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The Emerging Role of IL-17 in the Pathogenesis of Psoriasis: Preclinical and Clinical Findings

      Although the histological changes seen in psoriasis have long been well characterized, the underlying cellular and molecular mechanisms have only begun to be elucidated over the past 20 years. Proinflammatory factors such as tumor necrosis factor (TNF)-α have a central role in psoriasis pathogenesis, and many T-helper 1 (Th1) cytokines and messenger RNAs are elevated in psoriatic lesions. IL-17A, IL-17F, and other Th17 cell–derived cytokines have been shown in murine models to induce features that mimic human psoriasis. This review focuses on the emerging biology of the IL-17 cytokine family in psoriasis, and on the molecular and genetic information gained from animal models and human clinical studies that confirm IL-17 as a crucial proinflammatory cytokine in psoriasis. Expression of IL-17A, IL-17C, and IL-17F is strikingly increased in psoriatic lesions, and successful therapy is associated with restoration of the expression of a wide range of genes (including effector molecules downstream of IL-17 such as cytokines, chemokines, and antimicrobial peptides) to near-normal levels. Therapeutic agents in development that target IL-17 are discussed, and an emerging model of the key role of IL-17 in the pathogenesis of psoriasis is presented.

      Abbreviations

      AMPs
      antimicrobial peptides
      mRNA
      messenger RNAs
      PASI
      psoriasis area and severity index
      Tc
      cytotoxic T
      Th1, T-helper 1; TNF-α
      tumor necrosis factor-α

      Introduction

      Psoriasis is a chronic debilitating disease, affecting 1–2% of the Caucasian population (
      • Naldi L.
      Epidemiology of psoriasis.
      ;
      • Gudjonsson J.E.
      • Elder J.T.
      Psoriasis: epidemiology.
      ) and characterized by recurrent episodes of red and scaly well-demarcated skin plaques (
      • Schon M.P.
      • Boehncke W.H.
      Psoriasis.
      ). The histological changes observed within lesional skin include (1) a thickened epidermis from rapid keratinocyte proliferation and aberrant differentiation, (2) a reduced or absent granular layer, (3) marked dilatation of blood vessels in the papillary dermis, and (4) dense clusters of inflammatory cells composed of T cells and dendritic cells in the dermis, and CD8+ T cells and neutrophils in the epidermis (
      • Schon M.P.
      • Boehncke W.H.
      Psoriasis.
      ). Histological abnormalities in psoriasis have been well described for decades and include multiple elements that indicate immune-mediated inflammation. However, the cellular and molecular mechanisms underlying the pathophysiological changes have only recently been brought into sharp focus by studies describing global alterations in the psoriasis lesional transcriptome, as well as the impressive success of targeted therapeutics in the clinic.
      Our understanding of the role of various immune cells and inflammatory factors involved in psoriasis pathogenesis has progressed over the past 20 years. Early clinical studies, such as those with calcineurin inhibitors (
      • Ellis C.N.
      • Gorsulowsky D.C.
      • Hamilton T.A.
      • et al.
      Cyclosporine improves psoriasis in a double-blind study.
      ;
      • Griffiths C.E.
      • Powles A.V.
      • Leonard J.N.
      • et al.
      Clearance of psoriasis with low dose cyclosporin.
      ) and agents targeting IL-2 receptor–expressing cells (
      • Gottlieb S.L.
      • Gilleaudeau P.
      • Johnson R.
      • et al.
      Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis.
      ), have demonstrated the integral role of the immune system, and specifically T cells, in psoriasis pathogenesis (
      • Ghoreschi K.
      • Weigert C.
      • Rocken M.
      Immunopathogenesis and role of T cells in psoriasis.
      ). The central role of proinflammatory factors in the development of psoriasis was demonstrated by the success of therapeutic agents that target tumor necrosis factor (TNF)-α in the treatment of psoriasis (
      • Chaudhari U.
      • Romano P.
      • Mulcahy L.D.
      • et al.
      Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial.
      ;
      • Leonardi C.L.
      • Powers J.L.
      • Matheson R.T.
      • et al.
      Etanercept as monotherapy in patients with psoriasis.
      ). TNF-α, a proinflammatory factor, is secreted by activated T cells and dendritic cells. The T-helper 1 (Th1) subset of activated T cells is the numerically dominant T-cell subset in psoriatic lesions (
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • et al.
      Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.
      ;
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ) and has been the focus of much attention in psoriasis since the mid 1980s. Many recognized Th1 cytokines and messenger RNAs (mRNAs), including IFN-γ and TNF-α, are elevated in psoriatic skin lesions (
      • Austin L.M.
      • Ozawa M.
      • Kikuchi T.
      • et al.
      The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients.
      ;
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ). Development of Th1 cells is driven by IL-12, and a recent therapeutic agent targeting IL-12 through the shared IL-12/23p40 subunit, has also shown strong efficacy (
      • Leonardi C.L.
      • Kimball A.B.
      • Papp K.A.
      • et al.
      Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).
      ). However, more recently, the focus has shifted toward a novel subset of T cells expressing IL-17: Th17 cells, which are also elevated in psoriatic lesions (
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ;
      • Res P.C.
      • Piskin G.
      • de Boer O.J.
      • et al.
      Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis.
      ). Development of Th17 cells is driven by IL-23 and therefore, similar to Th1 cells, would be reduced by inhibition of the IL-12/23p40 shared subunit. Results from multiple rodent models of autoimmunity have led to a significant paradigm shift, with Th17 cells and IL-17 replacing the Th1 cells and associated cytokines as dominant mediators of tissue damage (
      • Harrington L.E.
      • Hatton R.D.
      • Mangan P.R.
      • et al.
      Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
      ;
      • Langrish C.L.
      • Chen Y.
      • Blumenschein W.M.
      • et al.
      IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
      ;
      • Park H.
      • Li Z.
      • Yang X.O.
      • et al.
      A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
      ;
      • Steinman L.
      A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage.
      ).
      Genome-wide association studies and analysis of candidate genomic regions have implicated components of the IL-23 and IL-17 signaling pathways in the development of psoriasis (Table 1), further focusing attention on Th17 cells in this disease. This review will focus on the emerging role of IL-17 in psoriasis, with particular emphasis on the biology of IL-17 in the skin and the lessons learned from animal models and human clinical studies that confirm IL-17 as a crucial cytokine in psoriasis.
      Table 1Summary of genetic association data for IL-17–related genes involved in psoriasis
      LocusOther diseasesPathwaysIL-17 relevanceReferences
      IL23AIL-23Upstream
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      IL12BIBD, PsA, AS, MSIL-23Upstream
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Fisher S.A.
      • Tremelling M.
      • Anderson C.A.
      • et al.
      Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn′s disease.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ;
      • Parkes M.
      • Barrett J.C.
      • Prescott N.J.
      • et al.
      Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.
      ;
      • Patsopoulos N.A.
      • Bayer Pharma M.S.G.W.G.
      • Steering Committees of Studies Evaluating, I-b, a C.C.R.A.
      • Consortium A.N.
      • GeneMsa
      • et al.
      Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.
      ;
      • Wellcome Trust Case Control C.
      • Australo-Anglo-American Spondylitis C.
      • Burton P.R.
      • et al.
      Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.
      ;
      • Zhang X.J.
      • Huang W.
      • Yang S.
      • et al.
      Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
      IL23RIBD, PsA, AS, BehcetIL-23Upstream
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Duerr R.H.
      • Taylor K.D.
      • Brant S.R.
      • et al.
      A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
      ;
      • Filer C.
      • Ho P.
      • Smith R.L.
      • et al.
      Investigation of association of the IL12B and IL23R genes with psoriatic arthritis.
      ;
      • Jiang Z.
      • Yang P.
      • Hou S.
      • et al.
      IL-23R gene confers susceptibility to Behcet′s disease in a Chinese Han population.
      ;
      • Mizuki N.
      • Meguro A.
      • Ota M.
      • et al.
      Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet′s disease susceptibility loci.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Remmers E.F.
      • Cosan F.
      • Kirino Y.
      • et al.
      Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet′s disease.
      ;
      • Wellcome Trust Case Control C.
      • Australo-Anglo-American Spondylitis C.
      • Burton P.R.
      • et al.
      Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.
      TYK2IBD, SLE, MS?IL-23Upstream
      • Australia and New Zealand Multiple Sclerosis Genetics Consortium
      Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20.
      ;
      • Ban M.
      • Goris A.
      • Lorentzen A.R.
      • et al.
      Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor.
      ;
      • Franke A.
      • McGovern D.P.
      • Barrett J.C.
      • et al.
      Genome-wide meta-analysis increases to 71 the number of confirmed Crohn′s disease susceptibility loci.
      ;
      • Sigurdsson S.
      • Nordmark G.
      • Goring H.H.
      • et al.
      Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      TRAF3IP2PsAIL-17 and NF-κBDownstream
      • Ellinghaus E.
      • Ellinghaus D.
      • Stuart P.E.
      • et al.
      Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
      ;
      • Huffmeier U.
      • Lascorz J.
      • Bohm B.
      • et al.
      Genetic variants of the IL-23R pathway: association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      RELPsA, RA, CeDNF-κBUp/downstream
      • Ellinghaus E.
      • Stuart P.E.
      • Ellinghaus D.
      • et al.
      Genome-wide meta-analysis of psoriatic arthritis identifies susceptibility locus at REL.
      ;
      • Gregersen P.K.
      • Amos C.I.
      • Lee A.T.
      • et al.
      REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Trynka G.
      • Zhernakova A.
      • Romanos J.
      • et al.
      Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.
      NFKBIAPsANF-κBUp/downstream
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Stuart P.E.
      • Nair R.P.
      • Ellinghaus E.
      • et al.
      Genome-wide association analysis identifies three psoriasis susceptibility loci.
      TNFAIP3PsA, SLE, RA, CeDNF-κBUp/downstream
      • Graham R.R.
      • Cotsapas C.
      • Davies L.
      • et al.
      Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus.
      ;
      • Musone S.L.
      • Taylor K.E.
      • Lu T.T.
      • et al.
      Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Plenge R.M.
      • Cotsapas C.
      • Davies L.
      • et al.
      Two independent alleles at 6q23 associated with risk of rheumatoid arthritis.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Thomson W.
      • Barton A.
      • Ke X.
      • et al.
      Rheumatoid arthritis association at 6q23.
      ;
      • Trynka G.
      • Zhernakova A.
      • Romanos J.
      • et al.
      Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.
      TNIP1PsA, SLE, SScNF-κBUp/downstream
      • Allanore Y.
      • Saad M.
      • Dieude P.
      • et al.
      Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis.
      ;
      • Gateva V.
      • Sandling J.K.
      • Hom G.
      • et al.
      A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      DEFB4IL-17–regulated geneDownstream
      • Hollox E.J.
      • Huffmeier U.
      • Zeeuwen P.L.
      • et al.
      Psoriasis is associated with increased beta-defensin genomic copy number.
      Abbreviations: AS, ankylosing spondylitis; CeD, celiac disease; IBD, inflammatory bowel disease (including Crohn's disease and ulcerative colitis); MS, multiple sclerosis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.

      The Role of IL-17 in Immune Defense and in Preclinical Disease Models

      T-helper 17 cells are CD4+ effector T-helper cells that are distinct from the classic Th1 and Th2 lineages. They are defined most notably by the ability to produce large quantities of IL-17A and are thought to have evolved to provide both innate and adaptive immunity against pathogens (
      • Gaffen S.L.
      Structure and signalling in the IL-17 receptor family.
      ). Th17 cells differentiate from naive T cells after stimulation with transforming growth factor-β, IL-6, IL-21, and IL-1β (
      • Acosta-Rodriguez E.V.
      • Napolitani G.
      • Lanzavecchia A.
      • et al.
      Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
      ;
      • Yang L.
      • Anderson D.E.
      • Baecher-Allan C.
      • et al.
      IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.
      ). Th17 cells are subsequently activated by IL-23, IL-1β, and IL-21 to produce multiple inflammatory factors in addition to IL-17A, including IL-17F and IL-22, although this latter cytokine is produced to a much greater extent in murine Th17 cells than in human cells (
      • Awasthi A.
      • Riol-Blanco L.
      • Jager A.
      • et al.
      Cutting edge: IL-23 receptor GFP reporter mice reveal distinct populations of IL-17-producing cells.
      ;
      • Ciric B.
      • El-behi M.
      • Cabrera R.
      • et al.
      IL-23 drives pathogenic IL-17-producing CD8+ T cells.
      ;
      • Sutton C.E.
      • Lalor S.J.
      • Sweeney C.M.
      • et al.
      Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity.
      ). In humans, Th17 and a separate type of IL-22–producing cells called Th22 cells have been identified, but the classification of T-helper sets is not simple. Human dermal T cells have been shown to produce any combination of IL-17, IL-22, and IFN-γ, although the number of cells uniquely producing either IL-17 or IL-22 exceeds the number producing both (
      • Nograles K.E.
      • Zaba L.C.
      • Guttman-Yassky E.
      • et al.
      Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways.
      ). The relative production of various cytokines in individual Th17 cells is influenced by the levels of different activating signals, most notably from cytokines and pathogens (
      • Zielinski C.E.
      • Mele F.
      • Aschenbrenner D.
      • et al.
      Pathogen-induced human T(H)17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta.
      ). In addition to Th17 cells, a subset of cytotoxic T cells (Tc) that also produce IL-17 (Tc17) is present in psoriatic lesions; these cells also produce Th17-related cytokines, including IL-17A (
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • et al.
      Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.
      ), IL-21, and IL-22 (
      • Ortega C.
      • Fernandez A.S.
      • Carrillo J.M.
      • et al.
      IL-17-producing CD8+ T lymphocytes from psoriasis skin plaques are cytotoxic effector cells that secrete Th17-related cytokines.
      ).
      IL-17 is part of a family of cytokines consisting of the prototypical ligand, IL-17 (IL-17A), and five other IL-17 ligands (IL-17B through IL-17F; Figure 1;
      • Gaffen S.L.
      Structure and signalling in the IL-17 receptor family.
      ;
      • Pappu R.
      • Ramirez-Carrozzi V.
      • Ota N.
      • et al.
      The IL-17 family cytokines in immunity and disease.
      ). IL-17A and IL-17F are known to act as homodimers or as IL-17A/F heterodimers (
      • Chang S.H.
      • Dong C.
      A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses.
      ;
      • Wright J.F.
      • Guo Y.
      • Quazi A.
      • et al.
      Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells.
      ). IL-17E (renamed IL-25) also exists in a dimeric form (
      • Rickel E.A.
      • Siegel L.A.
      • Yoon B.R.
      • et al.
      Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities.
      ;
      • Claudio E.
      • Sonder S.U.
      • Saret S.
      • et al.
      The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation.
      ). The IL-17 receptors consist of five receptor family members, namely, IL-17 receptor A through IL-17 receptor E. Among the several members of the IL-17 receptor family, IL-17 receptor A contains an extended cytoplasmic domain with unique signaling properties (
      • Gaffen S.L.
      Structure and signalling in the IL-17 receptor family.
      ) and has been implicated as a heteromeric partner for other IL-17 receptors, when binding various ligands. IL-17A and IL-17F homodimers and heterodimers signal through the heteromeric receptor consisting of IL-17 receptor A and IL-17 receptor C (
      • Kuestner R.E.
      • Taft D.W.
      • Haran A.
      • et al.
      Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F.
      ;
      • Wright J.F.
      • Bennett F.
      • Li B.
      • et al.
      The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex.
      ). IL-17E (IL-25) signals through a heteromeric receptor containing IL-17 receptor A and IL-17 receptor B (
      • Rickel E.A.
      • Siegel L.A.
      • Yoon B.R.
      • et al.
      Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities.
      ;
      • Claudio E.
      • Sonder S.U.
      • Saret S.
      • et al.
      The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation.
      ). Recently, IL-17C was demonstrated to require both IL-17 receptor E and IL-17 receptor A for signaling (
      • Ramirez-Carrozzi V.
      • Sambandam A.
      • Luis E.
      • et al.
      IL-17C regulates the innate immune function of epithelial cells in an autocrine manner.
      ;
      • Song X.
      • Zhu S.
      • Shi P.
      • et al.
      IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens.
      ). Much less is known about IL-17B and IL-17D, but IL-17B is believed to signal through IL-17 receptor B (
      • Shi Y.
      • Ullrich S.J.
      • Zhang J.
      • et al.
      A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity.
      ;
      • Gaffen S.L.
      Structure and signalling in the IL-17 receptor family.
      ). It is unclear whether the receptors for IL-17B and IL-17D are heteromeric, and whether IL-17 receptor A may be a common co-receptor for all IL-17 family ligands.
      Figure thumbnail gr1
      Figure 1IL-17 family ligands and receptors. There are six well-defined IL-17 ligands and five receptors. The IL-17A, IL-17F, and IL-17C ligands have elevated expression in psoriatic skin and have their presumed major cellular sources in the skin highlighted, although other sources may contribute. Those three ligands, and IL-17E (IL-25), have demonstrated heteromeric receptor complexes, which in all cases include the IL-17 receptor A subunit and one specific other IL-17 receptor subunit partner. Major cytoplasmic factors interacting with the IL-17 receptor complex are shown, as an example, for the IL-17RA/RC complex, where they are best studied. The IL-17A and IL-17F ligands form homo- and heterodimeric complexes. A dimeric state of the other ligands is illustrated by analogy, but has not been demonstrated, and the exact stoichiometries of the heteromeric receptor complexes are not fully determined. The ligand–receptor interactions are less well defined for IL-17B and IL-17D, and the requirement for an IL-17 receptor A subunit is unknown. GI, gastrointestinal; IL-17R, IL-17 receptor; LTi, lymphoid tissue inducer; Mφs, macrophages; NKT, natural killer T; Th17, T-helper 17.
      IL-17A acts on a variety of cell types including endothelial cells, fibroblasts, chondrocytes, synovial cells, monocytes, and epithelial cells including keratinocytes (
      • Yao Z.
      • Spriggs M.K.
      • Derry J.M.
      • et al.
      Molecular characterization of the human interleukin (IL)-17 receptor.
      ;
      • Honorati M.C.
      • Meliconi R.
      • Pulsatelli L.
      • et al.
      High in vivo expression of interleukin-17 receptor in synovial endothelial cells and chondrocytes from arthritis patients.
      ;
      • Harper E.G.
      • Guo C.
      • Rizzo H.
      • et al.
      Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis.
      ). IL-17A and IL-17F act directly on keratinocytes to stimulate the production of a number of molecules known to be elevated in psoriasis lesional tissue such as cytokines, β-defensins, and antimicrobial peptides (AMPs), and neutrophil-, macrophage-, and lymphocyte-attracting chemokines such as IL-8, CCL20 (also called macrophage inflammatory protein-3α), and CCL2 (also called monocyte chemotactic protein 1;
      • Guttman-Yassky E.
      • Lowes M.A.
      • Fuentes-Duculan J.
      • et al.
      Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis.
      ). IL-17C, similar to IL-17A and IL-17F, has also recently been demonstrated to act on keratinocytes to induce human β-defensin 2 and granulocyte colony–stimulating factor (
      • Ramirez-Carrozzi V.
      • Sambandam A.
      • Luis E.
      • et al.
      IL-17C regulates the innate immune function of epithelial cells in an autocrine manner.
      ). IL-17E (IL-25) is distinct from IL-17A, IL-17C, and IL-17F in that it is generally produced by epithelial cells during an allergic response and acts to induce Th2-type responses (
      • Kleinschek M.A.
      • Owyang A.M.
      • Joyce-Shaikh B.
      • et al.
      IL-25 regulates Th17 function in autoimmune inflammation.
      ;
      • Rickel E.A.
      • Siegel L.A.
      • Yoon B.R.
      • et al.
      Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities.
      ;
      • Barlow J.L.
      • McKenzie A.N.
      IL-25: a key requirement for the regulation of type-2 immunity.
      ). Expression of IL-17E (IL-25), IL-17B, and IL-17D is not increased in lesional psoriatic skin compared with nonlesional skin (
      • Johansen C.
      • Usher P.A.
      • Kjellerup R.B.
      • et al.
      Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin.
      ); therefore, these cytokines likely do not have a major role in the development of psoriasis.
      There is evidence suggesting involvement of the IL-17 system in antimicrobial defense via the maintenance of mucocutaneous immunity. In contrast to the low fungal burdens in mice lacking IL-12 or IL-22, IL-17RA-deficient mice are more susceptible to Candida albicans infections (
      • Huang W.
      • Na L.
      • Fidel P.L.
      • et al.
      Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice.
      ;
      • Kagami S.
      • Rizzo H.L.
      • Kurtz S.E.
      • et al.
      IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal skin host defense against Candida albicans.
      ), potentially due to neutrophil and AMP defects (
      • Conti H.R.
      • Baker O.
      • Freeman A.F.
      • et al.
      New mechanism of oral immunity to mucosal candidiasis in hyper-IgE syndrome.
      ;
      • Gaffen S.L.
      • Hernandez-Santos N.
      • Peterson A.C.
      IL-17 signaling in host defense against Candida albicans.
      ). This susceptibility is also evident in rare human genetic diseases associated with chronic mucocutaneous candidiasis that are linked to lack of IL-17 signaling, either through autosomal IL17RA or IL17F mutations (
      • Puel A.
      • Cypowyj S.
      • Bustamante J.
      • et al.
      Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity.
      ) or high titers of neutralizing antibodies to IL-17 cytokines (e.g., autoimmune polyendocrine syndrome type 1 due to mutations in the AIRE gene;
      • Puel A.
      • Doffinger R.
      • Natividad A.
      • et al.
      Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I.
      ). Finally, in a distinct but phenotypically related genetic twist-of-fate, most patients with hyper-IgE syndrome, who tend to be affected by mucocutaneous candidiasis and Staphylococcus aureus infections, have dominant negative mutations in STAT3, which can lead to Th17 and IL-17 deficiency due to a loss in the IL-6 and IL-23 signaling required for Th17 lineage induction and stabilization (
      • Milner J.D.
      • Brenchley J.M.
      • Laurence A.
      • et al.
      Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome.
      ). The degree to which these human genetic diseases that affect either IL-17/IL-17R or Th17 cells (and hence affect a broad number of cytokines) are relevant to partial blockade with antagonists specific to IL-17/IL-17R will be further informed by ongoing clinical studies.
      In addition to their potential role in mucocutaneous immunity, Th17 cells also may be involved in vascular inflammation, including atherosclerotic plaque responses to Chlamydophila pneumoniae (
      • Chen S.
      • Shimada K.
      • Zhang W.
      • et al.
      IL-17A is proatherogenic in high-fat diet-induced and Chlamydia pneumoniae infection-accelerated atherosclerosis in mice.
      ;
      • Benagiano M.
      • Munari F.
      • Ciervo A.
      • et al.
      Chlamydophila pneumoniae phospholipase D (CpPLD) drives Th17 inflammation in human atherosclerosis.
      ). Although atheroma formation in the mouse C. pneumoniae system can be inhibited by genetic defects of IL-17A (
      • Chen S.
      • Shimada K.
      • Zhang W.
      • et al.
      IL-17A is proatherogenic in high-fat diet-induced and Chlamydia pneumoniae infection-accelerated atherosclerosis in mice.
      ), results of biochemical blockade in other murine systems are mixed (
      • Taleb S.
      • Romain M.
      • Ramkhelawon B.
      • et al.
      Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis.
      ;
      • Smith E.
      • Prasad K.M.
      • Butcher M.
      • et al.
      Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice.
      ). A proatherogenic role for IL-17A is supported by the lack of atherosclerotic changes associated with coronary artery defects in patients with hyper-IgE syndrome (
      • Freeman A.F.
      • Avila E.M.
      • Shaw P.A.
      • et al.
      Coronary artery abnormalities in hyper-IgE syndrome.
      ). Furthermore, patients with psoriasis, who are at increased cardiovascular risk (
      • Mehta N.N.
      • Yu Y.
      • Pinnelas R.
      • et al.
      Attributable risk estimate of severe psoriasis on major cardiovascular events.
      ), have been reported to have increased circulating IL-17A–producing cells (
      • Kagami S.
      • Rizzo H.L.
      • Lee J.J.
      • et al.
      Circulating Th17, Th22, and Th1 cells are increased in psoriasis.
      ;
      • Bovenschen H.J.
      • van de Kerkhof P.C.
      • van Erp P.E.
      • et al.
      Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin.
      ).
      Expression of Th17-derived cytokines is elevated in murine models of the skin inflammation that mimic features of human psoriasis (
      • van der Fits L.
      • Mourits S.
      • Voerman J.S.
      • et al.
      Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.
      ;
      • Blumberg H.
      • Dinh H.
      • Dean Jr., C.
      • et al.
      IL-1RL2 and its ligands contribute to the cytokine network in psoriasis.
      ;
      • Singh T.P.
      • Schon M.P.
      • Wallbrecht K.
      • et al.
      8-methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3+ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder.
      ;
      • Nakajima K.
      • Kanda T.
      • Takaishi M.
      • et al.
      Distinct roles of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model.
      ), and decreases in IL-17A and IL-17F are seen with successful treatments (
      • Blumberg H.
      • Dinh H.
      • Dean Jr., C.
      • et al.
      IL-1RL2 and its ligands contribute to the cytokine network in psoriasis.
      ;
      • Singh T.P.
      • Schon M.P.
      • Wallbrecht K.
      • et al.
      8-methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3+ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder.
      ). Antibodies to IL-17A, IL-23p19, or to the shared IL-12/23p40 subunit show efficacy in some models (
      • Blumberg H.
      • Dinh H.
      • Dean Jr., C.
      • et al.
      IL-1RL2 and its ligands contribute to the cytokine network in psoriasis.
      ;
      • Nakajima K.
      • Kanda T.
      • Takaishi M.
      • et al.
      Distinct roles of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model.
      ). Data from mouse models have shown that inhibition of IL-23 alone provides comparable efficacy to IL-12/23p40 dual inhibition (
      • Blumberg H.
      • Dinh H.
      • Dean Jr., C.
      • et al.
      IL-1RL2 and its ligands contribute to the cytokine network in psoriasis.
      ;
      • Tonel G.
      • Conrad C.
      • Laggner U.
      • et al.
      Cutting edge: A critical functional role for IL-23 in psoriasis.
      ;
      • Nakajima K.
      • Kanda T.
      • Takaishi M.
      • et al.
      Distinct roles of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model.
      ;
      • Rizzo H.L.
      • Kagami S.
      • Phillips K.G.
      • et al.
      IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A.
      ), suggesting that IL-23 is the dominant p40-containing cytokine in psoriasis. IL-23 is known to induce IL-22 in addition to IL-17A, and inhibition of IL-22 has been shown to be efficacious in at least one mouse model of psoriasis (
      • Ma H.L.
      • Liang S.
      • Li J.
      • et al.
      IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation.
      ). Direct injection of IL-22 into mouse ears or human skin equivalents is sufficient to induce some gene expression changes similar to psoriasis, as well as keratinocyte hyperplasia and parakeratosis (
      • Boniface K.
      • Bernard F.X.
      • Garcia M.
      • et al.
      IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes.
      ;
      • Sa S.M.
      • Valdez P.A.
      • Wu J.
      • et al.
      The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
      ;
      • Ma H.L.
      • Liang S.
      • Li J.
      • et al.
      IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation.
      ). It is therefore possible that inhibition of IL-22 in addition to IL-17A would be required for full efficacy seen with IL-23 inhibition. However, IL-17 receptor A knockout mice (which lack signaling through multiple IL-17 family members) were shown to be as resistant as IL-23 knockout mice in a psoriasis-like model in which lesions are induced by imiquimod, a toll-like receptor 7/8 ligand (
      • van der Fits L.
      • Mourits S.
      • Voerman J.S.
      • et al.
      Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.
      ).
      We sought to address the question of differential efficacy by comparing IL-23 and IL-17 (both ligand and receptor) inhibition in a preclinical model of skin inflammation (Amgen, unpublished data on file). In this model, IL-36α (IL-36α/IL-1F6; an IL-1 ligand family member) transgenic mice under the control of a keratinocyte (K14) promoter were treated with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (
      • Blumberg H.
      • Dinh H.
      • Dean Jr., C.
      • et al.
      IL-1RL2 and its ligands contribute to the cytokine network in psoriasis.
      ), leading to the induction of many pathologic features of psoriasis and induction of cytokines and chemokines involved in psoriasis (
      • Blumberg H.
      • Dinh H.
      • Dean Jr., C.
      • et al.
      IL-1RL2 and its ligands contribute to the cytokine network in psoriasis.
      ). This model allowed direct comparison of inhibition of IL-12/23p40, IL-23, IL-17A and IL-17F, and IL-17 receptor A. Similar to published studies, IL-12/23p40– and IL-23–specific antagonism was highly efficacious (
      • Blumberg H.
      • Dinh H.
      • Dean Jr., C.
      • et al.
      IL-1RL2 and its ligands contribute to the cytokine network in psoriasis.
      ), whereas IL-17A–specific inhibition was only moderately effective (Amgen, unpublished data on file). Antagonism of IL-17F alone was similar to isotype control antibody. Interestingly, inhibition of IL-17 receptor A provided greater benefit over IL-17A-specific inhibition and was as efficacious as IL-23 inhibition. These data suggest that combined inhibition of multiple IL-17 family ligands through targeting of IL-17 receptor A may have more profound effects in the skin than inhibition of IL-17A alone and that inhibition of IL-22 is not necessary to achieve efficacy comparable to IL-23 inhibition (Amgen, unpublished data on file). Furthermore, these data suggest that another IL-17 family member in addition to IL-17A and IL-17F may be playing a role in the skin. IL-17C has recently been demonstrated to act on keratinocytes to induce proinflammatory cytokines, chemokines, and AMPs, and this activity requires both IL-17 receptor E and IL-17 receptor A (
      • Ramirez-Carrozzi V.
      • Sambandam A.
      • Luis E.
      • et al.
      IL-17C regulates the innate immune function of epithelial cells in an autocrine manner.
      ;
      • Song X.
      • Zhu S.
      • Shi P.
      • et al.
      IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens.
      ). Finally, IL-17C knockout mice had significantly decreased inflammation and epidermal thickening in the imiquimod psoriasis-like model (
      • Ramirez-Carrozzi V.
      • Sambandam A.
      • Luis E.
      • et al.
      IL-17C regulates the innate immune function of epithelial cells in an autocrine manner.
      ), further suggesting that IL-17C, in addition to IL-17A, could be contributing to the efficacy seen with IL-17 receptor A inhibition in the IL-36 transgenic model of psoriasis. These data collectively suggest that inhibition of one or more IL-17 family members has therapeutic potential for psoriasis.

      Biology of IL-17 in Human Psoriasis

      There is substantial evidence demonstrating the central contribution of Th17 cells and, more directly, IL-17 to plaque psoriasis in humans (
      • Harper E.G.
      • Guo C.
      • Rizzo H.
      • et al.
      Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis.
      ;
      • Johansen C.
      • Usher P.A.
      • Kjellerup R.B.
      • et al.
      Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin.
      ). Genome-wide association and other genetic studies clearly have linked multiple IL-17–related genes to psoriasis pathogenesis (Table 1). The molecular and cellular analyses of psoriatic skin have increased our understanding of disease pathogenesis beyond a Th1-driven disease, which was generally accepted until relatively recently. Finally, the remarkable and exciting results in clinical trials have confirmed the central contribution of IL-17 to psoriasis, including both a correlation of IL-17 pathway changes with successful therapy as well as demonstration of the direct effects of inhibition of both IL-17A and IL-17 receptor A.
      Expression of IL-17A, IL-17C, and IL-17F is elevated in psoriatic lesional tissue compared with nonlesional tissue (
      • Harper E.G.
      • Guo C.
      • Rizzo H.
      • et al.
      Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis.
      ;
      • Johansen C.
      • Usher P.A.
      • Kjellerup R.B.
      • et al.
      Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin.
      ;
      • Russell C.
      • Kerkof K.
      • Bigler J.
      • et al.
      Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
      ). Paired punch biopsies from lesional skin from patients with psoriasis showed significantly higher protein levels of IL-17A, IL-17C, and IL-17F (6.7-fold, 4.1-fold, and 8-fold higher, respectively) compared with nonlesional skin (
      • Johansen C.
      • Usher P.A.
      • Kjellerup R.B.
      • et al.
      Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin.
      ).
      CD4+ Th17 cells are present in higher numbers in psoriatic lesions than in healthy skin and are decreased after treatment (
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ). Immunostaining of lesional samples from inflamed skin also showed increased numbers of cells positive for IL-17A (
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ;
      • Harper E.G.
      • Guo C.
      • Rizzo H.
      • et al.
      Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis.
      ). Recent studies have suggested that many of these IL-17–positive cells could be CD8+ T cells (Tc17), lymphoid tissue–inducer cells, mast cells, and/or neutrophils rather than T-helper cells (
      • Cua D.J.
      • Tato C.M.
      Innate IL-17-producing cells: the sentinels of the immune system.
      ;
      • Res P.C.
      • Piskin G.
      • de Boer O.J.
      • et al.
      Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis.
      ;
      • Lin A.M.
      • Rubin C.J.
      • Khandpur R.
      • et al.
      Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis.
      ). The relative contribution of these different cell types will be important in understanding their role in psoriasis pathogenesis.
      Human genetic studies have shown that several of the risk alleles involved in psoriasis may be risk alleles for other autoimmune disorders (recently reviewed by
      • Capon F.
      • Burden A.D.
      • Trembath R.C.
      • et al.
      Psoriasis and other complex trait dermatoses: from Loci to functional pathways.
      ) and/or influence IL-17, both upstream of IL-17 expression at the IL-23 cytokine/IL-23R signaling level (
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ,
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ) and downstream of the IL-17 receptor (
      • Ellinghaus E.
      • Ellinghaus D.
      • Stuart P.E.
      • et al.
      Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
      ;
      • Huffmeier U.
      • Uebe S.
      • Ekici A.B.
      • et al.
      Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis.
      ). Four of these genes are part of the IL-23/IL-23R signaling system (Table 1;
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Huffmeier U.
      • Lascorz J.
      • Bohm B.
      • et al.
      Genetic variants of the IL-23R pathway: association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Ellinghaus E.
      • Ellinghaus D.
      • Stuart P.E.
      • et al.
      Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ): IL23A, IL12B, IL23R, and tyrosine kinase 2 (TYK2). IL23A and IL23R are specific to IL-23 signaling and IL12B codes for the shared IL12/23p40 subunit; TYK2 is a signaling kinase downstream of IL-12 and IL-23 (
      • Nakamura R.
      • Shibata K.
      • Yamada H.
      • et al.
      Tyk2-signaling plays an important role in host defense against Escherichia coli through IL-23-induced IL-17 production by gammadelta T cells.
      ). Notably, the association studies have failed to demonstrate a role for IL-12/Th1 pathway–specific genes such as IL12A, IL12RB2, and IFNG. Thus, the genetic evidence aligns more closely with a Th17 rather than Th1 immune skewing in psoriasis.
      There are a number of genes associated with psoriasis that may function downstream of the IL-17 receptor signaling. Of particular recent interest is TRAF3IP2 coding for the Act-1 protein (also known as TRAF3-interacting protein 2), an intracellular protein that directly binds the IL-17 receptor complex (
      • Ellinghaus E.
      • Ellinghaus D.
      • Stuart P.E.
      • et al.
      Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
      ). Act-1 can initiate two different signal transduction pathways in response to IL-17R activation. NF-κB signaling events can be initiated through interactions with TRAF6 (
      • Schwandner R.
      • Yamaguchi K.
      • Cao Z.
      Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction.
      ). In the TRAF6-independent pathway, Act-1 can bind to TRAF5 and sequester the RNA binding factor SF2, leading to stabilization of inflammatory mRNAs (
      • Hartupee J.
      • Liu C.
      • Novotny M.
      • et al.
      IL-17 enhances chemokine gene expression through mRNA stabilization.
      ;
      • Gaffen S.L.
      Recent advances in the IL-17 cytokine family.
      ;
      • Sun D.
      • Novotny M.
      • Bulek K.
      • et al.
      Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF).
      ; Figure 1). The risk haplotypes have a common defect in the ability of Act-1 to bind TRAF6 (
      • Huffmeier U.
      • Uebe S.
      • Ekici A.B.
      • et al.
      Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis.
      ) and thus presumably have decreased IL-17R–dependent NF-κB signaling, although this was not specifically demonstrated. This suggests the possibility that the psoriasis risk may be driven by increased proinflammatory activity through the Act1-TRAF5 mRNA stabilization pathway. Additional candidate genes implicated in psoriasis include other NF-κB pathway regulatory genes (REL, TNIP1, TNFAIP3, and NFKBIA) and increased copy number of the gene segment harboring the IL-17–regulated gene, DEFB4, which encodes for human β-defensin 2 (Table 1).
      The presence of both Th1 and Th17 subsets in psoriasis may seem counterintuitive given that these two polarized subsets have counter inhibitory effects on each other (
      • Bettelli E.
      • Carrier Y.
      • Gao W.
      • et al.
      Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
      ). Under certain conditions, however, such as those that exist in psoriatic lesions, Th1 cells promote expansion of Th17 cells (
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • et al.
      Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.
      ). In addition, there appears to be considerable plasticity in this system; Th17 cells have the ability to differentiate into IFN-γ–producing Th1 cells (
      • Nistala K.
      • Adams S.
      • Cambrook H.
      • et al.
      Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment.
      ;
      • Hirota K.
      • Duarte J.H.
      • Veldhoen M.
      • et al.
      Fate mapping of IL-17-producing T cells in inflammatory responses.
      ) although not vice versa. CD8+ T cells are found in increased numbers in the psoriatic epidermis, including subsets producing IFN-γ (Tc1), IL-17 (Tc17), and/or IL-22 (Tc22;
      • Res P.C.
      • Piskin G.
      • de Boer O.J.
      • et al.
      Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis.
      ). Similar to Th17 cells, Tc17 cells are dependent on IL-23 for maintenance and expansion (
      • Ciric B.
      • El-behi M.
      • Cabrera R.
      • et al.
      IL-23 drives pathogenic IL-17-producing CD8+ T cells.
      ). The notable presence of Tc17 cells in the epidermis, where IL-17 receptor is abundantly expressed on keratinocytes, suggests a potential pathogenic role for this subset of IL-17–producing cells (Figure 2).
      Figure thumbnail gr2
      Figure 2A model for the central role of IL-17 in psoriasis pathogenesis. This model includes core inflammatory elements that establish a self-reinforcing cycle, including T-helper 17 (Th17) skewing of naive T cells in the presence of IL-23 leading to the local production of IL-17 ligands. Keratinocytes in turn are stimulated by these IL-17 ligands, leading to an aberrant differentiation program and elevated production of proinflammatory factors including antimicrobial peptides (AMPs) and chemokines (including CCL20, which attracts both Th17 cells and dendritic cells [DCs]). These keratinocyte-derived factors in turn stimulate further recruitment of inflammatory cells, including IL-17–producing cells, and establish a self-sustaining inflammatory feedback loop. CXCLs, CXC ligands; Tc, T cytotoxic; TNF, tumor necrosis factor.
      Global gene expression studies have consistently demonstrated the upregulation of the IL-17 pathway in psoriasis. Several studies have used quantitative real-time PCR assays to show increased expression of IL-17 ligands and the IL-23 subunits in lesional skin compared with both nonlesional and normal skin (
      • Zaba L.C.
      • Cardinale I.
      • Gilleaudeau P.
      • et al.
      Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.
      ;
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ;
      • Harper E.G.
      • Guo C.
      • Rizzo H.
      • et al.
      Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis.
      ;
      • Johansen C.
      • Usher P.A.
      • Kjellerup R.B.
      • et al.
      Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin.
      ). Microarray studies demonstrate that many thousands of transcripts are differentially regulated in the disease state (
      • Yao Y.
      • Richman L.
      • Morehouse C.
      • et al.
      Type I interferon: potential therapeutic target for psoriasis?.
      ;
      • Gudjonsson J.E.
      • Ding J.
      • Johnston A.
      • et al.
      Assessment of the psoriatic transcriptome in a large sample: additional regulated genes and comparisons with in vitro models.
      ), and successful therapy is accompanied by rapid and nearly complete reversion of expression of a wide range of genes (including cytokines, AMPs, and downstream effector molecules) to near normal (nonlesional) levels, suggesting that these alterations in gene expression are necessary for therapeutic response (
      • Zaba L.C.
      • Suarez-Farinas M.
      • Fuentes-Duculan J.
      • et al.
      Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes.
      ;
      • Russell C.
      • Kerkof K.
      • Bigler J.
      • et al.
      Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in human psoriatic skin (abstract 273).
      ,
      • Russell C.
      • Kerkof K.
      • Bigler J.
      • et al.
      Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
      ). Again, elements upstream and downstream of IL-17 show higher expression, implicating the pathway in psoriasis. Notably, among the genes that are universally overexpressed across several studies are those for IL-17A and IL-17F, IL-23, and a number of proinflammatory genes regulated by IL-17A in keratinocytes, such as β-defensin, neutrophil chemoattractants, and the chemokine CCL20 (
      • Nograles K.E.
      • Zaba L.C.
      • Guttman-Yassky E.
      • et al.
      Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways.
      ).
      Consistent with the results described above is the observation that IL-17 ligands (including both IL-17A and IL-17C) and TNF-α amplify each other's effects, both additively and synergistically, and their combined activity accounts for many of the key inflammatory pathways in psoriasis (
      • Chiricozzi A.
      • Guttman-Yassky E.
      • Suarez-Farinas M.
      • et al.
      Integrative responses to IL-17 and TNF-alpha in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis.
      ). Some of this synergy may be the result of the distinct mechanisms by which IL-17 and TNF each regulate downstream gene expression. The TNF receptor stimulates several pathways that activate gene transcription, while major activities downstream of the IL-17 receptor include modulation of NF-κB signaling and stabilization of mRNAs induced by TNF (
      • Hartupee J.
      • Liu C.
      • Novotny M.
      • et al.
      IL-17 enhances chemokine gene expression through mRNA stabilization.
      ;
      • Sun D.
      • Novotny M.
      • Bulek K.
      • et al.
      Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF).
      ). The synergistic interaction between IL-17 and TNF, as well as the regulation of IL-17 by IL-23, is a potential unifying theme in understanding the success of different therapeutic agents in psoriasis, including the calcineurin inhibitors, and antibodies targeting TNF, IL-12/23-p40, IL-23p19, IL-17A, and IL-17 receptor A.

      Role of IL-17 Inhibition in the Clinic

      Along with our understanding of disease pathophysiology, therapeutic efficacy in psoriasis has also advanced tremendously over the past 20 years. Clinical response to TNF antagonism in psoriasis has been shown to correlate with the rapid early reduction of IL-23 and IL-17A, followed by later reductions in Th1-associated genes (
      • Zaba L.C.
      • Cardinale I.
      • Gilleaudeau P.
      • et al.
      Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.
      ). Studies with IL-12/23p40 (
      • Leonardi C.L.
      • Kimball A.B.
      • Papp K.A.
      • et al.
      Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).
      ;
      • Papp K.A.
      • Langley R.G.
      • Lebwohl M.
      • et al.
      Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).
      ) and IL-23p19 (
      • Sofen H.
      • Smith S.
      • Matheson R.
      • et al.
      Results of a single ascending dose study to assess the safety and tolerability of CNTO 1959 following intravenous or subcutaneous administration in healthy subjects and in subjects with moderate to severe psoriasis (abstract FC-21).
      ) antagonists have also demonstrated clinical efficacy and support the role of IL-12/IL-23 and Th17 cells in the pathogenesis of psoriasis. Although the key cytokines released from human Th17 cells that drive psoriasis pathogenesis, including IL-22 and/or IL-17, remain unclear, direct antagonism of the IL-17A ligand (
      • Genovese M.C.
      • Van den Bosch F.
      • Roberson S.A.
      • et al.
      LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study.
      ;
      • Hueber W.
      • Patel D.D.
      • Dryja T.
      • et al.
      Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis.
      ,
      • Hueber W.
      • Sands B.
      • Vandemeulebroecke M.
      • et al.
      Inhibition of IL-17A by secukinumab is ineffective for Crohn's disease (CD) (abstract 10).
      ) and the IL-17 receptor with brodalumab (
      • Russell C.
      • Kerkof K.
      • Bigler J.
      • et al.
      Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in human psoriatic skin (abstract 273).
      ,
      • Russell C.
      • Kerkof K.
      • Bigler J.
      • et al.
      Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
      ;
      • Papp K.A.
      • Leonardi C.
      • Menter A.
      • et al.
      Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.
      ) have demonstrated striking results in early-phase clinical trials in psoriasis.
      Secukinumab (AIN457) is an anti–IL-17A ligand mAb that has been assessed for the treatment of psoriasis, rheumatoid arthritis, chronic noninfectious uveitis, and Crohn's disease (
      • Hueber W.
      • Patel D.D.
      • Dryja T.
      • et al.
      Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis.
      ,
      • Hueber W.
      • Sands B.
      • Vandemeulebroecke M.
      • et al.
      Inhibition of IL-17A by secukinumab is ineffective for Crohn's disease (CD) (abstract 10).
      ). A phase 1 study in 36 patients with psoriasis showed that a single dose of secukinumab at 3mgkg−1 significantly reduced disease severity (mean psoriasis area and severity index [PASI] score) by 63% at week 12 versus 9% for placebo (
      • Hueber W.
      • Patel D.D.
      • Dryja T.
      • et al.
      Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis.
      ). Clinical responses were associated with reductions in epidermal hyperplasia, expression of IL-17A+ and CD3+ cells from immunostained micrographs, and gene expression of various cytokines and chemokines (e.g., IL-17A, IL-21, IL-22, CCL20, KRT16, and DEFB4;
      • Hueber W.
      • Patel D.D.
      • Dryja T.
      • et al.
      Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis.
      ). Data from three phase 2 studies showed 12-week PASI75 response rates of 81% in patients with psoriasis treated with subcutaneous secukinumab 150mg (three or four doses) and 83% in patients treated with intravenous secukinumab 10mgkg−1 (three doses;
      • Rich P.A.
      Secukinumab, a new fully human monoclonal anti-interleukin-17A antibody, in the treatment of moderate-to-severe plaque psoriasis: interim efficacy and safety data from a phase II regimen-finding trial (oral presentation FC01.6).
      ;
      • Papp K.A.
      Secukinumab efficacy and safety preliminary results from a phase II subcutaneous dose-ranging study in the treatment of moderate-to-severe plaque psoriasis (oral presentation FC01.5).
      ,
      • Papp K.A.
      Secukinumab, a novel fully human antibody to interleukin-17A in the treatment of moderate-to-severe plaque psoriasis: efficacy and safety interim results from a phase II intravenous induction dose-ranging study (oral presentation FC01.7).
      ). LY2439821 (ixekinumab) is a mAb to IL-17A that is being investigated for the treatment of psoriasis and rheumatoid arthritis (
      • Genovese M.C.
      • Van den Bosch F.
      • Roberson S.A.
      • et al.
      LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study.
      ). Recent data from a phase 2 study showed week 12 PASI75 response rates of 77%, 83%, and 82% following administration of subcutaneous ixekinumab 25mg, 75mg, and 150mg (weeks 0, 2, 4, 8, and 12), respectively, versus 7.7% for placebo (
      • Leonardi C.
      • Matheson R.
      • Zachariae C.
      • et al.
      Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis.
      ). Up to 72% of patients in the active-treatment groups achieved clear/almost clear status according to Physician's Global Assessment.
      Brodalumab (AMG 827) is an IL-17 receptor A mAb that is under investigation for a number of inflammatory conditions, including psoriasis, psoriatic arthritis, and asthma. A phase 1 proof-of-concept study in patients with psoriasis demonstrated significant improvements in clinical parameters: seven of eight and five of eight patients achieved PASI75 by week 6 in the high (700mg intravenous) and moderate (350mg subcutaneous) single-dose groups, respectively (
      • Russell C.
      • Kerkof K.
      • Bigler J.
      • et al.
      Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in human psoriatic skin (abstract 273).
      ,
      • Russell C.
      • Kerkof K.
      • Bigler J.
      • et al.
      Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
      ). Improvements in histopathological parameters included reductions in epidermal thickness, Ki-67 counts (an index of proliferation-specific nuclear antigen;
      • Gerdes J.
      • Schwab U.
      • Lemke H.
      • et al.
      Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation.
      ), keratin-16 gene expression, and infiltrating leukocyte subsets (
      • Russell C.
      • Kerkof K.
      • Bigler J.
      • et al.
      Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in human psoriatic skin (abstract 273).
      ,
      • Russell C.
      • Kerkof K.
      • Bigler J.
      • et al.
      Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
      ). In a phase 2 dose-ranging study, AMG 827 (70, 140, or 210mg at weeks 0, 1, and 2, then every other week or 280mg monthly) produced dose-dependent improvements in PASI and Physician Global Assessment responses (
      • Papp K.A.
      • Leonardi C.
      • Menter A.
      • et al.
      Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.
      ). Significant mean PASI improvements at week 12 were 45%, 86%, 86%, and 76% in the AMG 827 70-, 140-, 210-, and 280-mg groups, respectively, compared with 16% in the placebo group. PASI75 responses were observed in 33%, 77%, 82%, and 67% of patients, respectively, in the AMG 827 groups and 0% in the placebo group. Similar results were observed for other PASI measures and Physician's Global Assessment, with up to 85% of patients in the AMG 827 groups achieving clear/almost clear status.
      The significant clinical responses in patients with psoriasis following blockade of either IL-17 receptor A (with brodalumab) or its ligand IL-17A (with secukinumab and ixekinumab) confirm the hypothesis that IL-17 signaling has a critical role in this immune-mediated disease. Furthermore, the complete reversal of regenerative epidermal hyperplasia and high PASI responses seen with AMG 827 implies that factors signaling through the IL-17 receptor A, including IL-17A, IL-17C, and IL-17F, are central drivers of psoriasis immunopathogenesis.

      An Emerging Model for the Role of IL-17 in Psoriasis Pathogenesis

      This review has focused on the emerging role of IL-17 in the pathogenesis of psoriasis, including preclinical results, genetic data, and both indirect and direct evidence from clinical studies. These findings demonstrate the central importance of this innate family of proinflammatory cytokines in psoriasis. A model for the role of various factors in psoriasis pathogenesis is presented in Figure 2. Notable features in this model include a set of core inflammatory elements that establish a self-reinforcing cycle, along with ancillary proinflammatory elements that synergize with and amplify the core elements. The core elements include: (a) naive T-cell skewing into the Th17 lineage following interaction with activated dendritic cells in the presence of IL-23; (b) local Th17 production of IL-17A and IL-17F; and (c) keratinocyte stimulation by IL-17 ligands leading to aberrant differentiation and proliferation and the production of proinflammatory AMPs, chemokines, and angiogenic factors, which in turn stimulate further recruitment of inflammatory cells, setting up a positive feedback loop. The chemokine CCL20 is a notable keratinocyte-derived core component that functions to recruit both inflammatory dendritic cells and Th17 cells into active lesional skin. Additional ancillary factors in this inflammatory network include cytokines (e.g., IL-22, which promotes keratinocyte alterations, and TNF, which can synergize with IL-17 ligands to promote inflammation); Th1 and Th22 cells, which amplify the core response via the production of inflammatory factors; and keratinocyte-derived angiogenic and chemoattractant factors. The core and ancillary elements in this model function together to establish an activated inflammatory network, ultimately resulting in the formation of psoriasis lesions.
      Advances in genetics and immunology have enabled the development of targeted therapeutics in psoriasis, a number of which have shown impressive clinical efficacy. Clinical and molecular data from these therapeutic successes have provided additional opportunities to focus on and identify inhibitors or central drivers of psoriasis pathogenesis, including therapeutics targeting the IL-17 family. As our understanding of psoriasis pathogenesis increases, the parallel evolution of increasingly selective therapies may provide patients with an optimal balance between increased clinical benefit and reduced risk for side effects. The early clinical results from inhibition of IL-17 (ligand or receptor) have established this cytokine as a core downstream element in psoriasis, and ongoing late-phase studies will allow further confirmation of these findings.

      ACKNOWLEDGMENTS

      We thank Rick Davis, whose work was funded by Amgen, and Meera Kodukulla of Amgen for assistance in drafting the manuscript. JEG is supported by NIH K08 AR060802 and A. Alfred Taubman Medical Research Institute as the Kenneth and Frances Eisenberg Emerging Scholar. We also thank Dirk Smith, of Amgen, for graphical support.

      REFERENCES

        • Acosta-Rodriguez E.V.
        • Napolitani G.
        • Lanzavecchia A.
        • et al.
        Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
        Nat Immunol. 2007; 8: 942-949
        • Allanore Y.
        • Saad M.
        • Dieude P.
        • et al.
        Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis.
        PLoS Genet. 2011; 7: e1002091
        • Austin L.M.
        • Ozawa M.
        • Kikuchi T.
        • et al.
        The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients.
        J Invest Dermatol. 1999; 113: 752-759
        • Australia and New Zealand Multiple Sclerosis Genetics Consortium
        Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20.
        Nat Genet. 2009; 41: 824-828
        • Awasthi A.
        • Riol-Blanco L.
        • Jager A.
        • et al.
        Cutting edge: IL-23 receptor GFP reporter mice reveal distinct populations of IL-17-producing cells.
        J Immunol. 2009; 182: 5904-5908
        • Ban M.
        • Goris A.
        • Lorentzen A.R.
        • et al.
        Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor.
        Eur J Hum Genet. 2009; 17: 1309-1313
        • Barlow J.L.
        • McKenzie A.N.
        IL-25: a key requirement for the regulation of type-2 immunity.
        Biofactors. 2009; 35: 178-182
        • Benagiano M.
        • Munari F.
        • Ciervo A.
        • et al.
        Chlamydophila pneumoniae phospholipase D (CpPLD) drives Th17 inflammation in human atherosclerosis.
        Proc Natl Acad Sci USA. 2012; 109: 1222-1227
        • Bettelli E.
        • Carrier Y.
        • Gao W.
        • et al.
        Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
        Nature. 2006; 441: 235-238
        • Blumberg H.
        • Dinh H.
        • Dean Jr., C.
        • et al.
        IL-1RL2 and its ligands contribute to the cytokine network in psoriasis.
        J Immunol. 2010; 185: 4354-4362
        • Boniface K.
        • Bernard F.X.
        • Garcia M.
        • et al.
        IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes.
        J Immunol. 2005; 174: 3695-3702
        • Bovenschen H.J.
        • van de Kerkhof P.C.
        • van Erp P.E.
        • et al.
        Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin.
        J Invest Dermatol. 2011; 131: 1853-1860
        • Capon F.
        • Burden A.D.
        • Trembath R.C.
        • et al.
        Psoriasis and other complex trait dermatoses: from Loci to functional pathways.
        J Invest Dermatol. 2012; 132: 915-922
        • Cargill M.
        • Schrodi S.J.
        • Chang M.
        • et al.
        A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
        Am J Hum Genet. 2007; 80: 273-290
        • Chang S.H.
        • Dong C.
        A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses.
        Cell Res. 2007; 17: 435-440
        • Chaudhari U.
        • Romano P.
        • Mulcahy L.D.
        • et al.
        Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial.
        Lancet. 2001; 357: 1842-1847
        • Chen S.
        • Shimada K.
        • Zhang W.
        • et al.
        IL-17A is proatherogenic in high-fat diet-induced and Chlamydia pneumoniae infection-accelerated atherosclerosis in mice.
        J Immunol. 2010; 185: 5619-5627
        • Chiricozzi A.
        • Guttman-Yassky E.
        • Suarez-Farinas M.
        • et al.
        Integrative responses to IL-17 and TNF-alpha in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis.
        J Invest Dermatol. 2011; 131: 677-687
        • Ciric B.
        • El-behi M.
        • Cabrera R.
        • et al.
        IL-23 drives pathogenic IL-17-producing CD8+ T cells.
        J Immunol. 2009; 182: 5296-5305
        • Claudio E.
        • Sonder S.U.
        • Saret S.
        • et al.
        The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation.
        J Immunol. 2009; 182: 1617-1630
        • Conti H.R.
        • Baker O.
        • Freeman A.F.
        • et al.
        New mechanism of oral immunity to mucosal candidiasis in hyper-IgE syndrome.
        Mucosal Immunol. 2011; 4: 448-455
        • Cua D.J.
        • Tato C.M.
        Innate IL-17-producing cells: the sentinels of the immune system.
        Nat Rev Immunol. 2010; 10: 479-489
        • Duerr R.H.
        • Taylor K.D.
        • Brant S.R.
        • et al.
        A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
        Science. 2006; 314: 1461-1463
        • Ellinghaus E.
        • Ellinghaus D.
        • Stuart P.E.
        • et al.
        Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
        Nat Genet. 2010; 42: 991-995
        • Ellinghaus E.
        • Stuart P.E.
        • Ellinghaus D.
        • et al.
        Genome-wide meta-analysis of psoriatic arthritis identifies susceptibility locus at REL.
        J Invest Dermatol. 2012; 132: 1133-1140
        • Ellis C.N.
        • Gorsulowsky D.C.
        • Hamilton T.A.
        • et al.
        Cyclosporine improves psoriasis in a double-blind study.
        JAMA. 1986; 256: 3110-3116
        • Filer C.
        • Ho P.
        • Smith R.L.
        • et al.
        Investigation of association of the IL12B and IL23R genes with psoriatic arthritis.
        Arthritis Rheum. 2008; 58: 3705-3709
        • Fisher S.A.
        • Tremelling M.
        • Anderson C.A.
        • et al.
        Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn′s disease.
        Nat Genet. 2008; 40: 710-712
        • Franke A.
        • McGovern D.P.
        • Barrett J.C.
        • et al.
        Genome-wide meta-analysis increases to 71 the number of confirmed Crohn′s disease susceptibility loci.
        Nat Genet. 2010; 42: 1118-1125
        • Freeman A.F.
        • Avila E.M.
        • Shaw P.A.
        • et al.
        Coronary artery abnormalities in hyper-IgE syndrome.
        J Clin Immunol. 2011; 31: 338-345
        • Gaffen S.L.
        Structure and signalling in the IL-17 receptor family.
        Nat Rev Immunol. 2009; 9: 556-567
        • Gaffen S.L.
        Recent advances in the IL-17 cytokine family.
        Curr Opin Immunol. 2011; 23: 613-619
        • Gaffen S.L.
        • Hernandez-Santos N.
        • Peterson A.C.
        IL-17 signaling in host defense against Candida albicans.
        Immunol Res. 2011; 50: 181-187
        • Gateva V.
        • Sandling J.K.
        • Hom G.
        • et al.
        A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus.
        Nat Genet. 2009; 41: 1228-1233
        • Genovese M.C.
        • Van den Bosch F.
        • Roberson S.A.
        • et al.
        LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study.
        Arthritis Rheum. 2010; 62: 929-939
        • Gerdes J.
        • Schwab U.
        • Lemke H.
        • et al.
        Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation.
        Int J Cancer. 1983; 31: 13-20
        • Ghoreschi K.
        • Weigert C.
        • Rocken M.
        Immunopathogenesis and role of T cells in psoriasis.
        Clin Dermatol. 2007; 25: 574-580
        • Gottlieb S.L.
        • Gilleaudeau P.
        • Johnson R.
        • et al.
        Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis.
        Nat Med. 1995; 1: 442-447
        • Graham R.R.
        • Cotsapas C.
        • Davies L.
        • et al.
        Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus.
        Nat Genet. 2008; 40: 1059-1061
        • Gregersen P.K.
        • Amos C.I.
        • Lee A.T.
        • et al.
        REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.
        Nat Genet. 2009; 41: 820-823
        • Griffiths C.E.
        • Powles A.V.
        • Leonard J.N.
        • et al.
        Clearance of psoriasis with low dose cyclosporin.
        Br Med J (Clin Res Ed). 1986; 293: 731-732
        • Gudjonsson J.E.
        • Ding J.
        • Johnston A.
        • et al.
        Assessment of the psoriatic transcriptome in a large sample: additional regulated genes and comparisons with in vitro models.
        J Invest Dermatol. 2010; 130: 1829-1840
        • Gudjonsson J.E.
        • Elder J.T.
        Psoriasis: epidemiology.
        Clin Dermatol. 2007; 25: 535-546
        • Guttman-Yassky E.
        • Lowes M.A.
        • Fuentes-Duculan J.
        • et al.
        Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis.
        J Immunol. 2008; 181: 7420-7427
        • Harper E.G.
        • Guo C.
        • Rizzo H.
        • et al.
        Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis.
        J Invest Dermatol. 2009; 129: 2175-2183
        • Harrington L.E.
        • Hatton R.D.
        • Mangan P.R.
        • et al.
        Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
        Nat Immunol. 2005; 6: 1123-1132
        • Hartupee J.
        • Liu C.
        • Novotny M.
        • et al.
        IL-17 enhances chemokine gene expression through mRNA stabilization.
        J Immunol. 2007; 179: 4135-4141
        • Hirota K.
        • Duarte J.H.
        • Veldhoen M.
        • et al.
        Fate mapping of IL-17-producing T cells in inflammatory responses.
        Nat Immunol. 2011; 12: 255-263
        • Hollox E.J.
        • Huffmeier U.
        • Zeeuwen P.L.
        • et al.
        Psoriasis is associated with increased beta-defensin genomic copy number.
        Nat Genet. 2008; 40: 23-25
        • Honorati M.C.
        • Meliconi R.
        • Pulsatelli L.
        • et al.
        High in vivo expression of interleukin-17 receptor in synovial endothelial cells and chondrocytes from arthritis patients.
        Rheumatology. 2001; 40: 522-527
        • Huang W.
        • Na L.
        • Fidel P.L.
        • et al.
        Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice.
        J Infect Dis. 2004; 190: 624-631
        • Hueber W.
        • Patel D.D.
        • Dryja T.
        • et al.
        Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis.
        Sci Transl Med. 2010; 2: 52ra72
        • Hueber W.
        • Sands B.
        • Vandemeulebroecke M.
        • et al.
        Inhibition of IL-17A by secukinumab is ineffective for Crohn's disease (CD) (abstract 10).
        in: Paper presented at the 6th Congress of the European Crohn′s and Colitis Organisation-Inflammatory Bowel Diseases, Dublin, Ireland; 24–26 February 20112011
        • Huffmeier U.
        • Lascorz J.
        • Bohm B.
        • et al.
        Genetic variants of the IL-23R pathway: association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis.
        J Invest Dermatol. 2009; 129: 355-358
        • Huffmeier U.
        • Uebe S.
        • Ekici A.B.
        • et al.
        Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis.
        Nat Genet. 2010; 42: 996-999
        • Jiang Z.
        • Yang P.
        • Hou S.
        • et al.
        IL-23R gene confers susceptibility to Behcet′s disease in a Chinese Han population.
        Ann Rheum Dis. 2010; 69: 1325-1328
        • Johansen C.
        • Usher P.A.
        • Kjellerup R.B.
        • et al.
        Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin.
        Br J Dermatol. 2009; 160: 319-324
        • Kagami S.
        • Rizzo H.L.
        • Kurtz S.E.
        • et al.
        IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal skin host defense against Candida albicans.
        J Immunol. 2010; 185: 5453-5462
        • Kagami S.
        • Rizzo H.L.
        • Lee J.J.
        • et al.
        Circulating Th17, Th22, and Th1 cells are increased in psoriasis.
        J Invest Dermatol. 2010; 130: 1373-1383
        • Kleinschek M.A.
        • Owyang A.M.
        • Joyce-Shaikh B.
        • et al.
        IL-25 regulates Th17 function in autoimmune inflammation.
        J Exp Med. 2007; 204: 161-170
        • Kryczek I.
        • Bruce A.T.
        • Gudjonsson J.E.
        • et al.
        Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.
        J Immunol. 2008; 181: 4733-4741
        • Kuestner R.E.
        • Taft D.W.
        • Haran A.
        • et al.
        Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F.
        J Immunol. 2007; 179: 5462-5473
        • Langrish C.L.
        • Chen Y.
        • Blumenschein W.M.
        • et al.
        IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
        J Exp Med. 2005; 201: 233-240
        • Leonardi C.
        • Matheson R.
        • Zachariae C.
        • et al.
        Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis.
        N Engl J Med. 2012; 366: 1190-1199
        • Leonardi C.L.
        • Kimball A.B.
        • Papp K.A.
        • et al.
        Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).
        Lancet. 2008; 371: 1665-1674
        • Leonardi C.L.
        • Powers J.L.
        • Matheson R.T.
        • et al.
        Etanercept as monotherapy in patients with psoriasis.
        N Engl J Med. 2003; 349: 2014-2022
        • Lin A.M.
        • Rubin C.J.
        • Khandpur R.
        • et al.
        Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis.
        J Immunol. 2011; 187: 490-500
        • Lowes M.A.
        • Kikuchi T.
        • Fuentes-Duculan J.
        • et al.
        Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
        J Invest Dermatol. 2008; 128: 1207-1211
        • Ma H.L.
        • Liang S.
        • Li J.
        • et al.
        IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation.
        J Clin Invest. 2008; 118: 597-607
        • Mehta N.N.
        • Yu Y.
        • Pinnelas R.
        • et al.
        Attributable risk estimate of severe psoriasis on major cardiovascular events.
        Am J Med. 2011; 124:775: e1-e6
        • Milner J.D.
        • Brenchley J.M.
        • Laurence A.
        • et al.
        Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome.
        Nature. 2008; 452: 773-776
        • Mizuki N.
        • Meguro A.
        • Ota M.
        • et al.
        Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet′s disease susceptibility loci.
        Nat Genet. 2010; 42: 703-706
        • Musone S.L.
        • Taylor K.E.
        • Lu T.T.
        • et al.
        Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus.
        Nat Genet. 2008; 40: 1062-1064
        • Nair R.P.
        • Duffin K.C.
        • Helms C.
        • et al.
        Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
        Nat Genet. 2009; 41: 199-204
        • Nair R.P.
        • Ruether A.
        • Stuart P.E.
        • et al.
        Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
        J Invest Dermatol. 2008; 128: 1653-1661
        • Nakajima K.
        • Kanda T.
        • Takaishi M.
        • et al.
        Distinct roles of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model.
        J Immunol. 2011; 186: 4481-4489
        • Nakamura R.
        • Shibata K.
        • Yamada H.
        • et al.
        Tyk2-signaling plays an important role in host defense against Escherichia coli through IL-23-induced IL-17 production by gammadelta T cells.
        J Immunol. 2008; 181: 2071-2075
        • Naldi L.
        Epidemiology of psoriasis.
        Curr Drug Targets Inflamm Allergy. 2004; 3: 121-128
        • Nistala K.
        • Adams S.
        • Cambrook H.
        • et al.
        Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment.
        Proc Natl Acad Sci USA. 2010; 107: 14751-14756
        • Nograles K.E.
        • Zaba L.C.
        • Guttman-Yassky E.
        • et al.
        Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways.
        Br J Dermatol. 2008; 159: 1092-1102
        • Ortega C.
        • Fernandez A.S.
        • Carrillo J.M.
        • et al.
        IL-17-producing CD8+ T lymphocytes from psoriasis skin plaques are cytotoxic effector cells that secrete Th17-related cytokines.
        J Leukoc Biol. 2009; 86: 435-443
        • Papp K.A.
        Secukinumab efficacy and safety preliminary results from a phase II subcutaneous dose-ranging study in the treatment of moderate-to-severe plaque psoriasis (oral presentation FC01.5).
        in: Paper presented at the 20th Congress of the European Academy of Dermatology and Venereology, Lisbon, Portugal; 20–24 October 20112011
        • Papp K.A.
        Secukinumab, a novel fully human antibody to interleukin-17A in the treatment of moderate-to-severe plaque psoriasis: efficacy and safety interim results from a phase II intravenous induction dose-ranging study (oral presentation FC01.7).
        in: Paper presented at the 20th Congress of the European Academy of Dermatology and Venereology; 20–24 October 20112011
        • Papp K.A.
        • Langley R.G.
        • Lebwohl M.
        • et al.
        Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).
        Lancet. 2008; 371: 1675-1684
        • Papp K.A.
        • Leonardi C.
        • Menter A.
        • et al.
        Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.
        N Engl J Med. 2012; 366: 1181-1189
        • Pappu R.
        • Ramirez-Carrozzi V.
        • Ota N.
        • et al.
        The IL-17 family cytokines in immunity and disease.
        J Clin Immunol. 2010; 30: 185-195
        • Park H.
        • Li Z.
        • Yang X.O.
        • et al.
        A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
        Nat Immunol. 2005; 6: 1133-1141
        • Parkes M.
        • Barrett J.C.
        • Prescott N.J.
        • et al.
        Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.
        Nat Genet. 2007; 39: 830-832
        • Patsopoulos N.A.
        • Bayer Pharma M.S.G.W.G.
        • Steering Committees of Studies Evaluating, I-b, a C.C.R.A.
        • Consortium A.N.
        • GeneMsa
        • et al.
        Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.
        Ann Neurol. 2011; 70: 897-912
        • Plenge R.M.
        • Cotsapas C.
        • Davies L.
        • et al.
        Two independent alleles at 6q23 associated with risk of rheumatoid arthritis.
        Nat Genet. 2007; 39: 1477-1482
        • Puel A.
        • Cypowyj S.
        • Bustamante J.
        • et al.
        Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity.
        Science. 2011; 332: 65-68
        • Puel A.
        • Doffinger R.
        • Natividad A.
        • et al.
        Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I.
        J Exp Med. 2010; 207: 291-297
        • Ramirez-Carrozzi V.
        • Sambandam A.
        • Luis E.
        • et al.
        IL-17C regulates the innate immune function of epithelial cells in an autocrine manner.
        Nat Immunol. 2011; 12: 1159-1166
        • Remmers E.F.
        • Cosan F.
        • Kirino Y.
        • et al.
        Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet′s disease.
        Nat Genet. 2010; 42: 698-702
        • Res P.C.
        • Piskin G.
        • de Boer O.J.
        • et al.
        Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis.
        PLoS ONE. 2010; 5: e14108
        • Rich P.A.
        Secukinumab, a new fully human monoclonal anti-interleukin-17A antibody, in the treatment of moderate-to-severe plaque psoriasis: interim efficacy and safety data from a phase II regimen-finding trial (oral presentation FC01.6).
        in: Paper presented at the 20th Congress of the European Academy of Dermatology and Venereology, Lisbon, Portugal; 20–24 October 20112011
        • Rickel E.A.
        • Siegel L.A.
        • Yoon B.R.
        • et al.
        Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities.
        J Immunol. 2008; 181: 4299-4310
        • Rizzo H.L.
        • Kagami S.
        • Phillips K.G.
        • et al.
        IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A.
        J Immunol. 2011; 186: 1495-1502
        • Russell C.
        • Kerkof K.
        • Bigler J.
        • et al.
        Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065).
        J Invest Dermatol. 2011; 131: S11
        • Russell C.
        • Kerkof K.
        • Bigler J.
        • et al.
        Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in human psoriatic skin (abstract 273).
        J Invest Dermatol. 2010; 130: S46
        • Sa S.M.
        • Valdez P.A.
        • Wu J.
        • et al.
        The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
        J Immunol. 2007; 178: 2229-2240
        • Schon M.P.
        • Boehncke W.H.
        Psoriasis.
        N Engl J Med. 2005; 352: 1899-1912
        • Schwandner R.
        • Yamaguchi K.
        • Cao Z.
        Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction.
        J Exp Med. 2000; 191: 1233-1240
        • Shi Y.
        • Ullrich S.J.
        • Zhang J.
        • et al.
        A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity.
        J Biol Chem. 2000; 275: 19167-19176
        • Sigurdsson S.
        • Nordmark G.
        • Goring H.H.
        • et al.
        Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus.
        Am J Hum Genet. 2005; 76: 528-537
        • Singh T.P.
        • Schon M.P.
        • Wallbrecht K.
        • et al.
        8-methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3+ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder.
        J Immunol. 2010; 184: 7257-7267
        • Smith E.
        • Prasad K.M.
        • Butcher M.
        • et al.
        Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice.
        Circulation. 2010; 121: 1746-1755
        • Sofen H.
        • Smith S.
        • Matheson R.
        • et al.
        Results of a single ascending dose study to assess the safety and tolerability of CNTO 1959 following intravenous or subcutaneous administration in healthy subjects and in subjects with moderate to severe psoriasis (abstract FC-21).
        Br J Dermatol. 2011; 165: E10
        • Song X.
        • Zhu S.
        • Shi P.
        • et al.
        IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens.
        Nat Immunol. 2011; 12: 1151-1158
        • Steinman L.
        A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage.
        Nat Med. 2007; 13: 139-145
        • Strange A.
        • Capon F.
        • Spencer C.C.
        • et al.
        A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
        Nat Genet. 2010; 42: 985-990
        • Stuart P.E.
        • Nair R.P.
        • Ellinghaus E.
        • et al.
        Genome-wide association analysis identifies three psoriasis susceptibility loci.
        Nat Genet. 2010; 42: 1000-1004
        • Sun D.
        • Novotny M.
        • Bulek K.
        • et al.
        Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF).
        Nat Immunol. 2011; 12: 853-860
        • Sutton C.E.
        • Lalor S.J.
        • Sweeney C.M.
        • et al.
        Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity.
        Immunity. 2009; 31: 331-341
        • Taleb S.
        • Romain M.
        • Ramkhelawon B.
        • et al.
        Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis.
        J Exp Med. 2009; 206: 2067-2077
        • Thomson W.
        • Barton A.
        • Ke X.
        • et al.
        Rheumatoid arthritis association at 6q23.
        Nat Genet. 2007; 39: 1431-1433
        • Tonel G.
        • Conrad C.
        • Laggner U.
        • et al.
        Cutting edge: A critical functional role for IL-23 in psoriasis.
        J Immunol. 2010; 185: 5688-5691
        • Trynka G.
        • Zhernakova A.
        • Romanos J.
        • et al.
        Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.
        Gut. 2009; 58: 1078-1083
        • van der Fits L.
        • Mourits S.
        • Voerman J.S.
        • et al.
        Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.
        J Immunol. 2009; 182: 5836-5845
        • Wellcome Trust Case Control C.
        • Australo-Anglo-American Spondylitis C.
        • Burton P.R.
        • et al.
        Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.
        Nat Genet. 2007; 39: 1329-1337
        • Wright J.F.
        • Bennett F.
        • Li B.
        • et al.
        The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex.
        J Immunol. 2008; 181: 2799-2805
        • Wright J.F.
        • Guo Y.
        • Quazi A.
        • et al.
        Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells.
        J Biol Chem. 2007; 282: 13447-13455
        • Yang L.
        • Anderson D.E.
        • Baecher-Allan C.
        • et al.
        IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.
        Nature. 2008; 454: 350-352
        • Yao Y.
        • Richman L.
        • Morehouse C.
        • et al.
        Type I interferon: potential therapeutic target for psoriasis?.
        PLoS ONE. 2008; 3: e2737
        • Yao Z.
        • Spriggs M.K.
        • Derry J.M.
        • et al.
        Molecular characterization of the human interleukin (IL)-17 receptor.
        Cytokine. 1997; 9: 794-800
        • Zaba L.C.
        • Cardinale I.
        • Gilleaudeau P.
        • et al.
        Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.
        J Exp Med. 2007; 204: 3183-3194
        • Zaba L.C.
        • Suarez-Farinas M.
        • Fuentes-Duculan J.
        • et al.
        Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes.
        J Allergy Clin Immunol. 2009; 124 (e1–395, 10): 1022
        • Zhang X.J.
        • Huang W.
        • Yang S.
        • et al.
        Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
        Nat Genet. 2009; 41: 205-210
        • Zielinski C.E.
        • Mele F.
        • Aschenbrenner D.
        • et al.
        Pathogen-induced human T(H)17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta.
        Nature. 2012; 484: 514-518