T‐helper 17 cells expand in multiple sclerosis and are inhibited by interferon‐β

Durelli, Luca; Conti, Laura; Clerico, Marinella; Boselli, Daniela; Contessa, Giulia; Ripellino, Paolo; Ferrero, Bruno; Eid, Pierre; Novelli, Francesco

doi:10.1002/ana.21652

Cited by 336 publications

(324 citation statements)

References 47 publications

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“…Interestingly, these finding mirror changes as predicted by detailed in vitro mechanistic studies of IL-17 (9)(10)(11)(12)14) and . Another main finding of our study was the potential difference between responders and non-responders in IL-17A levels before and after treatment.…”

Section: Discussionsupporting

confidence: 63%

See 1 more Smart Citation

Longitudinal interferon-β effects in multiple sclerosis: Differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13

Kvarnström

Ydrefors

Ekerfelt

et al. 2013

Journal of the Neurological Sciences

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Section: Discussionsupporting

confidence: 63%

“…Thus, IFN-β was shown to reduce IL-17 production directly or indirectly by reduction of osteopontin and induction of IL-27 (10). Consequently, studies have demonstrated that IFN-β may exert its effect in MS by reduction of IL-17-associated immunity (11)(12)(13)(14). In contrast, it has been…”

Section: Inflammatory Effects Diminished Trafficking Of T Cells Intomentioning

confidence: 99%

Longitudinal interferon-β effects in multiple sclerosis: Differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13

Kvarnström

Ydrefors

Ekerfelt

et al. 2013

Journal of the Neurological Sciences

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“…Their role in relapsing remitting MS (RR MS) is supported by a recent report on the increased frequency of IL-17A-producing cells, which is positively associated with clinical disease activity (2). Th17 cell differentiation is orchestrated by multiple cytokines, including IL-6, IL-1b, TGF-b, IL-21, and IL-23, which stimulate Th17 cell differentiation, and IFN-g, IL-4, IL-12, IL-10, and IL-27, which inhibit Th17 cell differentiation (3).…”

mentioning

confidence: 93%

Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis

Zhang

Tao

Troiani

et al. 2011

The Journal of Immunology

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Subsequent to the clinical trial of simvastatin in patients with relapsing remitting multiple sclerosis (RR MS), which demonstrated the ability of simvastatin to inhibit new inflammatory CNS lesion formation, the current in vitro study has characterized the mechanisms through which simvastatin inhibits Th17 cell differentiation. The anti-inflammatory effects of statins are mediated by the inhibition of isoprenylation, which ensures proper membrane insertion and function of proteins. Small GTPases, involved in multiple signal transduction pathways, are the key targets for isoprenylation. We report that simvastatin, one of the most hydrophobic statins with good CNS penetration, inhibited Th17 cell differentiation and IL-17A, IL-17F, IL-21, and IL-22 secretion in in vitro-differentiated naive CD4+ T cells from RR MS patients. Simvastatin exerted a less prominent effect on the cells from healthy controls, as it inhibited only IL-17F secretion. The inhibition of Th17 cell differentiation was mediated via inhibition of IFN regulatory factor 4 (IRF4) expression, which was identified as a key transcription factor for human Th17 cell differentiation using both IRF4 gene knockdown and overexpression experiments. In studies addressing which isoprenylation pathway—geranylgeranylation or farnesylation—is inhibited by simvastatin, we demonstrated that the geranylgeranyl transferase inhibitor replicated the effect of simvastatin. Selective inhibition of geranylgeranylated RhoA-associated kinase replicated the effect of simvastatin on the inhibition of IRF4 expression and IL-17A, IL-17F, IL-21, and IL-22 secretion, presenting a promising new therapeutic approach for this disabling disease.

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“…In multiple sclerosis (MS), IL-17 expression in CD4 + T cells within CNS lesions has been observed and more IL-17 + T cells were found in active compared with inactive lesions (6,7). Moreover, expansion of peripheral T H 17 cells during active MS, as well as enhanced frequencies of T H 17 cells in the cerebrospinal fluid during relapse, indicates that this population might be involved in disease exacerbation (8,9). Another study demonstrated increased frequencies of memory T H 17 cells in the peripheral blood of MS patients, which was further enhanced during relapse (10).…”

mentioning

confidence: 99%

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

Herold

Posevitz

Chudyka

et al. 2015

The Journal of Immunology

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It is currently acknowledged that TH17 cells are critically involved in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). In this article, we demonstrate that signals delivered by the coinhibitory molecule B7-homologue 1 (B7-H1) via a B7-homologue 1 mouse-IgG2aFc (B7-H1-Ig) fusion protein nearly abolish TH17, but not TH1 and TH2, differentiation via direct interaction with the T cell. These effects were equally pronounced in the absence of programmed death-1 or B7.1 and B7.2 on the T cell side, thus providing clear evidence that B7-H1 modulates T cell differentiation via a novel receptor. Mechanistically, B7-H1 interfered with early TCR-mediated signaling and cytokine-mediated induction of the TH17-determining transcription factors retinoic acid-related orphan receptor γ t and IFN regulator factor-4 in a programmed death-1 and B7-independent fashion. In an animal model of MS, active myelin oligodendrocyte glycoprotein–induced experimental autoimmune encephalomyelitis, B7-H1-Ig exhibited a significant and long-lasting effect on disease severity upon administration during the first 5 d of the priming phase, which was accompanied by reduced TH17 responses in the periphery and within the CNS. Importantly, B7-H1-Ig was even capable of interfering with T cell encephalitogenicity when interaction with the T cells occurred after priming using an adoptive transfer experimental autoimmune encephalomyelitis model. In line with this, both naive human CD4+ T cells and differentiated TH17 effector cells from MS patients were highly sensitive toward B7-H1-Ig–mediated TH17 suppression. Together, we propose the existence of a novel B7-H1–mediated immune-regulatory pathway in T cells, which selectively limits murine and human TH17 cell responses and might be therapeutically exploited to control TH17-mediated autoimmunity.

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T‐helper 17 cells expand in multiple sclerosis and are inhibited by interferon‐β

Cited by 336 publications

References 47 publications

Longitudinal interferon-β effects in multiple sclerosis: Differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13

Longitudinal interferon-β effects in multiple sclerosis: Differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13

Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

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