Proinflammatory Cytokine Environments Can Drive Interleukin‐17 Overexpression by γ/δ T Cells in Systemic Juvenile Idiopathic Arthritis

Kessel, Christoph; Lippitz, K.; Weinhage, Toni; Hinze, Claas; Wittkowski, Helmut; Holzinger, Dirk; Fall, Ndate; Grom, Alexei A.; Gruen, Niklas; Foell, Dirk

doi:10.1002/art.40099

Cited by 73 publications

(80 citation statements)

References 58 publications

(96 reference statements)

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“…Elevated IL‐17 expression in γδ T cells, but not CD4 + T cells, was found in patients with systemic juvenile idiopathic arthritis,101 and IL‐17 production was detected in CD161 hi CCR6 + γδ T cells in cerebrospinal fluid of patients with MS 102. Treatment of patients with MS with secukinumab non‐significantly reduced the number of combined unique active lesions and significantly reduced the number of cumulative new gadolinium‐enhancing T1 lesions by 67% 103.…”

Section: γδ17 Cells In Human Inflammatory Diseasesmentioning

confidence: 99%

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Akitsu

Iwakura

2018

Immunology

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SummaryInterleukin‐17 (IL‐17) is a pro‐inflammatory cytokine and is involved in the development of many diseases. Recent studies have revealed that IL‐17‐producing γδ T cells (γδ17 cells) in addition to IL‐17‐producing CD4+ T cells [T helper type 17 (Th17) cells] are often the main producers of IL‐17 in mouse models of inflammatory diseases. γδ T cells are functionally committed during intra‐thymic differentiation. γδ thymocytes capable of producing IL‐17, which express the transcription factor retinoic‐acid‐receptor‐related orphan receptor γt and the signature cytokine receptor IL‐23R, leave the thymus, and produce IL‐17 rapidly by the stimulation with IL‐1β and IL‐23 in the periphery. Therefore, γδ17 cells play important roles in the early phase of host defence against pathogens and in inflammatory diseases. γδ T cells that can produce IL‐17 are also increased in the skin of patients with psoriasis and in peripheral blood of patients with ankylosing sclerosis. Indeed, the therapy targeting IL‐17 has been approved or is in clinical trials, and proved to be very efficient to treat psoriasis, psoriatic arthritis and ankylosing sclerosis. In this review, we discuss recent knowledge about the pathophysiological function of γδ17 cells in infection and inflammatory diseases and therapeutic advances targeting IL‐17.

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Section: γδ17 Cells In Human Inflammatory Diseasesmentioning

confidence: 99%

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Akitsu

Iwakura

2018

Immunology

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“…40 IL-18, however, induces IL-17 production by γδ T-cells which express IL-18Rα and this mechanism may be involved in diseases such as auto-immune encephalomyelitis, systemic JIA or neonatal sepsis. [41][42][43] In the Helicobacter pylori chronic infection, IL-18 has been shown to play a role in FoxP3-positive Tregs differentiation. 44…”

Section: Biologicalfunctionsinadaptiveimmunitymentioning

confidence: 99%

“…It should be noted that IL-17 has been found elevated in sJIA patients, due to increased IL-17 positive γδ cells expressing IL-18Rα whose proliferation is dependent on IL-1β and IL-18. 42 Another explanation may be the long-term recognized negative effect of IFNγ on IL-1β production. 214,221 On the contrary, IFNγ may be found in the serum of sJIA patients complicated by MAS and a decrease IL-18/IFNγ ratio may characterized MAS appearance.…”

Section: Il-18insystemicjuvenileidiopathicarthritis/ Adult Onset Stmentioning

confidence: 99%

Interleukin‐18: Biological properties and role in disease pathogenesis

Kaplanski

2017

Immunological Reviews

435

385

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Initially described as an interferon (IFN)γ-inducing factor, interleukin (IL)-18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL-17-producing γδ T cells and macrophage activation. IL-18, a member of the IL-1 family, is similar to IL-1β for being processed by caspase 1 to an 18 kDa-biologically active mature form. IL-18 binds to its specific receptor (IL-18Rα, also known as IL-1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL-18Rβ chain. IL-18 then uses the same signaling pathway as IL-1 to activate NF-kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL-18 also binds to the circulating high affinity IL-18 binding protein (BP), such as only unbound free IL-18 is active. IL-18Rα may also bind IL-37, another member of the IL-1 family, but in association with the negative signaling chain termed IL-1R8, which transduces an anti-inflammatory signal. IL-18BP also binds IL-37 and this acts as a sink for the anti-inflammatory properties of IL-37. There is now ample evidence for a role of IL-18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL-18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain-of-function mutations, IL-18 circulates in the range of tens of nanograms/mL. HS is treated with the IL-1 Receptor antagonist (anakinra) but also specifically with IL-18BP. Systemic juvenile idiopathic arthritis or adult-onset Still's disease are also characterized by high serum IL-18 concentrations and are treated by IL-18BP.

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“…Data from experimental autoimmune encephalomyelitis and mouse models of psoriasis implicate gd17 cells in immunopathology (6,52); however, the greater impact of Mif deficiency in suppressing these diseases (53,54) and verification in multiple sclerosis by pharmacologic MIF antagonism (55) suggests the likely dominance of MIF action over gd17 cell action. A mouse model of juvenile idiopathic arthritis has recently highlighted the role of gd17 cells in immunopathology (56), and it has been proposed that in human juvenile idiopathic arthritis, in which anti-IL-1 therapy is highly effective, IL-1b favors the induction of gd17 cells (57,58). These observations, together with human genetic data implicating variant MIF alleles in juvenile idiopathic arthritis (59,60) and other autoimmune arthritides (61,62), may suggest an upstream role for MIF in regulating gd17 cell responses by augmenting IL-1b expression.…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor regulates innate γδ T‐cell responsesviaIL‐17 expression

et al. 2019

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T cells expressing invariant γδ antigen receptors (γδ T cells) bridge innate and adaptive immunity and facilitate barrier responses to pathogens. Macrophage migration inhibitory factor (MIF) is an upstream mediator of host defense that up‐regulates the expression of pattern recognition receptors and sustains inflammatory responses by inhibiting activation‐induced apoptosis in monocytes and macrophages. Surprisingly, Mif−/− γδ T cells, when compared with wild type, were observed to produce >10‐fold higher levels of the proinflammatory cytokine IL‐17 after stimulation with gram‐positive exotoxins. High‐IL‐17 expression was associated with the characteristic features of IL‐17‐producing γδ T (γδ17) cells, including expression of IL‐23R, IL‐1R1, and the transcription factors RORγt and Sox13. In the gram‐positive model of shock mediated by toxic shock syndrome toxin (TSST‐1), Mif−/− mice succumbed to death more quickly with increased pulmonary neutrophil accumulation and higher production of cytokines, including IL‐lβ and IL‐23. Mif−/− γδ T cells also produced high levels of IL‐17 in response to Mycobacterium lipomannan, and depletion of γδ T cells improved survival from acutely lethal Mycobacterium infection or TSST‐1 administration. These data indicate that MIF deficiency is associated with a compensatory amplification of γδ17 cell responses, with implications for innate immunity and IL‐17‐mediated pathology in situations such as gram‐positive toxic shock or Mycobacterium infection.—Kim, H. K., Garcia, A. B., Siu, E., Tilstam, P., Das, R., Roberts, S., Leng, L., Bucala, R. Macrophage migration inhibitory factor regulates innate γδ T‐cell responses via IL‐17 expression. FASEB J. 33, 6919–6932 (2019). http://www.fasebj.org

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Proinflammatory Cytokine Environments Can Drive Interleukin‐17 Overexpression by γ/δ T Cells in Systemic Juvenile Idiopathic Arthritis

Abstract: A systemic JIA cytokine environment may prime γ/δ T cells in particular for IL-17A overexpression. Thus, our observations in systemic JIA patients strongly support a pathophysiologic role of these cells, as proposed by the recent murine model.

Cited by 73 publications

References 58 publications

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Interleukin‐18: Biological properties and role in disease pathogenesis

Macrophage migration inhibitory factor regulates innate γδ T‐cell responsesviaIL‐17 expression

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