominated immune response, four distinct patterns of demyelination have been identified. In this short review, possible paraclinical markers for tissue destruction on the basis of the main features of myelin destruction are discussed. Furthermore, the importance of early axonal damage in multiple sclerosis is highlighted.     

Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination

Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course, neuroradiological appearance of the lesions, involvement of susceptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different processes, such as autoimmunity or virus infection, may induce MS-like inflammatory demyelinating plaques and suggest that MS may be a disease with heterogeneous pathogenetic mechanisms. From a large pathology sample of MS, collected in three international centers, we selected 51 biopsies and 32 autopsies that contained actively demyelinating lesions defined by stringent criteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different patterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. At a given time point of the disease--as reflected in autopsy cases--the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this disease.     

Multiple sclerosis: novel perspectives on newly forming lesions

The mechanisms underlying lesion formation in multiple sclerosis are unknown. The prevailing view is that macrophages are primary mediators of myelin destruction in the relapsing and remitting forms of this disease. However, recent findings have revealed widespread oligodendrocyte apoptosis in the absence of a clear cellular immune response. These observations unveil a novel aspect of the pathogenesis of multiple sclerosis that is worthy of further exploration.     

Presence of anti-CSL antibodies in the cerebrospinal fluid of patients: A sensitive and specific test in the diagnosis of multiple sclerosis

The carbohydrate-binding protein (lectin) CSL is an antigen involved in the stabilization of the myelin structure by interacting with the carbohydrate moiety of myelin glycoproteins. Since anti-CSL Fab fragments were able to produce destruction of CNS myelin in vitro, CSL was considered as a potential immunological target in multiple sclerosis. The presence of anti-CSL antibodies has been examined in the cerebrospinal fluid of 1388 different patients with various neurological diseases. It is concluded that the presence of anti-CSL antibodies in the cerebrospinal fluid of patients less than 50 years old constitutes a very sensitive and specific test for multiple sclerosis.     

Immunopathogenic and clinical relevance of antibodies against myelin oligodendrocyte glycoprotein (MOG) in Multiple Sclerosis

Recent neuropathological findings identified four distinct immunopathogenic pathways of demyelination and tissue destruction in the most common inflammatory demyelinating central nervous system disorder, Multiple Sclerosis. One of this neuropathological subtypes is characterised by features of antibody-mediated demyelination. A role of anti-myelin antibodies in the disease evolution of multiple sclerosis has been suggested already for a long time, however, their pathogenetic and clinical relevance is not understood yet. This present article will discuss recently published and some preliminary data on the immunopathogenic role of antibodies against myelin oligodendrocyte glycoprotein (MOG) and other myelin/nonmyelin targets in multiple sclerosis, as well as possible clinical implications for prognosis and therapy in the future.     

Failure of allogeneic bone marrow transplantation to arrest disease activity in multiple sclerosis

Multiple sclerosis (MS) is thought to be an autoimmune disease in which activated T-cells initiate a macrophage mediated destruction of CNS myelin. Bone marrow transplantation (BMT) is currently being evaluated in the treatment of MS in patients with aggressive disease activity. Autologous BMT could potentially reset the immune response to myelin antigens leading to immune tolerance and decreased disease activity. Allogeneic transplantation could reconstitute the immune system potentially arresting the progression of autoimmune disease. The purpose of this paper is to report a patient with MS who underwent allogeneic BMT for chronic myelogenous leukemia (CML) and showed continued evidence of active demyelinating disease by clinical and radiologic criteria over a period of two years. While this is only a single case report with inherent limitations, it suggests that the immune mediated destruction of CNS myelin in MS may not be prevented or aborted by immune system reconstitution, and is consistent with the idea that immune mediated tissue destruction in MS could be targeted against an abnormal antigen.     

Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients

Multiple sclerosis (MS) lesions are associated with infiltration of T lymphocytes and macrophages that appear to mediate myelin destruction and gliosis (scarring). Mast cells are located perivascularly in the brain, are juxtaposed to neurons, and have been shown to secrete vasoactive and inflammatory mediators in response to neuropeptides and direct nerve stimulation. Mast cells have been previously identified in MS lesions, are activated by myelin basic protein, and can participate in the regulation of blood–brain barrier permeability, as well as in myelin destruction. Here, cerebrospinal fluid from MS patients and controls with other neurologic diseases was assayed for histamine, its major metabolite methylhistamine, and the specific mast cell marker tryptase. Histamine and methylhistamine were not elevated in MS. However, the mast cell specific proteolytic enzyme tryptase was significantly elevated in MS, suggesting that mast cell activation may be involved in the pathophysiology of this disease.     

Mechanisms of demyelination and tissue damage in multiple sclerosis

Although multiple sclerosis is generally believed to be a T-cell mediated inflammatory disease of the central nervous system, recent experimental and neuropathological studies show that additional pathogenetic factors are required to induce widespread primary demyelination and secondary tissue damage, such as axonal loss. This review summarises experimental evidence for multiple pathogenetic pathways, that can be responsible for myelin destruction in this disease. Furthermore, recent data are discussed which show that different immunopathological pathways seem to be involved in different patient subgroups. The pathogenetic heterogeneity of multiple sclerosis suggests that immunomodulatory treatment of this disease may be more complex than previously anticipated.     

Heterogeneity of the T-cell receptor beta gene rearrangements generated in myelin basic protein-specific T-cell clones isolated from a patient with multiple sclerosis.

Seventeen T-cell clones derived from the peripheral blood of a patient with multiple sclerosis and reactive with a synthetic peptide corresponding to residues 152-170 of the human myelin basic protein molecule were previously shown to be cytotoxic for myelin basic protein-coated target cells. Genetic restriction studies have now demonstrated that these clones recognize myelin basic protein in association with human leukocyte antigen DRw13. Studies of the T-cell receptor beta gene rearrangements generated by these clones demonstrated 12 different patterns, as evaluated by Southern blot analysis. Thus, the human T-cell response to myelin basic protein is exceedingly heterogeneous, even among T cells that recognize the same small fragment of the molecule in association with the same class II restriction element.     

Patterns of oligodendrocyte pathology in coronavirus-induced subacute demyelinating encephalomyelitis in the lewis rat

Intracerebral infection of rats with JHM coronavirus induces a chronic inflammatory demyelinating disease, which in many respects mimicks the pathology of multiple sclerosis. We investigated the patterns of demyelination and oligodendrocyte pathology in this model. In early stages of the disease infection of oligodendrocytes was associated with a downregulation of expression of mRNA for proteolipid protein in the absence of myelin destruction. When demyelinating lesions were formed infected oligodendrocytes were destroyed by necrosis, whereas oligodendrocytes that did not contain detectable virus antigen or RNA were in part dying by apoptosis. At this stage of the disease remyelination of the lesions was pronounced. At later stages after infection virus antigen was nearly completely cleared from the lesions. In spite of the lack of detectable virus, ongoing demyelination and unspecific tissue destruction occurred, and oligodendrocytes were mainly destroyed by apoptosis. These late lesions revealed only minimal central remyelination, but they were frequently repaired by Schwann cells. Our studies suggest that the mechanisms of myelin destruction in this model of virus-induced demyelination are complex and that the patterns of tissue damage may change during the course of the disease. Glia 19:1–7, 1997 © 1997 Wiley-Liss, Inc.     

Pathogenesis of tissue injury in MS lesions.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system. The primary pathological target in multiple sclerosis is myelin. Most MS patients follow a relapsing-remitting (RR-MS) course for 10 to 15 years that transforms into a chronic or secondary progressive disease (SP-MS). This review summarizes studies from our laboratory that implicate activated microglia and astrocytes in early stages of myelin destruction in MS brain. In addition, we review evidence that indicates that axonal transection is a major pathological process in multiple sclerosis. Our data support the hypothesis that neurological disability in RR-MS is due to inflammatory demyelination while axonal loss plays a significant role in the irreversible neurological decline in SP-MS. Further elucidation of the pathological targets and pathological mechanisms of tissue destruction in MS brain will help identify new therapeutics.     

Immunopathology of secondary-progressive multiple sclerosis.

Twenty-three plaques obtained at early autopsy from 2 patients with secondary-progressive multiple sclerosis were examined immunohistochemically for microglia/macrophages, and for immunoglobulins and components of activated complement. Most of the lesions examined in both cases exhibited evidence of low-grade active demyelination of an unusual type (frustrated phagocytosis) in periplaque white matter. This included linear groups of microglia engaging short segments of disrupted myelin that were associated with deposits of C3d, an opsonin formed during complement activation. Similar microglia/C3d/myelin profiles were not observed in newly forming lesions in cases of acute multiple sclerosis or other central white matter diseases. As C3d coupling is known to increase the immunogenicity of potential antigens enormously, present findings point to disrupted myelin close to plaques as a possible source of the putative multiple sclerosis antigen. Ongoing myelin destruction found in a high proportion of old, established plaques was surprising. It suggests that slowly expanding lesions (progressive plaques), in which ongoing myelin breakdown occurs in the absence of florid perivascular cell cuffing or other histological signs of acute inflammation, contribute to disease progression in cases of secondary-progressive multiple sclerosis.     

Role of microglia in multiple sclerosis

Microglia are the resident macrophages of the nervous system. They serve to protect and preserve neuronal cells from pathogens and facilitate recovery from metabolic insults. In addition, they appear to play a role in the neuropathology of noninfectious inflammatory disorders of the central nervous system, especially those that are autoimmune. Presentation of neural autoantigens to autoreactive T cells by microglia and the attendant secretion of proinflammatory cytokines are thought to facilitate the inflammatory process in diseases such as multiple sclerosis. They also serve as scavengers of damaged myelin following death of oligodendrocytes and the destruction of myelin and may, therefore, promote recovery of myelin damaged by the inflammatory insult. This review examines the current controversies on the pathology of multiple sclerosis and the role played by microglia in the development of central nervous system demyelination.     

On the development of CNS lesions in natural canine distemper encephalomyelitis

Acute lesions within spinal cord white matter have been studied by light and electron microscopy in 3 dogs suffering from the acute form of canine distemper encephalomyelitis (CDE). Prominent features of these lesions were viral inclusions, giant cell formation, cellular degeneration, myelin breakdown and phagocytic activity by cells believed to be derived from local glia. The viral inclusions occurred in giant cells, many astrocytes, macrophages and occasional oligodendroglia. Only suggestions of active viral replication from cell membranes were present. On the basis of the above features, these CDE lesions were classed as being acute. Perivascular inflammation and parenchymal invasion by haematogenous cells were lacking. However, older, gliotic, demyelinated lesions were always associated with inflammation. The pattern of demyelination in acute CDE lesions differed from those seen in other conditions, in particular the autoimmune demyelinating diseases. In acute CDE lesions, individual fibres became separated from others by rings of cells, the processes of which systematically stripped the myelin from the outer layers of the sheath inwards until a naked segment of axon remained. Some of the macrophages were recognisable as astroglia. Elsewhere, unequivocal astrocytes containing myelin debris were common. The results suggest that inflammation in acute CDE lesions is not a primary event, and that viral invasion causes breakdown of tissue which is accompanied pari passu by myelin destruction. The latter might be related to the non-specific release of host factors (viz. hydrolytic enzymes) or humoral factors during the cellular degeneration. Local cells appeared to participate in the process of myelin phagocytosis. Overt inflammation and damage by haematogenous cells were features only of chronic lesions and have been described previously in studies on chronic CDE lesions. The results are interpreted in terms of their relevance to the study of human subacute sclerosing panencephalitis, of which CDE is considered the animal analogue, and multiple sclerosis, the paradigm of the human demyelinating diseases.     

Inverse vaccination to silence immunity to myelin in multiple sclerosis

The adaptive immune response in multiple sclerosis is complex. We have devised large scale arrays to measure the antibody response to myelin proteins and lipids. Despite the widespread immune responses to myelin, we have devised an inverse vaccine aimed at turning off key drivers of this diverse response. Clinical trials in patients with multiple sclerosis show that it is possible to constrain antibody responses to myelin on a large scale with this approach.     

Neurodegeneration and neuroprotection in multiple sclerosis and other neurodegenerative diseases

Multiple sclerosis is considered a disease of myelin destruction; Parkinson's disease (PD), one of dopaminergic neuron depletion; ALS, a disease of motor neuron death; and Alzheimer's, a disease of plaques and tangles. Although these disorders differ in important ways, they also have common pathogenic features, including inflammation, genetic mutations, inappropriate protein aggregates (e.g., Lewy bodies, amyloid plaques), and biochemical defects leading to apoptosis, such as oxidative stress and mitochondrial dysfunction. In most disorders, it remains uncertain whether inflammation and protein aggregation are neurotoxic or neuroprotective. Elucidating the mechanisms that orchestrate neuronal diseases should facilitate development of neuroprotective and neurorestorative strategies.     

Antigen-specific therapy of multiple sclerosis: The long-sought magic bullet

The adaptive immune response in multiple sclerosis (MS) targets various myelin proteins and even some inducible heat shock proteins. A few attempts have been made to tolerize relapsing-remitting patients with MS to either full-length myelin basic protein or to a key peptide epitope between residues 83–99. These trials have demonstrated that this approach may potentially provide benefit to patients with relapsing-remitting MS. However, manipulation of responses to myelin proteins can have deleterious effects. The immune response to myelin components is positioned at a key tipping point in the pathophysiology of the disease. Clarification of the key target antigens in MS, and better understanding of practical methods to attain tolerance to a wide variety of myelin and neuronal molecules will provide the basis for the ultimately successful antigen specific therapy.     

Role of Fas--FasL interactions in the pathogenesis and regulation of autoimmune demyelinating disease

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) represent complex processes that lead to destruction of oligodendrocytes (ODCs) and myelin. T cells are integral to the development of these diseases, but whether T cell-mediated cytolytic mechanisms are involved in the destruction of MHC Class II-negative targets, such as oligodendroglia and myelin, in the CNS is unclear. The primary lytic mechanism employed by CD4⁺ T cells is Fas-dependent, but can be MHC-unrestricted. Thus, T cell-mediated Fas–FasL interactions could directly contribute to the pathology of EAE and MS. This review summarizes studies from our laboratory and others that implicate Fas–FasL interactions in both the pathogenesis and regulation of demyelinating diseases.     

Antimyelin basic protein and antimyelin antibody-producing cells in multiple sclerosis.

The B-cell response to myelin and myelin basic protein was studied in patients with multiple sclerosis and in patients with acute aseptic meningoencephalitis by using a nitrocellulose immunospot assay. This method allows detection of single cells producing antibodies. Twenty-seven (79%) of 34 patients with multiple sclerosis had cells producing IgG antibodies against myelin, and 11 (57%) of 19 had cells producing IgG antibodies against myelin basic protein in cerebrospinal fluid (CSF), with mean values of 30 and 14 per 10(4) mononuclear cells, respectively. Total numbers of IgG-producing cells occurred at a mean number of 75 per 10(4) CSF cells. Cells producing antimyelin or anti-myelin basic protein antibodies of IgA or IgM isotypes were rarely found in CSF. Patients with acute aseptic meningoencephalitis less frequently showed CSF cells producing IgG antibodies against myelin and myelin basic protein. No cells producing antibodies against myelin or myelin basic protein were detected in peripheral blood of patients with multiple sclerosis or meningoencephalitis. Thus, a majority of patients with multiple sclerosis had CSF cells that produced IgG antibodies against myelin and myelin basic protein. These cells comprised a large proportion of the total IgG-producing cells. A pronounced B-cell response against autoantigens produced at the target for immune attack might be important in the pathogenesis of multiple sclerosis.     

Experimental strategies to promote central nervous system remyelination in multiple sclerosis: Insights gained from the Theiler's virus model system

The Destruction of central nervous system (CNS) myelin, the lipid-rich insulator surrounding axons in the mammalian brain and spinal cord, is the primary pathological finding in multiple sclerosis. Myelin loss can result in a significant clinical deficit, and was originally thought to be permanent, similar to axonal destruction. However, myelin regeneration is now an established phenomenon in both human disease and animal models of CNS demyelination. In this review, the concept of remyelination in demyelinating deseases such as multiple sclerosis is discussed and the usefulness of animal models of CNS demyelination in developing experimental strategies to promote remyelination is examined Special emphasis is given to the Theiler's murine encephalomyelitis model, which has been the primary animal model used to investigate therapies designed specifically to stimulate myelin repair. © 1995 Wiley-Liss, Inc.