Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7–dependent homeostatic proliferation of CD4+ T cells

Sawa, Shin Ichiro; Kamimura, Daisuke; Jin, Gui Hua; Morikawa, Hideyuki; Kamon, Hokuto; Nishihara, Masateru; Ishihara, Katsuhiko; Murakami, Masaaki; Hirano, Toshio

doi:10.1084/jem.20052187

Cited by 162 publications

(180 citation statements)

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“…Treatment response to methotrexate in rheumatoid arthritis patients correlated with decreased IL-7 serum level, but not with TNF-a levels (50). In a mouse model for rheumatoid arthritis, anti-IL-7 treatment completely inhibited autoimmune arthritis (51). Moreover, IL-7 expression is increased in the inflamed salivary glands in primary Sjögren's syndrome compared with non-Sjögren's sicca syndrome patients (52).…”

Section: Discussionmentioning

confidence: 90%

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

Kreft

Verbraak

Wierenga‐Wolf

et al. 2012

The Journal of Immunology

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The IL-7Rα single nucleotide polymorphism rs6897932 is associated with an increased risk for multiple sclerosis (MS). IL-7Rα is a promising candidate to be involved in autoimmunity, because it regulates T cell homeostasis, proliferation, and antiapoptotic signaling. However, the exact underlying mechanisms in the pathogenesis of MS are poorly understood. We investigated whether CD4 and CD8 lymphocyte subsets differed in IL-7Rα expression and functionality in 78 MS patients compared with 59 healthy controls (HC). A significantly higher frequency of IL-7Rα+ CD8 effector memory (CD8EM) was found in MS. Moreover, IL-7Rα membrane expression was significantly increased in MS in naive and memory CD8 (all p < 0.05) with a similar trend in CD8EM (p = 0.055). No correlation was found between the expression level or frequency of IL-7Rα+CD8+ and rs6897932 risk allele carriership. Upon IL-7 stimulation, MS patients had stronger STAT5 activation in CD8EM compared with HC. IL-7 stimulation had a differential effect on both mRNA and protein expression of granzyme A and granzyme B between MS and HC. Stainings of different lesions in postmortem MS brain material showed expression of IL-7 and CD8+IL-7Rα+ in preactive, but not in active, demyelinating MS lesions, indicating involvement of IL-7Rα+ lymphocytes in lesion development. The intralesional production of IL-7 in combination with the lower threshold for IL-7–induced cytotoxicity in MS may enhance the pathogenicity of these CD8 T cells. This is of special interest in light of the established demyelinating and cytotoxic actions of granzyme A.

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Section: Discussionmentioning

confidence: 90%

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

Kreft

Verbraak

Wierenga‐Wolf

et al. 2012

The Journal of Immunology

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“…Targeting the IL-7Ra pathway might be a promising therapeutic intervention in MS and other in autoimmune diseases, for example, RA. 20 …”

Section: Resultsmentioning

confidence: 99%

Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients

et al. 2012

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Polymorphisms (single-nucleotide polymorphism (SNP)) in the interleukin-7 receptor-a (IL-7Ra)/IL-7 pathway are associated with an increased risk to develop multiple sclerosis (MS). The rs6897932 SNP in the IL-7Ra leads to increased soluble IL-7Ra production. Given the functional interaction between sIL-7Ra, membrane-bound IL-7Ra and IL-7, we assessed IL-7, mIL-7Ra and sIL-7Ra levels in MS patients and healthy controls (HCs). One-hundred and twenty eight MS patients had significantly lower sIL-7Ra levels compared with 73 HCs. The levels of sIL-7Ra increased dose-dependent upon rs6897932 [C] risk allele carriership in both HCs and MS. Next, we hypothesized that lower sIL-7Ra could result in a higher mIL-7Ra to soluble IL-7Ra ratio. Indeed, 52 MS patients had significantly increased mIL-7Ra to sIL-7Ra ratio for both CD4 and CD8 T cells compared with 44 HCs. Given the supposed role of IL-7 in autoimmunity, we determined whether sIL-7Ra influences IL-7 levels. IL-7 levels were significantly decreased in 40 MS patients compared with 40 HCs. In conclusion, MS patients had lower free IL-7 and a higher membrane to soluble IL-7Ra ratio. The soluble IL-7Ra levels correlate with the rs6897932 [C] risk allele carriership. The skew at the IL-7 and IL-7Ra level may influence responsiveness of IL-7Ra þ cells.

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“…Moreover, signals mediated by gp130 regulate multiple other biological functions, including acute phase response, immune reactions and inflammation [7,8]. The receptor is also involved in sustaining the disease state in inflammatory bowel disease, rheumatoid arthritis (RA) or MS [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

et al. 2009

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Gp130 is the common receptor of the IL-6 family of cytokines and is involved in many biological processes, including acute phase response, inflammation and immune reactions. To investigate the role of gp130 under inflammatory conditions, T-cell-specific conditional gp130 mice were first bred to the IL-10-deficient background and were then infected with the gastrointestinal nematode Trichuris muris. While IL-10 À/À mice were highly susceptible to T. muris, developed a mixed Th1/Th17 response and displayed severe inflammation of the caecum, infection of mice with an additional T-cell-specific deletion of gp130 signalling completely reversed the phenotype. These mice showed an accelerated worm expulsion that was associated with the rapid generation of a strong Th2 immune response and a significant increase in Foxp3-expressing Treg. Therefore, gp130 signalling in T cells regulates a switch between proinflammatory and pathogenic Th1/Th17 cells and regulatory Th2/Treg in vivo. Taken together, the data demonstrate that gp130 signalling in T cells is a positive regulator of inflammatory processes, favouring the Th1/Th17 axis.Key words: Cytokine receptor . Helminthic infection . Inflammation Th1/Th2/Th17 cells Transgenic mice IntroductionThe common receptor gp130 is constitutively expressed on immune and non-immune cells and is used by all members of the IL-6 family, which comprises IL-6, IL-11, leukaemia inhibitory factor, oncostatin M and the recently characterized cytokine IL-27, among others [1,2]. While gp130 acts as the obligate signalling subunit, each cytokine first binds to its specific receptor, which accounts for the difference in activities [3,4]. The lethality of mice with classical disruptions of two gp130 alleles demonstrated that gp130 signalling is important for the development of the nervous and hematopoietic systems [5,6]. Moreover, signals mediated by gp130 regulate multiple other biological functions, including acute phase response, immune reactions and inflammation [7,8]. The receptor is also involved in sustaining the disease state in inflammatory bowel disease, rheumatoid arthritis (RA) or MS [9][10][11]. The Th pathway is composed of, at least, three distinct subsets: Th1 cells produce IFN-g and are involved in the fight against intracellular pathogens. The Th2 immune response with T cells producing IL-4, IL-5 and IL-13 provides immunity to helminths [2]. Th17 cells produce cytokines like IL-17, IL-22 and mediate immunity to extracellular bacteria and fungi, but are also responsible for autoimmunity and inflammation [12,13]. Development of naïve T cells to Th17 cells requires the presence of IL-6, TGF-b1 and the transcription factor RORgt [14][15][16][17]. [20,21]. Since TGF-b1 is a common factor for Treg and Th17 cells, it is possible that a switch from Th17 to Treg exists in vivo in the absence of IL-6 signalling in T cells. The gastrointestinal helminth Trichuris muris is a good model to investigate Th-cell pathways. In common inbred mouse strains (BALB/c, C57BL/6), infection with T. muris is...

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Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7–dependent homeostatic proliferation of CD4+ T cells

Cited by 162 publications

References 50 publications

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

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