Immunopathogenesis Of Multiple Sclerosis Research Articles

Glatiramer Acetate or Interferon-?? for Multiple Sclerosis?

The 1990s, the decade of the brain, have seen major advances in the management of multiple sclerosis (MS). For the first time, effective agents are available for the treatment of relapsing-remitting MS. These include glatiramer acetate (’Copaxone’) and 3 varieties of recombinant human interferon-β (IFNβ): IFNβ-1b (‘Betaseron’/‘Betaferon’) and 2 types of IFNβ-1a (‘Avonex’ and ‘Rebif ’). The modes of action of all these agents are not fully understood; however, recent advances in our understanding of the immunopathogenesis of MS suggest that the immunomodulatory properties of these drugs are involved in their effects in the disease.

A role for CD16+ CD57+ natural killer (NK) cells in the immunopathogenesis of multiple sclerosis (MS)

A role for CD16+ CD57+ natural killer (NK) cells in the immunopathogenesis of multiple sclerosis (MS)

Oligodendrocyte Apoptosis and Primary Demyelination Induced by Local TNF/p55TNF Receptor Signaling in the Central Nervous System of Transgenic Mice: Models for Multiple Sclerosis with Primary Oligodendrogliopathy

The scientific dogma that multiple sclerosis (MS) is a disease caused by a single pathogenic mechanism has been challenged recently by the heterogeneity observed in MS lesions and the realization that not all patterns of demyelination can be modeled by autoimmune-triggered mechanisms. To evaluate the contribution of local tumor necrosis factor (TNF) ligand/receptor signaling pathways to MS immunopathogenesis we have analyzed disease pathology in central nervous system-expressing TNF transgenic mice, with or without p55 or p75TNF receptors, using combined in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling and cell identification techniques. We demonstrate that local production of TNF by central nervous system glia potently and selectively induces oligodendrocyte apoptosis and myelin vacuolation in the context of an intact blood-brain barrier and absence of immune cell infiltration into the central nervous system parenchyma. Interestingly, primary demyelination then develops in a classical manner in the presence of large numbers of recruited phagocytic macrophages, possibly the result of concomitant pro-inflammatory effects of TNF in the central nervous system, and lesions progress into acute or chronic MS-type plaques with axonal damage, focal blood-brain barrier disruption, and considerable oligodendrocyte loss. Both the cytotoxic and inflammatory effects of TNF were abrogated in mice genetically deficient for the p55TNF receptor demonstrating a dominant role for p55TNF receptor-signaling pathways in TNF-mediated pathology. These results demonstrate that aberrant local TNF/p55TNF receptor signaling in the central nervous system can have a potentially major role in the aetiopathogenesis of MS demyelination, particularly in MS subtypes in which oligodendrocyte death is a primary pathological feature, and provide new models for studying the basic mechanisms underlying oligodendrocyte and myelin loss.

Cytokine gene expression in cells derived from CSF of multiple sclerosis patients

Cytokines are produced by numerous cell types in the peripheral blood and central nervous system (CNS), and have been implicated in the immunopathogenesis of multiple sclerosis (MS). We examined the relationship between cytokine gene expression of cerebrospinal fluid (CSF) derived cells from MS patients and disease activity as measured by contrast enhanced MRI. There was a significant correlation between the number of CSF cells and the number of contrast enhancing MRI lesions. Cytokine gene expression of TNF-α, IFN-γ, and IL-10 was routinely seen, but IL-4 expression was absent except in two clinically quiescent patients. Trends were observed toward decreased TNF-α expression, but increased IL-10 expression, after treatment with IFN-β1b.

A role for natural killer cells in the immunopathogenesis of multiple sclerosis

Seventeen relapsing–remitting (R/R) multiple sclerosis (MS) patients and age/sex matched controls were studied every 6 weeks for 2 years. Disease activity, determined both clinically and by serial MRI, was correlated with natural killer (NK) cell functional activity (FA) and phenotype. Mean NK cell FA is significantly lower in MS patients, compared to controls ( P<0.001), while variability around the means is significantly greater ( P<0.01). The spectrum of mean NK cell FA, observed in the patient cohort, along with cyclical nature of the FA and phenotype over time, observed in both patients and controls, may begin to explain the discrepant results reported in previous studies. In R/R MS, there is a significant correlation between reductions (valleys) in NK cell FA and the development of active lesions on MRI, new ( P<0.001) or enlarging ( P=0.05). More importantly, a significant number of active lesions, new ( P=0.01) and enlarging ( P=0.02), are preceded by a reduction in NK cell FA. The correlation between the onset of clinical attacks and valleys of NK cell FA is also significant ( P=0.002). When taken together, the results suggest that reductions (valleys) in NK cell FA represent periods of susceptibility for the development of active lesions on MRI and clinical attacks. A significant positive correlation is also identified between mean NK cell FA for each R/R MS patient and total number of active MRI lesions developed by that patient over the 2 years ( P=0.001). The results would suggest that R/R MS patients with a higher mean NK cell FA are at greater risk for the development of active lesions. These results support the proposal that NK cells may play a role in the immunopathogenesis of R/R MS.

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys ( Callithrix jacchus)

Accessory molecules and cytokines are involved in the immunopathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) in rodent models, and are potential targets for immunotherapy. Evaluation of such experimental therapies requires appropriate animal models. Therefore, we analysed the expression of selected accessory molecules and cytokines in the brain of marmoset monkeys ( Callithrix jacchus) with acute EAE, a newly described non-human primate model for MS. All animals experienced active disease clinically and histopathologically with strong resemblance to MS. Perivascular infiltrates of mononuclear cells showed abundant expression of CD40. CD40 was expressed on macrophages, indicating that T cell priming and macrophage effector functions may result from local CD40–CD40L interactions. CD40 ligand (CD40L) and B7-2 (CD86) were also expressed, but to a lower extent, while B7-1 (CD80) expression was limited. Both pro-inflammatory and anti-inflammatory cytokines were produced within individual lesions during active disease (IFN- α, IFN- γ, TNF- α, IL-1 α, IL-1 β, IL-2, IL-4, IL-10 and IL-12). This suggests that relative levels rather than sequential expression of Th1- and Th2-type cytokines determine disease activity. These findings demonstrate the value of EAE in marmoset monkeys as a model to assess the role of accessory molecules and cytokines in multiple sclerosis, and to evaluate targeted intervention.

ELI-spot of Th-1 cytokine secreting PBMC's in multiple sclerosis: correlation with MRI lesions

The Th1-like cytokines, interleukin 2 (IL-2), interferon gamma (IFN- γ), and lymphotoxin alpha (LT- α) have been implicated in the immunopathogenesis of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), an animal model of immune mediated demyelination. These cytokines have been associated with opening of the blood brain barrier (BBB) in EAE and in vitro, but not in MS. We used an enzyme-linked immunospot (ELI-spot) assay to measure relative numbers of cytokine-secreting peripheral blood mononuclear cells (PBMC) from eight MS patients who were followed with serial monthly contrast-enhanced head magnetic resonance imagings (MRI) and phlebotomy. We found a significant positive correlation between changes in IL-2 secreting cells and MRI lesions over a 6-month time period. There was a weaker association between contrast-enhancing MRI lesions and IFN- γ or LT- α secreting cells. These data are the first to show a significant positive correlation between any cytokine and serial gadolinium (Gd-) MRI disease activity in MS patients. The association between IFN- γ and LT- α secretion and MRI lesions is less clear.

VLA-4 expression on peripheral blood lymphocytes is downregulated after treatment of multiple sclerosis with interferon beta.

Adhesion molecules are likely to play a critical role in the immunopathogenesis of multiple sclerosis (MS). The interaction of vascular cell adhesion molecule-1 (VCAM-1) with its lymphocyte ligand very late antigen-4 (VLA-4) may mediate migration of lymphocytes into the CNS. We have previously demonstrated that MS patients treated with interferon beta (IFN-beta) have a significant increase in soluble VCAM-1 (sVCAM-1) soon after the initiation of treatment, and this effect correlated with the resolution of contrast-enhancing MRI lesions. We studied the cell surface expression of VLA-4 by flow cytometry in 10 MS patients before and during IFN-beta treatment. We found a significant decrease in mean VLA-4 fluorescence of MS patients' lymphocytes on treatment and no change in untreated controls. In vitro treatment of lymphocytes with IFN-beta did not reproduce this effect, but the addition of sVCAM-1 did result in a decrease in VLA-4 expression. These data indicate that the previously identified increase in sVCAM-1 may lead to a decrease in VLA-4 expression and that this effect may partially explain the mechanism of action of IFN-beta.

γδ T-cell–human glial cell interactions. II. Relationship between heat shock protein expression and susceptibility to cytolysis

γ δ T-cells have been implicated in the immunopathogenesis of multiple sclerosis (MS), possibly through interaction with heat shock proteins ( hsp). We have previously demonstrated that human oligodendrocytes (OGC) express hsp on their surface and induce the proliferation and expansion of γ δ T-cells. We also showed that γ δ T-cells are highly cytolytic to OGC in vitro. The current study addresses whether γ δ T-cell-induced cytotoxicity to OGC involves the recognition of hsp on OGC or some other ligand. We first compared the lytic potential for different human glial cells and found that γ δ T-cells lysed OGC, microglia and human fetal astrocytes to the same extent, despite the preferential expression of hsp only on OGC. This suggested that either hsp was not involved in cytolytic recognition or that more than one ligand exists. To address this we used cell lines that either shared OGC properties of hsp expression and the ability to stimulate γ δ T-cells (RPMI 8226, Daudi) or did not (U937) in cold target competition assays with OGC. Results demonstrated that although all the cell lines were effectively killed by γ δ T-cells, only the RPMI 8226 and Daudi cells were able to effectively compete for lysis with the OGC. These results support the notion that probably more than one ligand for γ δ T-cell cytotoxic recognition exists but hsp could still be involved in γ δ T-cell-induced lysis of OGC. Regulating the expression of hsp on OGC might therefore be a way of interfering with potential γ δ T-cell-induced damage in MS.

The possible role of prolactin in the immunopathogenesis of multiple sclerosis

Multiple sclerosis is a disease of the central nervous system characterized by multiple areas of inflammation and demyelination in the white matter of brain and spinal cord. A complex mechanism of the immunopathogenesis of the disease involves mononuclear cells infiltrating multiple sclerosis plaques, as well numerous cell products, such as interleukins, interferons, certain growth factors, etc. Some recent studies have emphasized the immunoregulatory role of certain neuroendocrine peptides, including prolactin. Prolactin, a hypophyseal hormone which is also produced by activated immunocytes, has been considered in this work as a co-factor participating in the immunopathogenic mechanism of multiple sclerosis.

The immunopathogenesis of multiple sclerosis and Guillain-Barré syndrome.

This review covers current hypotheses regarding antigen-specific disease induction, immune responses within the central and peripheral nervous systems, the nonspecific inflammatory cascade, and mechanisms responsible for demyelination, axonal loss, and disease progression in multiple sclerosis and Guillain-Barré syndrome. We also discuss the new evidence on the role of infection as an aetiological factor in multiple sclerosis and Guillain-Barré syndrome.

New treatments for multiple sclerosis

The steady flow of potential new treatments for multiple sclerosis continues with data resulting from studies ranging in complexity from early pilot trials to phase three studies. While this is in itself encouraging, interpretation of the data presented, and in particular evaluation of the potential clinical usefulness of an agent, is often less than straightforward. Improved understanding of the immunopathogenesis of multiple sclerosis and better trial design incorporation more appropriate and responsive outcome measures should be grounds for continuing therapeutic optimism.

T-lymphocyte immunointerferon receptors in patients with multiple sclerosis.

Multiple sclerosis (MS) is a T-cell-mediated autoimmune demyelinating disease of the central nervous system (CNS), associated with an altered immunoregulation. Interferon (IFN)-gamma, also known as immune IFN, is a cytokine with several effects on the immune system. Specific IFN-gamma receptors have been found on human lymphocytes, as well as on other cell types (e.g. gliocytes), even in the CNS. The aim of the present study was to evaluate IFN-gamma binding on peripheral blood T-lymphocytes from MS patients, compared with those from healthy subjects. Thirty-two patients were selected according to the classical criteria for definite MS; as controls, 21 healthy subjects were studied. We have found that T-lymphocytes from MS patients bear a significantly smaller amount of IFN-gamma receptors than those from controls [Bmax: 568, 18 vs 708, 14 (mean, SE) receptors/ cell]. Such IFN-gamma binding sites are of the same type in patients and healthy subjects [Kd: 1.0, 0.05 vs 0.9, 0.02 (mean, SE) nM]. These findings are discussed in terms of immunopathogenesis of MS, since it has been reported that activated T-lymphocytes have decreased amounts of IFN-gamma receptors.

The N-terminal domain of the myelin oligodendrocyte glycoprotein (MOG) induces acute demyelinating experimental autoimmune encephalomyelitis in the Lewis rat

Using a highly purified recombinant protein, mMOG, we demonstrate that autoimmune responses to the N-terminal domain (a.a. 1–125) of the myelin oligodendrocyte glycoprotein (MOG) induce an acute demyelinating variant of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Immunisation with 100 μg of mMOG in adjuvant at the base of the tail induced mild clinical disease in 9 of 11 animals (mean clinical score 1.1). The disease was characterised histopathologically by the presence of inflammation and focal demyelinating lesions in the central nervous system (CNS). Adoptive transfer experiments suggest that this inflammatory demyelinating pathology is mediated by synergy between a weakly encephalitogenic, MOG-specific T cell response and a demyelinating, MOG-specific autoantibody response. Using in vitro selected mMOG-reactive T cell lines, the encephalitogenic T cell response to this domain of MOG was found to recognise two distinct epitopes, MOG 1–20 and MOG 35–55; whereas ELISA demonstrated that the immunodominant B cell epitope was located within the amino acid sequence MOG 1–25. However although active immunisation with synthetic peptides corresponding to the T cell epitopes, MOG 1–20 or MOG 35–55, induced an inflammatory response in the CNS, this was not associated with demyelination indicating that the demyelinating antibody response recognises other, possibly conformation dependent epitopes. This study unequivocally demonstrates that MOG-specific autoimmune responses are alone sufficient to induce a demyelinating disease of the CNS and supports the proposal that MOG may play an important role in the immunopathogenesis of multiple sclerosis.

T-cell autoimmunity in multiple sclerosis

Autoreactive T cells are crucial in the immunopathogenesis of multiple sclerosis. As discussed at a recent meeting, research in this area has provided the basis for innovative immunotherapies.

Differential antigenic stimulation may influence cytokine production patterns in T cells and CD4+ subpopulations

The Th1-like cytokines, interleukin 2 (IL-2), interferon gamma (IFN-γ), and lymphotoxin alpha (LT-α) have been implicated in the immunopathogenesis of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), an animal model of immune mediated demyelination. These cytokines have been associated with opening of the blood brain barrier (BBB) in EAE and in vitro, but not in MS. We used an enzyme-linked immunospot (ELI-spot) assay to measure relative numbers of cytokine-secreting peripheral blood mononuclear cells (PBMC) from eight MS patients who were followed with serial monthly contrast-enhanced head magnetic resonance imagings (MRI) and phlebotomy. We found a significant positive correlation between changes in IL-2 secreting cells and MRI lesions over a 6-month time period. There was a weaker association between contrast-enhancing MRI lesions and IFN-γ or LT-α secreting cells. These data are the first to show a significant positive correlation between any cytokine and serial gadolinium (Gd-) MRI disease activity in MS patients. The association between IFN-γ and LT-α secretion and MRI lesions is less clear.

Tumor necrosis factor-alpha and interferon-gamma synthesis by cerebrospinal fluid-derived T cell clones in multiple sclerosis.

T cell clones derived from cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) were analysed for their capacity to produce interleukin 2 (IL-2), interleukin 4 (IL-4), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). They were also compared with liver-infiltrating T cell clones from patients with chronic active hepatitis. All the CSF T clones (both CD4+ and CD8+) produced large amounts of IFN-gamma and particularly of TNF-alpha, that was synthesized in a significantly larger amount than compared clones. Moreover, they were capable of secreting IL-2, but not IL-4. From our results, we conclude that first, the CSF CD4+ T clones could constitute a subset with functional properties similar to the T helper 1 (Th1)/inflammatory cell subset of the mouse; and second, the large amounts of TNF produced by CSF T cell clones strongly suggests a significant role for this cytokine as well as of IFN-gamma in MS immunopathogenesis.

Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions.

Multiple sclerosis (MS) brain tissue, spleen, and PBMC were studied using immunocytochemistry and FACS for immunoreactivity for lymphotoxin (LT) and TNF. Both cytokines were identified in acute and chronic active MS lesions but were absent from chronic silent lesions. LT was associated with CD3+ lymphocytes and Leu-M5+ microglia cells at the lesion edge and to a lesser extent, in adjacent white matter. TNF was associated with astrocytes in all areas of the lesion, and with foamy macrophages in the center of the active lesion. In acute lesions, immunoreactivity for TNF in endothelial cells was noted at the lesion edge. No LT or TNF reactivity was detected in Alzheimer's or Parkinson's disease brain tissues but was present at lower levels in central nervous system (CNS) tissue from other inflammatory conditions, except for adrenoleucodystrophy which displayed high levels of LT in microglia. No increase in LT and TNF reactivity was detected in spleen and PBMC of MS patients suggesting specific reactivity within the CNS. These results indicate that LT and TNF may be involved in the immunopathogenesis of MS, and can be detected in both inflammatory cells and cells endogenous to the CNS.

Multiple sclerosis: evidence for immunopathogenesis.

I have attempted to review the evidence that one or more immunopathologic mechanisms are responsible for the clinical and pathologic findings in multiple sclerosis (MS). I believe that there is considerable evidence for an immunopathogenesis of MS, but it is not clear what type or types of reactions are involved or against which autoantigen, neoantigen, or microbial antigen the reaction is directed. In addition, there is growing evidence that there are abnormalities in immunologic control mechanisms in patients with MS, although whether these changes are a cause or a result of the disease is not clear.