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IL-17 and Th17 cells in human inammatory diseases

Pierre Miossec*
Department of Immunology and Rheumatology, Hopital Edouard Herriot and Immunogenomics and inammation research unit EA 4130, University of Lyon; Lyon, France Available online 14 April 2009

Abstract IL-17 was discovered in 1995/96 as a T cell derived cytokine with effects on inammation and neutrophil activation. In 2006, the precise cell source of IL-17 was identied in the mouse, and these cells were named Th17 cells. They play a role in various human diseases associated with inammation and destruction such as rheumatoid arthritis, psoriasis, Crohns disease, multiple sclerosis, where IL-17 can be seen as a therapeutic target. 2009 Elsevier Masson SAS. All rights reserved.
Keywords: IL-17; Cytokines; Inammation; Destruction; TNFa; IL-1

IL-17 has gained much publicity very recently, when in 2005e2006, the cell source of IL-17 named Th17 cells was identied in the mouse. The protein IL-17 itself had been discovered 10 years before as a T cell derived cytokine. These new ndings on Th17 cells conrmed and extended the results obtained previously following the identication of IL-17. Demonstration of the role of IL-17 in many chronic inammatory conditions further supported the concept of IL17 targeting for treatment. We will review these new ndings in light of the previous knowledge [1]. This paper will focus on the possible contribution of IL-17, a central player in immune regulation, and the related Th17 cells to chronic inammatory diseases, in some of which IL-17 could be a therapeutic target.

cytokine production, showing immediately its link to inammation [2,3]. At the same time, IL-17 was shown to induce neutrophil induction and maturation, an indication of its role in the acute mechanisms in host defense. This result indicated very early the link between IL-17 and neutrophil biology. IL-17 was discovered under the name of CTLA-8, a gene product without clear function. Its link with rheumatoid arthritis (RA) was immediately established. Synoviocytes obtained from the synovium membrane of RA patients were used in these rst experiments. The results suggested a potential contribution of IL-17 to RA pathogenesis. This was later extended to other chronic inammatory diseases. 2. The IL-17 family and its receptors IL-17 now referred to as IL-17A, is the founding member of the IL-17 family, which includes IL-17AeF. IL-17F shows a 50% sequence homology with IL-17A and has similar effects as IL-17A but to a lower extend [4]. However when combined with TNF, a synergistic effect is observed, almost as potent as with IL-17A. IL-17A and F are produced as dimers including a signicant proportion of A/F heterodimers. Th17 cells have been rst described in the mouse by the production of IL-17A, and they also produced a list of other proinammatory cytokines including IL-17F, IL-22, TNF, IL6. IL-22 is a member of the IL-10 family, that synergizes with

1. Identication of IL-17 IL-17 was described in 1995/96 as a proinammatory cytokine produced by T cells. The key experiment was the demonstration that the addition of IL-17 to mesenchymal cells/ broblasts was able to increase IL-6 and other proinammatory

* Tel.: 334 72 11 74 87; fax: 334 72 11 74 29. E-mail address: miossec@univ-lyon1.fr 1286-4579/$ - see front matter 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.micinf.2009.04.003

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IL-17A or IL-17F to regulate genes associated with skin innate immunity [5]. In particular IL-22 was shown to mediate dermal inammation [6]. In addition, Th17 cells are involved in cell interactions through the expression of RANKL. Such RANKe RANKL interaction is the nal bridge whereby osteoblasts activate osteoclasts leading to bone destruction. Similar interactions are found between broblasts and dendritic cells. A rst receptor for IL-17 named IL-17R was described in 1995e1996 when IL-17 was discovered. Its rather low afnity for IL-17 suggested the presence of additional chains [7,8]. Sequence screening showed proteins with a partial homology with IL-17R [9]. The rst member of the IL-17R family is the original IL-R receptor renamed as IL-17RA. The second is IL17RC. The physical association of the two receptors has been shown although it is still unclear whether these are two chains of a single receptor or two different receptors. It was previously proposed that IL-17A could be the receptor for IL-17A and IL-17RC the receptor for IL-17F. It appears now that IL17RA and RC interact together for an optimal response, in particular when IL-17 is combined with TNF. Indeed the inhibition of the two receptors is needed to reduce the response to the combination of IL-17 with TNF [4].

4. IL-17 and human inammatory diseases Following the discovery of IL-17 and of its key properties, a number of both human and mouse, spontaneous as well induced diseases, were shown to be associated with IL-17 overexpression and production. Although the list of diseases will certainly increase, RA emerged as the best studied situation and we will rst focus on this disease. It should be kept in mind that most of these results could also apply to the long list of chronic inammatory diseases. Diseases such as RA, multiple sclerosis (MS), Crohns disease have in common the local chronic inammatory reaction with production of inammatory cytokines, leading to matrix destruction and defective repair [20]. 5. Rheumatoid arthritis RA is characterized by the chronic inammation of the synovium membrane of joints. Resulting cell interactions induce proinammatory cytokine production which in turn activates the release of proteases leading to bone and cartilage destruction. Concordant results using mouse and human models of RA showed that IL-17 is involved in the proinammatory patterns associated with joint inammation [21]. In the mouse, a single injection of IL-17 alone into a normal knee is sufcient to induce cartilage damage [22]. The continuous administration of IL-17 by gene over-expression into a normal knee induces massive damage with extensive inammatory cell migration, bone erosions, and cartilage degradation [23]. The results indicate that the local release of IL-17 alone could reproduce the key features of human RA. Conversely, inhibition with specic inhibitors including blocking antibodies and soluble receptor, provided protection from inammation and destruction [24]. Addition of IL-4 through gene therapy acting more broadly on other cytokines could inhibit IL-17 production and action and protect from bone destruction by reducing the key interactions between RANK and RANK ligand [24]. The link between IL-17 and human RA was reinforced when it was shown that pieces of RA synovium could produce bioactive IL-17. This activity was measured with a bioassay where supernatants of RA synovium pieces induced a massive production of IL-6 by RA synoviocytes [25]. Using the rst available monoclonal antibody blocking human IL-17, such production was reduced by two-thirds. This robust production of IL-6 using supernatants containing IL-17 was in contrast with the limited effect of recombinant IL-17 alone. The same ndings were obtained with human bone explants obtained during wrist surgery. Here again high levels of functional IL17 were detected, indicating the role of T cells from bone marrow in juxta-articular bone destruction [25,26]. As expected this effect was associated with RANK ligand expression by these T cells, interacting with RANK expressing cells, not only osteoclasts but also mature dendritic cells [26,27]. In addition to synovium inammation, IL-17 induces inammation associated bone resorption [26] and contributes to similar conditions such as joint prosthesis loosening and periodontal disease [28,29]. In a clinical study of a series of

3. Th17, the cellular source of IL-17 The most recent step was the identication in 2006 of the cell source of IL-17 [10,11]. IFNg was dened as a maker of Th1 cells and IL-4 of Th2 cells. The source of IL-17 was found to be different and these cells were named Th17. In the mouse, this new subset was identied by the demonstration of the inhibitory effect of IFNg on IL-17 production in mouse models of autoimmune diseases [12e14]. The next step was the discovery of IL-23, a monocyte product, shown to be a key cytokine in the induction of brain inammation in experimental models of encephalomyelitis [15]. These results have been obtained in the mouse and as such should be considered with caution when applied to the human situation. This will be discussed in detail in another chapter. Even in the mouse, more recent results indicated the frequent co-expression of IFNg and IL-17. Contribution of one of the two cytokines could lead to different pathogenic pathways, leading to the same clinical presentation as observed in mouse models of autoimmunity [16,17]. Results with RA T cells clones indicated that IL-17 was often produced in association with IFNg but not with IL-4 [18]. However in situ immunostaining of the RA synovium showed two isolated populations of T cells producing either IFNg or IL-17. Double positive cells were rarely seen. It thus remains to be demonstrated whether these secreting patterns are still dynamic or xed. Of interest in this context was the demonstration that cytokine secreting T cells have a particular morphology with a plasma cell appearance, a pattern that can be induced in vitro and is associated with the loss of TCR and CD3 but not of CD4 [19]. As for B cells, the plasma cell morphology of the IFNg and IL-17 producing cells strongly suggests that this is a xed pattern related to a nal stage of differentiation.

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RA patients, expression of IL-17 in RA synovium biopsies was associated with an increase in both activity and severity of the disease, conrmed on biopsies showing increased joint damage and higher IL-17 expression [30]. The role of IL-17 in chronicity was conrmed, by showing that in the mouse collagen arthritis model, the IL-17 effect was dependent on the presence of TNF at the early phase, whereas at a later stage the disease was mostly IL-17 driven, and now TNF independent [31]. 6. Psoriasis Psoriasis is an inammatory skin disease with skin inltration by immune cells which have migrated from blood. Some patients have joint manifestations combining inammation and destruction during psoriatic arthritis. Among the inltrated cells, activated T cells represent a large proportion. Using various approaches, skin biopsies from patients with psoriasis show a high expression of IL-17 as well of IL-23 and IL-22 [32]. At this stage the respective contribution of these three cytokines is still unclear. Of the three, mouse results have demonstrated the specicity of IL-22 for skin defense. This could suggest that inhibition of IL-22 would be more appropriate as being more skin specic. However, the rst positive results from a clinical trial with an anti-IL-17 antibody were obtained in patients with psoriasis. These results demonstrated the implication of IL-17, but do not exclude an indirect effect. Indeed interactions with less specic inammatory cytokines such as TNF are also involved. In skin biopsies from psoriasis patients treated with a TNFa inhibitor, a reduced expression of IL-23, IL-22 and IL-17 was observed [32]. 7. Crohns disease Crohns disease is an inammatory bowel disease which affects specic locations of the digestive tract. These locations are different in ulcerative colitis. In both diseases, local inammation in the mucosa leads to destruction of the lamina, with complications such as perforations, and internal or external stulas. Inammatory joint manifestations different from those seen in RA can be associated as part of the spondylarthropathies. As in RA and psoriasis, the contribution of TNF has been demonstrated by the positive effect of TNF inhibition in a signicant proportion of patients with inammatory bowel disease. Clinical studies have used biopsies obtained from endoscopy. The key cytokines IL-23 and IL-17 and also IL-12 were found over expressed in lesions of Crohns disease [33]. However Crohns disease and ulcerative colitis may differ in some aspects of pathogenesis. Some studies have found differences in cytokine expression with IL-17 being more associated with ulcerative colitis and IFNg with Crohns disease [34]. 8. Multiple sclerosis Multiple sclerosis is an inammatory disease which affects the central nervous system. Accumulation of inammatory

immune cells from blood results from their migration through the brain blood barrier. Such migration is differently regulated when compared to that seen in inamed organs outside the central nervous system. Chronic inammation of the brain leads to the destruction of myelin sheaths leading to reduction in inux transmission and function loss. When considering human MS, IL-17 was on the top list of genes found to be over expressed in brain biopsies from MS patients through extensive gene array studies. Mouse models of MS have been instrumental in the denition of the contribution of cytokines to the differentiation of Th17 cells. The key studies were performed in mice with experimental autoimmune encephalomyelitis (EAE). The rst step was the discovery of IL-23. Before, it was considered that IL-12 and IFNg were the key cytokines involved in EAE, then classied as a Th1 disease. IL-12, which induces IFNg, is composed of two chains: p35 and p40 [35]. IL-23 was later described as a new cytokine, composed of two chains, the p40 chain shared with IL-12, and of a unique chain p19, not found in IL-12 [36]. Mice lacking the p35 chain, and thus lacking IL12, developed EAE. Surprisingly mice lacking the p19 chain, and thus lacking IL-23, were resistant [15]. In contrast to what was previously thought, IL-12 and IFNg were not crucial for inducing EAE, but IL-23 was necessary [37,38]. In EAE, Th17 cells can disrupt the blood barrier leading to central nervous system inammation [39,40]. Recently the association between IL-17/Th17 and EAE/MS has been revisited. Experiments in the mouse indicated that in fact the two Th1 and Th17 pathways could contribute to disease but it was impossible to differentiate clinically the two forms [17]. Studies of brain lesions showed accumulation of neutrophils when the Th17 pathway is activated and accumulation of monocytes when the Th1 pathway is activated. These results are of interest when trying to link disease to particular cytokine/pathway contribution. This may explain disease heterogeneity as indicated by clinical response to a particular cytokine/cellular inhibitor. 9. Hyper IgE syndrome The hyper IgE syndrome is a primary immunodeciency associated with very high levels of IgE, skin and lung manifestations, bone disorders and infections. IgE is the prototypic immunoglobulins produced under the action of the Th2 cytokines, IL-4 and IL-13. Recently, various mutations in the Stat3 gene have been identied in those patients resulting in Stat3 loss of function [41]. Stat3 is a key transcription factor associated with the Th17 pathway. Indeed defects in Th17 cells have been observed in these hyper IgE patients [42]. These ndings result from the balance between the Th17 and Th2 pathways, where the Th17 pathway inhibits the Th2 pathway and IgE production. 10. IL-17 targeting for treatment Cytokine targeting has shown efcacy with various inhibitors including monoclonal antibodies against TNF or against

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the cell receptor of IL-6, a TNF soluble receptor and an IL-1 receptor antagonist. Some of the tools based on similar concepts are now available to target the IL-17 pathway. 11. IL-17 specic inhibitors The two major options are the targeting of the ligand or the receptor [43]. Tools ready for human applications include monoclonal antibodies against IL-17 and against IL-17R. Preclinical studies have demonstrated their efcacy in mouse and human models of inammatory diseases [44], where the combination of IL-17 and TNFa inhibitors is often more potent [45]. Additional targets have been identied from recent research on IL-17 and IL-17R families. Regarding the ligand, the possible choice is now between IL-17A or IL-17F or both, and for the receptor, IL-17RA or IL-17RC or both. In addition, as for the other proinammatory cytokines, active research is looking for small molecules able to control the intracellular signaling pathways, particularly RORgammat, the transcription factor characteristic of the Th17 pathway [46]. 12. Use of non-IL-17 anti-cytokine inhibitors Such inhibitors can act on pathways upstream of IL-17 and/ or on other cytokines in addition to IL-17. Since IL-23 is implicated in IL-17 production, the inhibition of IL-23 is a way to control the Th17 pathway by acting upstream. Treatment with a monoclonal antibody against p40, which is common to IL-12 and IL-23, has shown efcacy in psoriasis and Crohns disease, but not clearly in RA and MS [47,48]. In active Crohns disease, a local reduction of IL-12 and IL-23 was seen after treatment [49]. Specic inhibitors of IL-23 remain to be tested and compared with the p40 inhibitors. Similarly specic inhibitors of IL-21 and IL-22 will have to be compared with IL-17 inhibitors. Some cytokines have broad anti-IL-17 properties. IL-4 inhibits the production and functions of IL-17 as well as TNF, IL-1, IL-6 [24,50]. IL-25/IL-17E is a member of the IL-17 family [51], with anti-inammatory properties on Th17 cells [52]. 13. Acting on regulatory pathways New treatments could use the effects of Th17 cells on the function of regulatory T cells [53]. IL-17, TNF-a, IL-6 and IL-1, not only promote inammation but also inhibit regulatory T cell functions. The use of IL-17 inhibitors could be a way to control rst inammation but also to restore regulatory T cell functions. In RA patients TNFa inhibitors may control the disease not only by inhibiting TNFa, but also by correcting part of the defective regulatory T cell functions [54]. Other options include targeting the IL-6 receptor with a monoclonal antibody or the IL-1 receptor with an IL-1 receptor antagonist, known to have clear effects on systemic inammation [55,56].

14. Limitations of IL-17 targeting Targeting cytokines may interfere with immune defense. Inhibition of TNF was associated with an increased risk of tuberculosis reactivation. For IL-17, the link with neutrophil biology was apparent from the rst results. Thus inhibition of IL-17 may affect the acute defense mechanisms involving neutrophils. Indeed in the mouse, inhibition of IL-17 has been associated with increased mortality from bacterial lung infections [57]. IL-17 appears to be critical for neutrophil activation and migration [58]. IL-17 is a strong inducer of IL8, a key chemokine for neutrophils. Conversely, IL-17 appears to have inhibitory effect on the production of chemokines for mononuclear cells. In addition, inhibition of the IL-23 pathway has been associated with defects in the cell mediated immunity including increased severity of mycobacterial infections in the mouse. 15. Position of IL-17 targeting as a treatment The position of IL-17 inhibition in the treatment of inammatory conditions remains to be dened. As of today positive results have been obtained with a monoclonal against IL-17A in patients with psoriasis. Trials have started or are ready to start in RA, Crohns disease. Limitations for targeting IL-17 could be the rather low effect of IL-17 at least when used alone, the reduced numbers of IL-17 secreting cells in tissues, and the overlap with the effects of TNF. The combined inhibition of TNF and IL-17 possibly used sequentially, may allow the targeting of two different cell types, monocytes and T cells. Anti-TNF nonresponders may have an IL-17 driven disease. In addition secondary loss of response to TNF inhibition may result from the induction of other pathways, possibly involving IL-17, and replacing the initial TNF contribution, as observed in the mouse [31]. 16. Conclusion The story of IL-17 and of the Th17 subset is a new revival of the contribution of some T cells to chronic inammation and extra-cellular matrix destruction. A growing list of diseases has been associated with IL-17 but the nal demonstration of its contribution to disease pathogenesis is still missing. Tools are now getting ready to test these concepts in the clinic. References
[1] P. Miossec, Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inammation and destruction through synergy, Arthritis Rheum 48 (2003) 594e601. [2] F. Fossiez, O. Djossou, P. Chomarat, L. Flores-Romo, S. Ait-Yahia, C. Maat, J.J. Pin, P. Garrone, E. Garcia, S. Saeland, D. Blanchard, C. Gaillard, B. Das Mahapatra, E. Rouvier, P. Golstein, J. Banchereau, S. Lebecque, T cell interleukin-17 induces stromal cells to produce proinammatory and hematopoietic cytokines, J Exp Med 183 (1996) 2593e2603.

P. Miossec / Microbes and Infection 11 (2009) 625e630 [3] Z. Yao, S.L. Painter, W.C. Fanslow, D. Ulrich, B.M. Macduff, M.K. Spriggs, R.J. Armitage, Human IL-17: a novel cytokine derived from T cells, J Immunol 155 (1995) 5483e5486. [4] S. Zrioual, M.L. Toh, A. Tournadre, Y. Zhou, M.A. Cazalis, A. Pachot, V. Miossec, P. Miossec, IL-17RA and IL-17RC receptors are essential for IL-17A-induced ELR CXC chemokine expression in synoviocytes and are overexpressed in rheumatoid blood, J Immunol 180 (2008) 655e663. [5] S.C. Liang, X.Y. Tan, D.P. Luxenberg, R. Karim, K. Dunussi-Joannopoulos, M. Collins, L.A. Fouser, Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides, J Exp Med 203 (2006) 2271e2279. [6] Y. Zheng, D.M. Danilenko, P. Valdez, I. Kasman, J. Eastham-Anderson, J. Wu, W. Ouyang, Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inammation and acanthosis, Nature 445 (2007) 648e651. [7] Z. Yao, W.C. Fanslow, M.F. Seldin, A.M. Rousseau, S.L. Painter, M.R. Comeau, J.I. Cohen, M.K. Spriggs, Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor, Immunity 3 (1995) 811e821. [8] Z. Yao, M.K. Spriggs, J.M. Derry, L. Strockbine, L.S. Park, T. VandenBos, J.D. Zappone, S.L. Painter, R.J. Armitage, Molecular characterization of the human interleukin (IL)-17 receptor, Cytokine 9 (1997) 794e800. [9] D. Toy, D. Kugler, M. Wolfson, T.V. Bos, J. Gurgel, J. Derry, J. Tocker, J. Peschon, Cutting edge: interleukin 17 signals through a heteromeric receptor complex, J Immunol 177 (2006) 36e39. [10] L.E. Harrington, P.R. Mangan, C.T. Weaver, Expanding the effector CD4 T-cell repertoire: the Th17 lineage, Curr Opin Immunol 18 (2006) 349e356. [11] P. Miossec, Interleukin-17 in fashion, at last: ten years after its description, its cellular source has been identied, Arthritis Rheum 56 (2007) 2111e2115. [12] Y. Iwakura, H. Ishigame, The IL-23/IL-17 axis in inammation, J Clin Invest 116 (2006) 1218e1222. [13] C.T. Weaver, L.E. Harrington, P.R. Mangan, M. Gavrieli, K.M. Murphy, Th17: an effector CD4 T cell lineage with regulatory T cell ties, Immunity 24 (2006) 677e688. [14] E. Bettelli, T. Korn, M. Oukka, V.K. Kuchroo, Induction and effector functions of T(H)17 cells, Nature 453 (2008) 1051e1057. [15] D.J. Cua, J. Sherlock, Y. Chen, C.A. Murphy, B. Joyce, B. Seymour, L. Lucian, W. To, S. Kwan, T. Churakova, S. Zurawski, M. Wiekowski, S.A. Lira, D. Gorman, R.A. Kastelein, J.D. Sedgwick, Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inammation of the brain, Nature 421 (2003) 744e748. [16] D. Luger, P.B. Silver, J. Tang, D. Cua, Z. Chen, Y. Iwakura, E.P. Bowman, N.M. Sgambellone, C.C. Chan, R.R. Caspi, Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category, J Exp Med 205 (2008) 799e810. [17] M.A. Kroenke, T.J. Carlson, A.V. Andjelkovic, B.M. Segal, IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine prole, and response to cytokine inhibition, J Exp Med 205 (2008) 1535e1541. [18] T. Aarvak, M. Chabaud, P. Miossec, J.B. Natvig, IL-17 is produced by some proinammatory Th1/Th0 cells but not by Th2 cells, J Immunol 162 (1999) 1246e1251. [19] G. Page, A. Sattler, S. Kersten, A. Thiel, A. Radbruch, P. Miossec, Plasma cell-like morphology of Th1-cytokine-producing cells associated with the loss of CD3 expression, Am J Pathol 164 (2004) 409e417. [20] G.S. Firestein, Evolving concepts of rheumatoid arthritis, Nature 423 (2003) 356e361. [21] M.I. Koenders, L.A. Joosten, W.B. van den Berg, Potential new targets in arthritis therapy: interleukin (IL)-17 and its relation to tumour necrosis factor and IL-1 in experimental arthritis, Ann Rheum Dis 65 (Suppl. 3) (2006) iii29eiii33. [22] M. Chabaud, E. Lubberts, L. Joosten, W. van Den Berg, P. Miossec, IL17 derived from juxta-articular bone and synovium contributes to joint degradation in rheumatoid arthritis, Arthritis Res 3 (2001) 168e177.

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[23] E. Lubberts, L.A. Joosten, F.A. van de Loo, P. Schwarzenberger, J. Kolls, W.B. van den Berg, Overexpression of IL-17 in the knee joint of collagen type II immunized mice promotes collagen arthritis and aggravates joint destruction, Inamm Res 51 (2002) 102e104. [24] E. Lubberts, L.A. Joosten, M. Chabaud, L. van Den Bersselaar, B. Oppers, C.J. Coenen-De Roo, C.D. Richards, P. Miossec, W.B. van Den Berg, IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion, J Clin Invest 105 (2000) 1697e1710. [25] M. Chabaud, J.M. Durand, N. Buchs, F. Fossiez, G. Page, L. Frappart, P. Miossec, Human interleukin-17: a T cell-derived proinammatory cytokine produced by the rheumatoid synovium, Arthritis Rheum 42 (1999) 963e970. [26] K. Sato, A. Suematsu, K. Okamoto, A. Yamaguchi, Y. Morishita, Y. Kadono, S. Tanaka, T. Kodama, S. Akira, Y. Iwakura, D.J. Cua, H. Takayanagi, Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction, J Exp Med 203 (2006) 2673e2682. [27] G. Page, P. Miossec, RANK and RANKL expression as markers of dendritic cell-T cell interactions in paired samples of rheumatoid synovium and lymph nodes, Arthritis Rheum 52 (2005) 2307e2312. [28] M.K. Andersson, P. Lundberg, A. Ohlin, M.J. Perry, A. Lie, A. Stark, U.H. Lerner, Effects on osteoclast and osteoblast activities in cultured mouse calvarial bones by synovial uids from patients with a loose joint prosthesis and from osteoarthritis patients, Arthritis Res Ther 9 (2007) R18. [29] T. Oda, H. Yoshie, K. Yamazaki, Porphyromonas gingivalis antigen preferentially stimulates T cells to express IL-17 but not receptor activator of NF-kappaB ligand in vitro, Oral Microbiol Immunol 18 (2003) 30e36. [30] B.W. Kirkham, M.N. Lassere, J.P. Edmonds, K.M. Juhasz, P.A. Bird, C.S. Lee, R. Shnier, I.J. Portek, Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a twoyear prospective study (the DAMAGE study cohort), Arthritis Rheum 54 (2006) 1122e1131. [31] M.I. Koenders, E. Lubberts, F.A. van de Loo, B. Oppers-Walgreen, L. van den Bersselaar, M.M. Helsen, J.K. Kolls, F.E. Di Padova, L.A. Joosten, W.B. van den Berg, Interleukin-17 acts independently of TNF-alpha under arthritic conditions, J Immunol 176 (2006) 6262e6269. [32] L.C. Zaba, I. Cardinale, P. Gilleaudeau, M. Sullivan-Whalen, M.S. Farinas, J. Fuentes-Duculan, I. Novitskaya, A. Khatcherian, M.J. Bluth, M.A. Lowes, J.G. Krueger, Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses, J Exp Med (2007). [33] Y. Yagi, A. Andoh, O. Inatomi, T. Tsujikawa, Y. Fujiyama, Inammatory responses induced by interleukin-17 family members in human colonic subepithelial myobroblasts, J Gastroenterol 42 (2007) 746e753. [34] T. Kobayashi, S. Okamoto, T. Hisamatsu, N. Kamada, H. Chinen, R. Saito, M.T. Kitazume, A. Nakazawa, A. Sugita, K. Koganei, K.I. Isobe, T. Hibi, IL-23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohns disease, Gut (2008). [35] G. Trinchieri, Interleukin-12 and the regulation of innate resistance and adaptive immunity, Nat Rev Immunol 3 (2003) 133e146. [36] C.S. Constantinescu, M. Wysocka, B. Hilliard, E.S. Ventura, E. Lavi, G. Trinchieri, A. Rostami, Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis, J Immunol 161 (1998) 5097e5104. [37] T. Yago, Y. Nanke, M. Kawamoto, T. Furuya, T. Kobashigawa, N. Kamatani, S. Kotake, IL-23 induces human osteoclastogenesis via IL17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats, Arthritis Res Ther 9 (2007) R96. [38] Y. Chen, C.L. Langrish, B. McKenzie, B. Joyce-Shaikh, J.S. Stumhofer, T. McClanahan, W. Blumenschein, T. Churakovsa, J. Low, L. Presta, C.A. Hunter, R.A. Kastelein, D.J. Cua, Anti-IL-23 therapy inhibits multiple inammatory pathways and ameliorates autoimmune encephalomyelitis, J Clin Invest 116 (2006) 1317e1326. [39] C. Lock, G. Hermans, R. Pedotti, A. Brendolan, E. Schadt, H. Garren, A. Langer-Gould, S. Strober, B. Cannella, J. Allard, P. Klonowski,

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P. Miossec / Microbes and Infection 11 (2009) 625e630 A. Austin, N. Lad, N. Kaminski, S.J. Galli, J.R. Oksenberg, C.S. Raine, R. Heller, L. Steinman, Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis, Nat Med 8 (2002) 500e508. H. Kebir, K. Kreymborg, I. Ifergan, A. Dodelet-Devillers, R. Cayrol, M. Bernard, F. Giuliani, N. Arbour, B. Becher, A. Prat, Human T(H)17 lymphocytes promote bloodebrain barrier disruption and central nervous system inammation, Nat Med (2007). Y. Minegishi, M. Saito, S. Tsuchiya, I. Tsuge, H. Takada, T. Hara, N. Kawamura, T. Ariga, S. Pasic, O. Stojkovic, A. Metin, H. Karasuyama, Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome, Nature 448 (2007) 1058e1062. C.S. Ma, G.Y. Chew, N. Simpson, A. Priyadarshi, M. Wong, B. Grimbacher, D.A. Fulcher, S.G. Tangye, M.C. Cook, Deciency of Th17 cells in hyper IgE syndrome due to mutations in STAT3, J Exp Med 205 (2008) 1551e1557. C. Dong, IL-23/IL-17 biology and therapeutic considerations, J Immunotoxicol 5 (2008) 43e46. M.I. Koenders, E. Lubberts, B. Oppers-Walgreen, L. van den Bersselaar, M.M. Helsen, F.E. Di Padova, A.M. Boots, H. Gram, L.A. Joosten, W.B. van den Berg, Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inammation and bone erosion by decreasing RANKL and interleukin-1, Am J Pathol 167 (2005) 141e149. M. Chabaud, P. Miossec, The combination of tumor necrosis factor alpha blockade with interleukin-1 and interleukin-17 blockade is more effective for controlling synovial inammation and bone resorption in an ex vivo model, Arthritis Rheum 44 (2001) 1293e1303. B.S. Ivanov II, McKenzie, L. Zhou, C.E. Tadokoro, A. Lepelley, J.J. Lafaille, D.J. Cua, D.R. Littman, The orphan nuclear receptor RORgammat directs the differentiation program of proinammatory IL17 T helper cells, Cell 126 (2006) 1121e1133. G.G. Krueger, R.G. Langley, C. Leonardi, N. Yeilding, C. Guzzo, Y. Wang, L.T. Dooley, M. Lebwohl, A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis, N Engl J Med 356 (2007) 580e592. P.J. Mannon, I.J. Fuss, L. Mayer, C.O. Elson, W.J. Sandborn, D. Present, B. Dolin, N. Goodman, C. Groden, R.L. Hornung, M. Quezado, Z. Yang, M.F. Neurath, J. Salfeld, G.M. Veldman, U. Schwertschlag, W. Strober, Anti-interleukin-12 antibody for active Crohns disease, N Engl J Med 351 (2004) 2069e2079. I.J. Fuss, C. Becker, Z. Yang, C. Groden, R.L. Hornung, F. Heller, M.F. Neurath, W. Strober, P.J. Mannon, Both IL-12p70 and IL-23 are synthesized during active Crohns disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody, Inamm Bowel Dis 12 (2006) 9e15. S. Sarkar, L.A. Tesmer, V. Hindnavis, J.L. Endres, D.A. Fox, Interleukin17 as a molecular target in immune-mediated arthritis: immunoregulatory properties of genetically modied murine dendritic cells that secrete interleukin-4, Arthritis Rheum 56 (2006) 89e100. M.A. Kleinschek, A.M. Owyang, B. Joyce-Shaikh, C.L. Langrish, Y. Chen, D.M. Gorman, W.M. Blumenschein, T. McClanahan, F. Brombacher, S.D. Hurst, R.A. Kastelein, D.J. Cua, IL-25 regulates Th17 function in autoimmune inammation, J Exp Med 204 (2007) 161e170. A.M. Owyang, C. Zaph, E.H. Wilson, K.J. Guild, T. McClanahan, H.R. Miller, D.J. Cua, M. Goldschmidt, C.A. Hunter, R.A. Kastelein, D. Artis, Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inammation in the gastrointestinal tract, J Exp Med 203 (2006) 843e849. E. Bettelli, M. Oukka, V.K. Kuchroo, T(H)-17 cells in the circle of immunity and autoimmunity, Nat Immunol 8 (2007) 345e350. S. Nadkarni, C. Mauri, M.R. Ehrenstein, Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta, J Exp Med 204 (2007) 33e39. C.A. Dinarello, Blocking IL-1 in systemic inammation, J Exp Med 201 (2005) 1355e1359. S. Yokota, T. Miyamae, T. Imagawa, N. Iwata, S. Katakura, M. Mori, P. Woo, N. Nishimoto, K. Yoshizaki, T. Kishimoto, Therapeutic efcacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis, Arthritis Rheum 52 (2005) 818e825. P.J. Dubin, J.K. Kolls, IL-23 mediates inammatory responses to mucoid Pseudomonas aeruginosa lung infection in mice, Am J Physiol Lung Cell Mol Physiol (2006). D.R. Chung, D.L. Kasper, R.J. Panzo, T. Chtinis, M.J. Grusby, M.H. Sayegh, A.O. Tzianabos, CD4 T cells mediate abscess formation in intra-abdominal sepsis by an IL-17-dependent mechanism, J Immunol 170 (2003) 1958e1963.

[49]

[40]

[50]

[41]

[51]

[42]

[52]

[43] [44]

[53] [54]

[45]

[55] [56]

[46]

[47]

[57]

[58]

[48]