Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis

Matusevičius, Darius; Kivisäkk, Pia; He, Bing; Kostulas, Nikolaos; Özenci, Volkan; Fredrikson, Sten; Link, Hans

doi:10.1177/135245859900500206

Cited by 654 publications

(388 citation statements)

References 23 publications

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“…Recent studies have shown that pathogenic IL-23-driven IL-17-producing cells can invade the CNS and promote the development of chronic CNS inflammation associated with autoimmunity (21). Indeed, microarray analysis demonstrated IL-17 expression in the plaques of MS brains (22) and increased IL-17-expressing mononuclear cells present in the cerebrospinal fluid of MS patients (21). Using bone marrow chimeric mice in which the p40 subunit common to IL-12 and IL-23 was absent in the CNS, it was shown that IL-23 produced by resident microglia and infiltrating macrophages in the CNS was critical to the clinical onset of EAE, but not for chronic CNS inflammation, suggesting that IL-23R engagement in the CNS was critical to the pathogenicity of infiltrating myelinspecific T cells (20).…”

Section: Discussionmentioning

confidence: 99%

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

Gocke¹,

Cravens²,

Ben³

et al. 2007

The Journal of Immunology

236

224

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IL-17-producing T cells (Th17) have recently been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. However, little is known about the transcription factors that regulate these cells. Although it is clear that the transcription factor T-bet plays an essential role in the differentiation of IFN-γ-producing CD4+ Th1 lymphocytes, the potential role of T-bet in the differentiation of Th17 cells is not completely understood. In this study, therapeutic administration of a small interfering RNA specific for T-bet significantly improved the clinical course of established EAE. The improved clinical course was associated with suppression of newly differentiated T cells that express IL-17 in the CNS as well as suppression of myelin basic protein-specific Th1 autoreactive T cells. Moreover, T-bet was found to directly regulate transcription of the IL-23R, and, in doing so, influenced the fate of Th17 cells, which depend on optimal IL-23 production for survival. We now show for the first time that suppression of T-bet ameliorates EAE by limiting the differentiation of autoreactive Th1 cells, as well as inhibiting pathogenic Th17 cells via regulation of IL-23R.

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Section: Discussionmentioning

confidence: 99%

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

Gocke¹,

Cravens²,

Ben³

et al. 2007

The Journal of Immunology

236

224

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“…It was initially reported that IL-17 could be secreted by human CD4 1 T cells [15] and that IL-17 mRNA was elevated in the CSF and blood of patients with MS [16]. It was later demonstrated that IL-17-producing T cells were a distinct linage from Th1 or Th2 cells [17][18][19].…”

Section: T-cell Subtypes That Secrete Il-17mentioning

confidence: 99%

Induction, function and regulation of IL‐17‐producing T cells

2008

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Recent reports have provided convincing evidence that IL-17-producing T cells play a key role in the pathogenesis of organ-specific autoimmune diseases, a function previously attributed exclusively to IFN-c-secreting Th1 cells. Furthermore, it appears that IL-17-producing T cells can also function with Th1 cells to mediate protective immunity to pathogens. Although much of the focus has been on IL-17-secreting CD4 1 T cells, termed The main function of IL-17-secreting T cells is to mediate inflammation, by stimulating production of inflammatory cytokines, such as TNF-a, IL-1b and IL-6, and inflammatory chemokines that promote the recruitment of neutrophils and macrophages.Key words: Autoimmunity . IL-17 . Infection . Inflammation IntroductionMore than 20 years ago Mosmann and Coffman reported that distinct CD4 1 T-cell subtypes, termed Th1 and Th2 cells, could be distinguished on the basis of cytokine secretion and function [1]. The Th1-Th2 model provided a useful but simplistic basis for our understanding of the mechanisms of immunity to infection and also attempted to explain the role of T cells in the pathogenesis of autoimmunity and allergy/asthma. The original hypothesis was that IFN-g-secreting CD4 1 cells mediated protective immunity to intracellular pathogens by promoting macrophage activation and stimulating production of complement fixing and virus neutralizing antibodies, but also promoted inflammatory responses and mediated the pathology in certain autoimmune diseases. In contrast, CD4 1 T cells that secreted IL-4, IL-5, IL-10 and IL-13 were considered to be the main helper T cells providing help for B-cell production of antibody, especially IgG1 in mice, and mediated protective immunity to extracellular pathogens. These Th2 cells were also anti-inflammatory, controlling Th1 responses, but at the same time mediated allergic reactions and had an inflammatory and pathological role in asthma.The identification of additional T-cell subtypes has led to a shift in the Th1-Th2 paradigm and has helped to explain some anomalies in the original model. In the mid 1990s suppressor T cells were re-discovered as Treg cells and were shown to have a major role in controlling immune responses to self-antigens, thereby preventing autoimmunity. Furthermore, these cells rather than the reciprocal Th1 or Th2 populations were shown to be the major regulator of effector T cells, functioning to maintain self-tolerance, prevent autoimmunity and limit collateral damage during immune responses to pathogens [2,3].There were a number of other observations which could not be explained on the basis of the two Th1 and Th2 subtypes. Mini-ReviewDespite the assumption that Th1 cells mediated autoimmunity, mice deficient in IFN-g or IFN-g receptors were found to have increased susceptibility to EAE and collagen-induced arthritis (CIA) [4,5]. Furthermore, EAE was exacerbated in mice deficient in the Th1 polarizing cytokine, 7]. It was then discovered that mice deficient in the novel IL-12 family member, IL-23 were resistant to EAE [6]....

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“…Increased levels of IL-17 were reported to correlate with disease intensity in allergic lung inflammation as observed in OVA-sensitized mice [12], in peritoneal inflammation after infection with Bacteroides fragilis [13], in rheumatoid arthritis [14], in multiple sclerosis [15] and in psoriasis [16].…”

Section: Introductionmentioning

confidence: 99%

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

2006

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IL-17 has been associated with multiple inflammatory disorders such as rheumatoid arthritis, asthma and multiple sclerosis. As these diseases require long-term treatment we turned to an auto-vaccine strategy for IL-17 neutralization in vivo. Mouse IL-17A was covalently linked to ovalbumin and used to immunize C57BL/6 mice. This vaccine induced the production of antibodies that blocked IL-17A bioactivity in vitro but did not react with the other IL-17 isoforms, including IL-17F. As the half-life of the Ab titers after the last immunogen administration was approximately 4 months, the vaccine provides for long lasting and selective inhibition of IL-17A activity in vivo. A monoclonal Ab (mAb) derived from these mice showed the same specificity for IL-17A. To test the ability of the vaccine to confer protection against an IL-17-dependent disorder, SJL mice were vaccinated with IL-17-OVA and encephalomyelitis (EAE) was induced by proteolipid protein (PLP) peptide 139-151. Vaccinated mice were completely protected against the disease. The above-mentioned anti-IL-17A mAb also prevented EAE development. The absence of clinical symptoms contrasted with unaltered PLP-induced cytokine production in vitro and unmodified anti-PLP IgG titers and isotypes. These results suggest that an anti-IL-17A auto-vaccine offers new perspectives for therapy of autoimmune diseases.

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Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis

Cited by 654 publications

References 23 publications

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity

Induction, function and regulation of IL‐17‐producing T cells

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

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