1. |
- Bergkvist, My, et al.
(author)
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No evidence for genetic linkage between development of multiple sclerosis and components of the IFN system and the JAK-STAT pathway.
- 2004
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In: Multiple Sclerosis Journal. - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 10:1, s. 87-88
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Journal article (peer-reviewed)abstract
- Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Several observations suggest that the interferon system may be of interest in the study of MS development. To investigate whether polymorphism in components of the IFN system and the JA K-STAT pathway influence susceptibility to MS, we performed a linkage analysis between polymorphic loci in or close to the IFN gamma, IFN gamma recepto r, IFN alpha/beta recepto r, JA K 1, STAT 1 and STAT 3 genes in 27 Swedish families with at least two members having MS. Tests for transmission disequilibrium and nonparametric linkage analysis gave negative results. We found no evidence for linkage between MS and any of these loci.
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2. |
- Dai, Y, et al.
(author)
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Analysis of an interferon-gamma gene dinucleotide-repeat polymorphism in Nordic multiple sclerosis patients
- 2001
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 7:3, s. 157-163
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Journal article (peer-reviewed)abstract
- The proinflammatory cytokine interferon (IFN)-γ has been shown to influence the course of multiple sclerosis (MS). The IFN-γ (IFNG) contains a multiallelic dinucleotide repeat in intron l. To investigate whether alleles at this locus influence susceptibility to MS, we performed linkage and familial association analyses on 100 sibling pairs from four Nordic countries, and case-control association analysis on 220 intermediately disabled sporadic MS patients and 266 controls. To determine the effect of the polymorphism on disease outcome, we compared genotype frequencies in the most and least disabled octiles of a total cohort of 913 cases. We also measured IFN-γ mRNA levels in unstimulated peripheral blood mononuclear cells from 46 MS patients and 27 controls grouped according to IFNG intron l genotype. Both nonparametric linkage analysis and transmission disequilibrium testing of the 100 sibling pairs produced negative results. Genotype frequencies for intermediate-MS patients did not differ significantly from those for controls; nor did genotype frequencies in the benign-MS octile differ significantly from those in the severe-MS octile. Comparison of IFN-γ mRNA levels in genotype-conditioned subgroups revealed no significant differences. Thus, alleles at the IFNG intron l dinucleotide repeat appear to affect neither MS susceptibility and severity nor IFN-γ mRNA expression in vivo.
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4. |
- Freedman, MS, et al.
(author)
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International consensus statement on the use of disease-modifying agents in multiple sclerosis
- 2002
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In: Multiple Sclerosis Journal. - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 8:1, s. 19-23
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Journal article (peer-reviewed)abstract
- Objective. To provide recommendations on the use of disease-modifying agents in the management of multiple sclerosis (MS) and to ensure that treatment will be available to those patients who may benefit. Methods. An initial draft of the consensus statement was prepared by the Steering Committee and amended in the light of written comments from a group of MS specialists. At a subsequent workshop, the wording of the consensus statement was discussed, modified if necessary, and the participants indicated their level of support using an electronic voting system. A new draft of the statement was then sent to a much larger group of international opinion leaders in MS for further comment Results: A number of statements were agreed, which outline the criteria for consideration of disease-modifying therapy for MS and recommendations for treatment. Each statement was accepted completely, or with only minor reservations by 95% or more of those present at the workshop. Conclusions: Periodic reviews and modifications to the statement will be required, as new approaches to the treatment of MS and other therapeutic agents become available.
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6. |
- Huang, WX, et al.
(author)
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Increased expression of caspase-1 and interleukin-18 in peripheral blood mononuclear cells in patients with multiple sclerosis
- 2004
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 10:5, s. 482-487
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Journal article (peer-reviewed)abstract
- Multiple sclerosis (MS) is supposedly a T-cell mediated autoimmune disorder of the central nervous system. Cytokines and other molecules involved in the regulation of apoptosis are thought to be of importance for the pathogenesis of MS. In this study, the mRNA levels of interleukin 18 (IL-18), IL-1b and their processing enzyme caspase-1 were quantified by a competitive RT-PCR method in unstimulated peripheral blood mononuclear cells (PBMCs) in MS patients never treated with disease modifying drugs. Western blot was used to support the expression pattern at the protein level. We found that the expression of caspase-1 and IL-18 was significantly increased in MS patients compared with healthy controls. Analysis of clinical subgroups revealed that caspase-1 was increased in all subgroups, whereas IL-18 was upregulated in chronic progression (P-0.001) and relapsing MS patients in remission (P-0.002) but not significantly during relapses (P-0.12). mRNA levels of IL-1b were not significantly altered in MS except for a possible decrease in chronic progression (P-0.03). An increased IL-18 expression, potentially augmented at the mature protein level, may indicate a pathway worth considering in future therapeutic strategies in MS.
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7. |
- Huang, WX, et al.
(author)
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Systemic upregulation of CD40 and CD40 ligand mRNA expression in multiple sclerosis
- 2000
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 6:2, s. 61-65
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Journal article (peer-reviewed)abstract
- It is increasingly clear that the CD40 and CD40 ligand (CD40L) receptor-ligand pair mediates a crucial activation signal in both cell-mediated and humoral immune responses. Here, we detected mRNA levels of CD40 and CD40L in non-stimulated peripheral blood mononuclear cells in 46 patients with multiple sclerosis (MS) and 46 healthy controls by a competitive RT-PCR procedure allowing quantification without previous culture or antigenic stimulation. The levels of CD40 and CD40L mRNA were markedly increased in MS patients (P <0.0001) compared with healthy controls. There was no difference between clinical MS subgroups or stage of disease. Our findings indicate that, although MS is an organ specific disorder an increased signaling via the CD40 and CD40L pathway may be present at the systemic level. The nature of this upregulation, whether primary or secondary to the organ-specific autoimmune response, is yet to be determined. Since interference with CD40/CD40L is an effective way to interfere with autoimmune model diseases such as experimental autoimmune encephalomyelitis, it may be relevant to investigate further the role of these molecules in the pathogenesis of MS.
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8. |
- Huang, YM, et al.
(author)
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Dendritic cells derived from patients with multiple sclerosis show high CD1a and low CD86 expression
- 2001
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 7:2, s. 95-99
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Journal article (peer-reviewed)abstract
- Dendritic cells (DC) are important antigen presenting cells (APC) and play a major role in initiating and orchestrating immune responses by priming T cells. Little is known about involvement of DC in multiple sclerosis (MS), where auto-aggressive T cells against myelin autoantigens are considered to contribute to inflammation and demyelination in the central nervous system. In this study, we compared phenotype and cytokine secretion of DC from patients with MS, other neurological diseases (OND) and healthy subjects. DC were generated from blood adherent mononuclear cells (MNC) by culture for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The yield and morphology of DC were similar in MS patients and controls. In both, the DC phenotype was that of immature myeloid lineage, comprising CD1a+ and CD11c+. The proportion of CD1a+ DC, being important for presentation of lipid antigens to T cells, was higher in MS patients compared to controls. The proportion of CD86+ DC, a co-stimulatory molecule that is assumed to promote Th2 differentiation, was low in MS. Low proportions of CD86+ DC were only observed in untreated MS patients but not in patients treated with IFN-b. Production of IL-10 and IL-12 p40 by DC did not differ in MS patients and controls. These findings indicate that alterations of functionally important surface molecules on DC are associated with MS.
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9. |
- Hussien, Y, et al.
(author)
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Multiple sclerosis: expression of CD1a and production of IL-12p70 and IFN-gamma by blood mononuclear cells in patients on combination therapy with IFN-beta and glatiramer acetate compared to monotherapy with IFN-beta
- 2004
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 10:1, s. 16-25
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Journal article (peer-reviewed)abstract
- Current therapy of multiple sclerosis (MS) with interferon-beta (IFN-b) or glatiramer acetate (GA) has modest effects on the course of MS. Both compounds affect several immune variables, like expression of cell surface molecules and cytokine levels. Here we compared untreated MS, therapy with IFN-b alone and combined with GA, and healthy controls (HC), regarding expression on HLA -DR+ blood mononuclear cells (MNC) of C D1a that is a cell surface molecule with capacity to present glycolipids to T cells, and of C D80 and C D86 which are costimulatory molecules that activate Th1 and Th2 responses. C ytokine production by MNC was also measured. Flow cytometry and ELISA were used. C ross-sectional comparisons revealed that untreated MS patients had higher C D1a+ HLA -DR+ MNC and lower IL-10 production compared to patients treated with IFN-b or IFN-b+G A or HC. Untreated MS patients also had higher spontaneous IFN-g and IL-12p70 production compared to MS patients treated with IFN-b+G A or HC, but not when compared to MS patients on monotherapy with IFN-b. Low C D1a+ HLA -DR+ MNC and low spontaneous production of IL-12p70 and IFN-g were more pronounced in patients treated with IFN-b+G A than with IFN-b alone. In order to clarify whether these changes reflect disease activity or treatment effects, we performed a follow up study. Nineteen MS patients with disease progression, despite monotherapy with IFN-b for more than one year, were re-examined after one to three and four to six months of treatment with IFN-b+G A. This combination therapy was associated with normalization of C D1a+ HLA -DR+ MNC, IL-12p70 and IFN-g. It remains to be shown whether these immunological changes imply a clinical benefit. Follow up studies of immune variables versus clinical effects during combined therapy of MS with IFN-b+G A are ongoing.
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