Elevated osteopontin levels in active relapsing‐remitting multiple sclerosis

Vogt, Monica; Lopatinskaya, Luba; Smits, M.; Polman, Chris H.; Nagelkerken, Lex

doi:10.1002/ana.10606

Cited by 119 publications

(95 citation statements)

References 19 publications

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“…37 Moreover, several reports detected high serum levels of osteopontin, a cytokine capable to inhibit AICD, in MS patients and we found that this is partly associated with variants of the osteopontin gene. [38][39][40][41] In conclusion, this work suggests that PRF1 variations may be a predisposing factor for MS by affecting either the antiviral response or the immune response switching off. Defects of both of these functions may favor development of autoimmunity by prolonging the immune response and increasing the risk of crossreactions between viral and self-antigens.…”

Section: Discussionmentioning

confidence: 69%

Variations of the perforin gene in patients with multiple sclerosis

et al. 2008

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Perforin is involved in cell-mediated cytotoxicity and mutations of its gene (PRF1) cause familial hemophagocytic lymphohistiocytosis (FLH2). PRF1 sequencing in 190 patients with multiple sclerosis and 268 controls detected two FLH2-associated variations (A91V, N252S) in both groups and six novel mutations (C999T, G1065A, G1428A, A1620G, G719A, C1069T) in patients. All together, carriers of these variations were more frequent in patients than in controls (phenotype frequency: 17 vs 9%, P ¼ 0.0166; odds ratio (OR) ¼ 2.06, 95% confidence interval (CI): 1.13-3.77). Although A91V was the most frequent variation and displayed a trend of association with multiple sclerosis (MS) in the first population of patients and controls (frequency of the 91V allele: 0.076 vs 0.043, P ¼ 0.044), we used it as a marker to confirm PRF1 involvement in MS and assessed its frequency in a second population of 966 patients and 1520 controls. Frequency of the 91V allele was significantly higher in patients than in controls also in the second population (0.075 vs 0.058%, P ¼ 0.019). In the combined cohorts of 1156 patients and 1788 controls, presence of the 91V allele in single or double dose conferred an OR ¼ 1.38 (95% CI ¼ 1.10-1.74). These data suggest that A91V and possibly other perforin variations indicate susceptibility to MS.

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Section: Discussionmentioning

confidence: 69%

Variations of the perforin gene in patients with multiple sclerosis

et al. 2008

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“…The plaques found in human multiple sclerosis patients have a 5-fold increase in OPN transcripts (Chabas et al, 2001). Significantly increased OPN protein levels were found in the plasma of relapsing-remitting MS patients whereas the OPN protein levels in primary progressive and secondary progressive MS patients were similar to healthy control levels (Vogt et al, 2003).…”

Section: Autoimmunitymentioning

confidence: 86%

“…Increased levels of OPN transcripts were reported in both the brain tissue of MS patients and the spinal cords of an EAE rat model (Chabas et al, 2001). In contrast, in autoimmune myocarditis it appears that neither OPN nor CD44 play any role in the development of the disease (Vogt et al, 2003).…”

Section: Autoimmunitymentioning

confidence: 99%

Osteopontin: Role in immune regulation and stress responses

Wang¹,

Denhardt²

2008

Cytokine & Growth Factor Reviews

605

558

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“…Further characterization by the same investigators revealed that OPN plays a critical role in the induction and disease process of EAE, an animal model for MS, when they compared WT with OPN gene knockout mice [14]. More recently, studies have confirmed that serum levels of OPN appear elevated in patients with MS as compared with controls [15][16][17], raising the possibility that the phenomenon may be attributable to inflammatory processes in MS. However, although the properties of OPN as a pro-inflammatory cytokine are known, the exact mechanism underlying the role of OPN in CNS inflammation in MS remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Chen

Nie

et al. 2009

Eur J Immunol

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IFN-b currently serves as one of the major treatments for MS. Its anti-inflammatory mechanism has been reported as involving a shift in cytokine balance from Th1 to Th2 in the T-cell response against elements of the myelin sheath. In addition to the Th1 and Th2 groups, two other important pro-inflammatory cytokines, IL-17 and osteopontin (OPN), are believed to play important roles in CNS inflammation in the pathogenesis of MS. In this study, we examined the potential effects of IFN-b on the regulation of OPN and IL-17 in MS patients. We found that IFN-b used in vitro at 0.5-3 ng/mL significantly inhibited the production of OPN in primary T cells derived from PBMC. The inhibition of OPN was determined to occur at the CD4 1 T-cell level. In addition, IFN-b inhibited the production of IL-17 and IL-21 in CD4 1 T cells. It has been described that IFN-b suppresses IL-17 production through the inhibition of a monocytic cytokine, the intracellular translational isoform of OPN. Our further investigation demonstrated that IFN-b also acted directly on the CD4 1 T cells to regulate OPN and IL-17 expression through the type I IFN receptor-mediated activation of STAT1 and suppression of STAT3 activity. Administration of IFN-b to EAE mice ameliorated the disease severity. Furthermore, spinal cord infiltration of OPN 1 and IL-17 1 cells decreased in IFN-b-treated EAE mice along with decreases in serum levels of OPN and IL-21. Importantly, decreased OPN production by IFN-b treatment contributes to the reduced migratory activity of T cells. Taken together, the results from both in vitro and in vivo experiments indicate that IFN-b treatment can down-regulate the OPN and IL-17 production in MS. This study provides new insights into the mechanism of action of IFN-b in the treatment of MS. IntroductionMS is a disease of the CNS characterized by chronic inflammatory and demyelinating processes [1]. CNS inflammation is considered as an important feature in MS pathology, and is directly associated with the disease process in MS [2]. Agents that have anti-inflammatory properties have been shown to suppress the disease activity to various degrees. MS is now commonly treated with an immunomodulatory agent, IFN-b, which has shown significant treatment efficacy and is Ã These authors contributed equally to the work. Eur. J. Immunol. 2009. 39: 2525-2536 Immunomodulation 2525 thought to involve a number of different mechanisms of action [3,4]. However, despite extensive clinical experience in the use of IFN-b, its mechanism of action has not been fully elucidated. Studies into its mechanism of action have revealed that anti-inflammatory properties of IFN-b function through the regulation of Th1 and Th2 cytokines [5,6]. Further, there is an evidence indicating that IFN-b promotes the production of IL-10 and inhibits the action of pro-inflammatory cytokines [7,8].Osteopontin (OPN), also known as early T lymphocyte activation-1, has been recently recognized as a pro-inflammatory cytokine promoting the production of IFN-g and IL-12 in macrophages...

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Elevated osteopontin levels in active relapsing‐remitting multiple sclerosis

Cited by 119 publications

References 19 publications

Variations of the perforin gene in patients with multiple sclerosis

Variations of the perforin gene in patients with multiple sclerosis

Osteopontin: Role in immune regulation and stress responses

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

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Elevated osteopontin levels in active relapsing‐remitting multiple sclerosis

Cited by 119 publications

References 19 publications

Variations of the perforin gene in patients with multiple sclerosis

Variations of the perforin gene in patients with multiple sclerosis

Osteopontin: Role in immune regulation and stress responses

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4+ T Cells in MS

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Product

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Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS