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PubMed1999

The cellular immunology of multiple sclerosis.

Multiple sclerosis (MS) is a neurological disease that affects the central nervous system (brain and spinal cord) resulting in debilitating motor and sensory dysfunction. Its mean age of onset is 30 years and, with the exception of trauma, MS remains the most frequent cause of neurological disabilities for young adults. The disease is highly variable in its onset and progression. It may not be easily diagnosed, at least in its earliest stages. Significant disability is a hallmark of MS. Indeed, up to 50% of patients require walking aids and 10% are wheelchair-bound at 15 years after an initial diagnosis. Clinical features include deficits in sensory (parasthesias and numbness), motor (difficulties with fine movements and gait), balance, bladder, and sexual functions. Although the etiology for MS is not yet known, it is thought to be related to microbial, genetic, and/or environmental factors. Pathologically, MS is characterized by inflammation. An influx of mononuclear cells occurs through a disrupted blood-brain barrier into an immune-privileged central nervous system. The secretion of a variety of inflammatory cytokines and chemokines from glial cells leads to loss of myelin, disruption of oligodendrocyte integrity, and axonal loss. These events, in large measure, affect progressive neural atrophy. How brain inflammatory activities affect transendothelial migration of leukocytes into the brain and alter the process of myelination are the focal points for MS research activities.

Animals↗

PubMed2005

Poly(ADP-ribose) polymerase-1 activation in a primate model of multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated disabling neurological disorder involving inflammation, demyelination, axonal damage, and neurodegeneration. Poly(ADP-ribose)polymerase-1 (PARP-1), a nuclear enzyme linked to DNA repair, has been shown to regulate the cellular inflammatory response through interactions with nuclear factor-kappaB. Extensive PARP-1 activation can, by separate mechanisms, also cause cell death. PARP-1 activation in brain occurs in several settings associated with oxidative stress and DNA damage, and PARP-1 inhibition has been shown to attenuate inflammation and improve neuronal survival in these settings. Here we studied the pattern of PARP-1 activation in a nonhuman primate model of MS, marmoset (Callithrix jacchus) experimental allergic encephalomyelitis (EAE). Characteristic of this model is relapsing and remitting focal demyelination typical of human MS. Immunostaining for poly(ADP-ribose), the enzymatic product of PARP-1, showed PARP-1 activation specifically in plaque areas of EAE brains. Robust immunostaining was found in astrocytes surrounding demyelinated EAE plaques and in scattered nearby microglia, oligodendrocytes, and neurons. The immunostaining also suggested PARP-1 activation in occasional endothelial cells surrounded by microglia or infiltrating peripheral blood cells. Given the importance of PARP-1 in both inflammation and cell death processes, these findings suggest that PARP-1 activation may be a significant factor in the pathogenesis of MS.

Animals↗

PubMed1994

Gamma interferon activates a previously undescribed Ca2+ influx in T lymphocytes from patients with multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. The etiology of the disease is still unknown. Activated T lymphocytes are considered essential in mediating the inflammatory process leading to demyelination in MS. They operate through a complex network of cytokines among which gamma interferon (gamma-IFN) plays a key role. Here we report that exposure to gamma-IFN of T lymphocytes from patients with MS activates, by a protein kinase C-mediated pathway, a previously undescribed gamma-IFN-activated Ca2+ influx, functionally coupled to the gamma-IFN receptor. The influx mainly expressed by CD4+ T lymphocytes, was found in 12 of 15 (80%) patients with clinically active MS and in 14 of 30 (46%) patients with stable MS. The influx was found in only 3 of 24 (12%) control patients and in none of the 15 healthy subjects studied. Our results document the appearance in MS lymphocytes of a gamma-IFN-activated, protein kinase C-dependent, Ca2+ influx that might be due to the expression of a new cation-specific plasmalemma channel. This finding suggests that at least part of gamma-IFN's contribution to the pathogenesis of MS is exerted through a Ca(2+)-dependent regulation of T lymphocyte activity.

Adult↗

PubMed1987

Does delay in acquiring childhood infection increase risk of multiple sclerosis?

Multiple sclerosis (MS) appears to be more common in technically advanced countries than in underdeveloped regions and migration from one area to another at a young age affects the risk of acquiring MS. One way of explaining both the peculiar frequency distribution and the effect of migration while young is to postulate that an infection early in life decreases the chance of central demyelination. However, no specific infection has been implicated consistently. Alternatively, an aberrant host response to infection in childhood might induce central demyelination. Thus, the aberrant host response could be age-dependent. In seeking associations between age of infection and risk of MS, we observed a direct relationship: where childhood diseases were acquired early in life, the frequency of MS in that population was low; where childhood diseases tended to occur nearer adolescence, MS frequency in that population was high. Since immune responsiveness to antigenic challenges matures through early adolescence, we reason that early infection might be protective and delay in acquiring childhood infections might increase the risk of developing MS. Indeed, in experimental models, the chance of inducing chronic relapsing central demyelination is increased by using adolescent rather than newborn or mature animals. In this paper, epidemiologic evidence showing the strong association between age of infection and risk of MS is presented.

Adolescent↗

PubMed2005

Clinical implications of neuropathological findings in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The pathological hallmarks of MS lesions in the brain and spinal cord are inflammation, demyelination, axon loss and gliosis. Recent studies revealed heterogeneity in the mechanisms leading to the formation of lesions, which include typical autoimmune patterns of demyelination involving T cells and macrophages, as well as antibody/complement as characteristic effector mechanisms. Additionally, oligodendrocyte dystrophy patterns of demyelination, with disturbances of oligodendroglial myelin protein expression and oligodendrocyte apoptosis, were observed. Treatment of MS has advanced dramatically in recent years, with the introduction of beta-interferons, glatiramer acetate and mitoxantrone. However, not all MS patients respond well to treatment with these drugs, and this may be a consequence of disease heterogeneity. Although immunomodulatory therapy has been clinically proven to be effective in patients with relapsing-remitting MS, studies in secondary-progressive MS patients have only demonstrated a positive therapeutic effect with interferon beta-1b. The pathology and pathogenesis of lesions suggest the need for a subtype-specific treatment, which may be possible when observations from pathology can be acted upon in the living MS patient. In addition to myelin and oligodendrocyte damage, the loss of axons represents another key element of MS lesions that lacks a therapeutic approach. However, axon-protective therapy is yet to be established and the mechanisms and effector molecules involved in axonal degeneration are still to be defined.

Biomarkers↗

PubMed2004

Chemokines and chemokine receptors: potential therapeutic targets in multiple sclerosis.

Multiple sclerosis (MS) is a common inflammatory and demyelinating disease of the central nervous system (CNS), which causes progressive neurological disability. The disease is characterised pathologically by destruction of the myelin sheaths, which surround nerve fibres in the CNS. It is believed that this tissue damage in the brain and spinal cord of MS patients is caused by an inflammatory response that is initiated when autoreactive T cells, specific for myelin antigens, cross the blood-brain barrier and detect their antigen within the CNS. As a result, most therapies to date have been immunosuppressive and/or anti-inflammatory in nature, targeting the processes involved in activation and migration of leukocytes and promotion of the immune response. Over the last decade, a family of chemotactic cytokines called chemokines, have been found to be involved in the trafficking of leukocytes in both the normal and pathological states. The expression of these chemokines and their receptors is increased during the acute phase of MS and also in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). As a result, these chemokines have become an emerging focus for research into novel therapeutics for EAE and ultimately MS. This review will briefly describe the structure and function of chemokines and their receptors, before discussing the latest advances in developing pharmacological agents to block the effects of chemokines involved in promoting the inflammatory response in EAE and MS.

Animals↗

PubMed1987

Does delay in acquiring childhood infection increase risk of multiple sclerosis?

Multiple sclerosis (MS) appears to be more common in technically advanced countries than in underdeveloped regions, and migration from one area to another at a young age affects the risk of acquiring MS. One way of explaining both the peculiar frequency distribution and the effect of migration while young is to postulate that an infection early in life decreases the chance of central demyelination. However, no specific infection has been implicated consistently. Alternatively, an aberrant host response to infection in childhood might induce central demyelination. Thus, the aberrant host response could be age-dependent. In seeking associations between age of infection and risk of MS, we observed a direct relationship: where childhood diseases were acquired early in life, the frequency of MS in that population was low; where childhood diseases tended to occur nearer adolescence, MS frequency in that population was high. Since immune responsiveness to antigenic challenges matures through early adolescence, we reason that early infection might be protective and that delay in acquiring childhood infections might increase the risk of developing MS. Indeed, in experimental models, the chance of inducing chronic relapsing central demyelination is increased by using adolescent rather than newborn or mature animals. In this paper, epidemiologic evidence showing the strong association between age of infection and risk of MS is presented.

Age Factors↗

PubMed2005

[Diagnosis of multiple sclerosis].

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system. The disorder displays marked clinical heterogeneity. In certain cases, making diagnosis can be challenging. Diagnosis of MS has become more important in the era of treatments that change the natural history of the disease. Several general diagnostic principles are useful to guide the diagnostic approach to MS. Clinically, MS requires neurological problems associated with objective abnormalities. Certain basic principles, first outlined by Schumacher et al. (1965) are still pertinent. Poser et al. (1983) have further modified the criteria using data derived from clinical evaluation and laboratory studies, including cerebrospinal fluid analysis, evoked potentials, and imaging studies. Poser criteria have long been familial for most neurologists. The most recent addition to our diagnostic armamentarium are the McDonald criteria (2001), which are the first attempt to incorporate standardized MRI criteria into the MS diagnostic process. The most innovative use of MRI to support an MS diagnosis is dissemination of demyelination can be demonstrated by MRI alone, in the absence of any new clinical attacks. Diagnosing MS by such sensitive MRI criteria will occur more quickly than waiting for a second clinical event. This has added some sensitivity, some controversy, and a lot of confusion. The application of the new criteria on Asian MS patients remains to be validated. Each of the criteria will be discussed, with major emphasis on the McDonald criteria.

Diagnosis, Differential↗

PubMed2005

Therapeutic role of beta-interferons in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). In the last 12 years, there has been a proliferation of studies elucidating the immune mechanisms that mediate tissue damage in MS. Interferons (IFNs) have an important role in regulating innate and adaptive immune responses. They decrease pro-inflammatory responses such as the autoimmunity in MS, but other autoimmune responses such as systemic lupus erythematosus (SLE) may be exacerbated. This review offers a general overview of the biological properties of IFNs, effects on immune cells, and clinical effectiveness in MS treatment. IFN signaling is complex, from receptor binding events to the generation of effector mechanisms that dampen inflammation. Immune cell function is altered in MS. IFN treatment of MS patients ameliorates immune dysfunction, but not completely. The incomplete resolution of immune dysfunction by IFNs partly explains their significant, but modest therapeutic effects. This observation also suggests that there are immune mechanisms in MS that are resistant to IFN therapy. In MS, abnormalities may exist at several points along the IFN signaling pathway, including molecular defects in the IFN second messenger system. Currently, several studies are ongoing evaluating ways of potentiating IFN effects. IFNs were the first agents to show clinical efficacy in treatment of MS. More than a decade of experience with IFNs has showed continued clinical efficacy over time. In the near future, IFNs will continue to play a major role in MS.

Humans↗

PubMed2001

Anti-DNA antibodies are a major component of the intrathecal B cell response in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of unknown cause that afflicts the central nervous system. MS is typified by a highly clonally restricted antigen-driven antibody response that is confined largely to the central nervous system. The major antigenic targets of this response and the role of antibody in disease pathogenesis remain unclear. To help resolve these issues, we cloned the IgG repertoire directly from active plaque and periplaque regions in MS brain and from B cells recovered from the cerebrospinal fluid of a patient with MS with subacute disease. We found that high-affinity anti-DNA antibodies are a major component of the intrathecal IgG response in the patients with MS that we studied. Furthermore, we show DNA-specific monoclonal antibodies rescued from two subjects with MS as well as a DNA-specific antibody rescued from an individual suffering from systemic lupus erythematosus bound efficiently to the surface of neuronal cells and oligodendrocytes. For two of these antibodies, cell-surface recognition was DNA dependent. Our findings indicate that anti-DNA antibodies may promote important neuropathologic mechanisms in chronic inflammatory disorders, such as MS and systemic lupus erythematosus.

Adult↗

PubMed2004

Biomarkers and surrogate outcomes in neurodegenerative disease: lessons from multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease of the CNS that most commonly affects young adults. It is usually characterized in the early years by acute relapses followed by partial or complete remission; in later years progressive and irreversible disability develops. Because of the protracted and unpredictable clinical course, biological surrogate markers are much needed to make clinical trials of potential disease-modifying treatments more efficient. Magnetic resonance (MR) outcome measures are now widely used to monitor treatment outcome in MS trials. Areas of multifocal inflammation are detected with a high sensitivity as new areas of gadolinium enhancement and T2 abnormality, and these may be considered as surrogate markers for clinical relapses. However, progressive disability is not clearly related to inflammatory lesions but rather to a progressive and diffuse process with increasing neuroaxonal loss. MR surrogate measures for neuroaxonal loss include atrophy (tissue loss in brain and spinal cord), N-acetyl aspartate, and T1 hypointense lesions. Diffuse abnormality in normal appearing brain tissue may also be monitored using magnetization transfer ratio and other quantitative MR measures. For treatment trials of new agents aimed at preventing disability, measures of neuroaxonal damage should be acquired, especially atrophy, which occurs at all stages of MS and which can be quantified in a sensitive and reproducible manner. Because the MR surrogates for neuroaxonal loss are not yet validated as predicting future disability, definitive trials should continue to monitor an appropriate disability endpoint.

Biomarkers↗

PubMed1998

HLA-DP: a class II restriction molecule involved in epitope spreading during the development of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. It is widely believed that complex polygenic inheritance patterns involving HLA-DR and -DQ class II genes contribute to MS susceptibility, and current evidence indicates that disease risk vs disease outcome may be associated with distinctly different HLA class II alleles. We have recently shown that the early development of MS is accompanied by an extensive plasticity of myelin self-recognition with the acquisition of neo-autoreactivity, or epitope spreading, as a prominent feature. Although we did not observe a common determinant recognized by patients sharing identical HLA-DR or -DQ class II alleles, we did observe epitope spreading to the p50-63 determinant of myelin proteolipid protein (PLP) in two study subjects showing complete disparity at HLA-DR and -DQ but identity at the HLA-DP allele DPB1*0301. In the present study we show that self-recognition during the early stages in the development of MS involves HLA-DP class II restricted responses to the PLP 50-63 spreading determinant. Our results suggest that self-presentation by HLA-DP may play an important role in epitope spreading and in the propagation of self-recognition during the clinical progression of MS.

Adult↗

PubMed2000

A point mutation in PTPRC is associated with the development of multiple sclerosis.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is widely accepted that a dysregulated immune response against brain resident antigens is central to its yet unknown pathogenesis. Although there is evidence that the development of MS has a genetic component, specific genetic factors are largely unknown. Here we investigated the role of a point mutation in the gene (PTPRC) encoding protein-tyrosine phosphatase, receptor-type C (also known as CD45) in the heterozygous state in the development of MS. The nucleotide transition in exon 4 of the gene locus interferes with mRNA splicing and results in altered expression of CD45 isoforms on immune cells. In three of four independent case-control studies, we demonstrated an association of the mutation with MS. We found the PTPRC mutation to be linked to and associated with the disease in three MS nuclear families. In one additional family, we found the same variant CD45 phenotype, with an as-yet-unknown origin, among the members affected with MS. Our findings suggest an association of the mutation in PTPRC with the development of MS in some families.

Base Sequence↗

PubMed2005

Husbands and wives living with multiple sclerosis.

Multiple sclerosis (MS) frequently is diagnosed in young adults. Coping with symptoms of MS is challenging not only for the person with the disease, but also for his or her spouse. The well spouse often assumes the caregiving role. The purpose of this qualitative research was to investigate the experiences of persons whose spouses have MS. Twelve people participated in a 2-hour focus group: 8 men and 4 women. The husbands were, on average, 50 years old, and the wives averaged 55 years old. The length of time since diagnosis ranged from 2 to 11 years for the husbands and from 3 to 13 years for the wives. The focus group discussions were audiotaped and transcribed verbatim. Participants talked freely. Four major themes emerged: caregiver roles, need for information, relationship changes, and barriers. Men attempted to protect their wives' energy, intervening for them. Wives encouraged independence in their husbands. Spouses need information about MS, complementary interventions, and support. They want increased public awareness of invisible symptoms and awareness in the workplace of continuing capabilities of persons with MS. Role reversals were challenging for the women who felt that "MS is the third person in a marriage." Spouses need help to maintain appropriate boundaries. Limitations of the study include the small, economically homogeneous sample and the single encounter with the subjects. A longitudinal intervention study is needed.

Adaptation, Psychological↗

PubMed1997

[Pathogenesis and therapy of multiple sclerosis].

Multiple sclerosis (MS) is one of the most frequent serious neurologic diseases. Etiologically, MS involves genetic, viral and other factors. The key pathogenic mechanisms reside in the autoimmune reaction of activated CD4+ T lymphocytes crossing the haematoencephalic barrier and attacking different epitopes of the basic protein and proteolipid of myelin sheaths. The damaging reaction involving activated macrophages, destructive inflammatory cytokines and toxic radicals leads to the development of disseminated plaques. The passage of autoimmune T lymphocytes to the brain tissue is facilitated by overexpression of adhesion molecules on endothelial cells, neural cells and immunocytes. The diagnosis of MS is based on characteristic changes in the blood and liquor, and on the results of modern methods, especially (gadolinium enhanced) MRI. The "classical" treatment is based on glucorticosteroids, azathioprine, cyclophosphamide and other chemicals which are not fully satisfactory and are accompanied by serious side-effects. Therefore, attention will be paid to three prospective biological methods of treatment: 1) peroral application of bovine myelin, its fractions, and synthetic copolymer-1, aimed at the restoration of immune tolerance; 2) injections of natural and recombinant interferon-beta, interfering with the pathogenic IFN-gamma and other cytokines; 3) systemic enzyme therapy (residing in peroral application of combinations of animal and herbal hydrolytic enzymes), which modulates adhesion molecules and suppresses the activation of autoimmune T lymphocytes. The chief results of clinical studies with respect to the effectiveness and safety of these therapeutic methods, will be summarized. (Ref. 34.)

Humans↗

PubMed2002

Autoreactivity to myelin antigens related to HLA associations with multiple sclerosis.

Multiple sclerosis (MS) is considered as an immune process influenced by genetic and environmental factors. HLA-DR2 and -DR4 have been documented to be associated with MS. The HLA-dependent differences of immune response to myelin and other antigens might point out some relevant mechanisms in MS development The responses to myelin antigens and to PPD have been compared in 21 MS patients and 25 healthy controls (HCs) by primary proliferation and by short-term T-cell lines. There was a significantly higher response to MBP in DR2+ HCs compared to MS patients (SI: 5.9 versus 1.5, p = 0.02). In short-term T-cell lines, we observed a higher response to PLP30-49 in both DR4+ HCs and MS patients This response was significantly more frequent in DR4+ MS patients (34.6%) than both DR2+ MS patients (0%, p = 0.0001) and DR4+ HCs (7.7%, p = 0.001). The comparison between DR2+ and DR4+ MS patients has revealed that the response to MBP was also increased in DR4+ (p = 0.02). Among DR4+ groups, an increased PPD response was detected in HCs compared to MS (65.2% versus 33.3%, p = 0.01). These results may indicate that HLA-related differences to specific and recall antigens are detectable in MS and these differences may have implications in the disease pathogenesis.

Adult↗

PubMed2003

Sex steroid regulation of microglial cell activation: relevance to multiple sclerosis.

Multiple sclerosis (MS) occurs more commonly in females than males. However, the mechanisms resulting in gender differences in MS are unknown. Several studies have suggested that sex steroids influence the development and severity of MS. For example, pregnancy influences MS symptoms, with remission in the third trimester of gestation, followed by exacerbation in the postpartum period. In addition, oral contraceptives containing female sex steroids have been associated with a lower risk of developing MS and decreased disability. Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disorder initiated by T cells reactive against central nervous system (CNS) antigens. EAE is characterized by inflammation and demyelination of the CNS, and by remittent paralysis-features consistent with MS. Recent studies have suggested that female sex steroids may modulate EAE, at least in part, through effects on T cells. For example, sex steroids shift T cells toward a Th2 phenotype in vitro, and cytokines produced by Th2 cells generally suppress EAE. Activated microglia also are believed to contribute to MS pathology; perhaps due in part to production of nitric oxide (NO) and TNF-alpha, molecules which can be toxic to CNS cells, including oligodendrocytes. We are currently investigating the role of sex steroids in modulating microglial cell function in relation to MS. It is hoped that elucidation of the mechanisms by which sex steroids modulate CNS inflammation will lead to future therapies in the treatment of MS.

Animals↗

PubMed2004

Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis.

Multiple sclerosis (MS) is characterized by synthesis of oligoclonal immunoglobulins and the presence of B-cell clonal expansions in the central nervous system (CNS). Because ectopic lymphoid tissue generated at sites of chronic inflammation is thought to be important in sustaining immunopathological processes, we have investigated whether structures resembling lymphoid follicles could be identified in the CNS of MS patients. Sections from post-mortem MS brains and spinal cords were screened using immunohistochemistry for the presence of CD20+ B-cells, CD3+ T-cells, CD138+ plasma cells and CD21+, CD35+ follicular dendritic cells, and for the expression of lymphoid chemokines (CXCL 13, CCL21) and peripheral node addressin (PNAd). Lymphoid follicle-like structures containing B-cells, T-cells and plasma cells, and a network of follicular dendritic cells producing CXCL13 were observed in the cerebral meninges of 2 out of 3 patients with secondary progressive MS, but not in relapsing remitting and primary progressive MS. We also show that proliferating B-cells are present in intrameningeal follicles, a finding which is suggestive of germinal center formation. No follicle-like structures were detected in parenchymal lesions. The formation of ectopic lymphoid follicies in the meninges of patients with MS could represent a critical step in maintaining humoral autoimmunity and in disease exacerbation.

Adult↗