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Current Rheumatology Reports

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01.08.2015 | Psoriatic Arthritis (O FitzGerald and P Helliwell, Section Editors)

Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis

verfasst von: L. E. Durham, B. W. Kirkham, L. S. Taams

Erschienen in: Current Rheumatology Reports | Ausgabe 8/2015

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Abstract

Investigators have accrued compelling evidence that the IL-17 pathway is central to the pathogenesis of psoriasis and psoriatic arthritis. The evidence comprises genome-wide association studies (GWAS), data from experimental murine models and findings from in vitro studies on patients’ cells or tissue biopsies. More recently, the success of drugs blocking the IL-17 pathway in treating both psoriasis (PsO) and psoriatic arthritis (PsA) confirms that IL-17 is a clinically relevant therapeutic target. However, there remain many unanswered questions: is PsA simply an extension of PsO from the skin to the synovial tissue or are there differences in the underlying pathogenesis of these diseases? Which cell type represents the primary source of IL-17 in PsO and PsA? And how are these cells regulated? This review outlines the IL-17 pathway, summarises the evidence supporting its role in PsO and PsA and discusses recent data that may help to address these yet unresolved questions.

Kane D et al. A prospective, clinical and radiological study of early psoriatic arthritis: an early synovitis clinic experience. Rheumatology (Oxford). 2003;42(12):1460–8.CrossRef

Sommer DM et al. Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis. Arch Dermatol Res. 2006;298(7):321–8.PubMedCrossRef

McDonough E et al. Depression and anxiety in psoriatic disease: prevalence and associated factors. J Rheumatol. 2014;41(5):887–96.PubMedCrossRef

Rouvier E et al. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol. 1993;150(12):5445–56.PubMed

Yao Z et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity. 1995;3(6):811–21.PubMedCrossRef

Yao Z et al. Molecular characterization of the human interleukin (IL)-17 receptor. Cytokine. 1997;9(11):794–800.PubMedCrossRef

Gaffen Jr SL, Garg AV, Cua DJ. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol. 2014;14(9):585–600.PubMedCrossRef

Chabaud M et al. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J Immunol. 1998;161(1):409–14.PubMed

Zhang X et al. Structure and function of interleukin-17 family cytokines. Protein Cell. 2011;2(1):26–40.PubMedCrossRef

10.

Hymowitz SG et al. IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. EMBO J. 2001;20(19):5332–41.PubMedCentralPubMedCrossRef

11.

Bordon Y. Cytokines: IL-17C joins the family firm. Nat Rev Immunol. 2011;11(12):805.PubMed

12.

Farahani R et al. Cytokines (interleukin-9, IL-17, IL-22, IL-25 and IL-33) and asthma. Adv Biomed Res. 2014;3:127.PubMedCentralPubMedCrossRef

13.

Doyle MS et al. New insight into the functions of the interleukin-17 receptor adaptor protein Act1 in psoriatic arthritis. Arthritis Res Ther. 2012;14(5):226.PubMedCentralPubMedCrossRef

14.

Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, 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(11):1123–32.PubMedCrossRef

15.

Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233–40.PubMedCentralPubMedCrossRef

16.

Bettelli E et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8.PubMedCrossRef

17.

McGeachy MJ et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009;10(3):314–24.PubMedCentralPubMedCrossRef

18.••

Lee Y et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol. 2012;13(10):991–9. This study compares the induction and gene expression profile of pathogenic and non pathogenic Th17 cells.

19.

McGeachy MJ et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007;8(12):1390–7.PubMedCrossRef

20.

Ivanov II et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126(6):1121–33.PubMedCrossRef

21.

Brüstle A et al. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol. 2007;8(9):958–66.PubMedCrossRef

22.

Yang XO et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007;282(13):9358–63.PubMedCrossRef

23.

Ciric B et al. IL-23 drives pathogenic IL-17-producing CD8+ T cells. J Immunol. 2009;182(9):5296–305.PubMedCrossRef

24.

Hirota K et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011;12(3):255–63.PubMedCentralPubMedCrossRef

25.

Tajima M et al. IL-17/IFN-gamma double producing CD8+ T (Tc17/IFN-gamma) cells: a novel cytotoxic T-cell subset converted from Tc17 cells by IL-12. Int Immunol. 2011;23(12):751–9.PubMedCrossRef

26.

van Hamburg JP et al. Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum. 2011;63(1):73–83.PubMedCrossRef

27.

Nair RP et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet. 2006;78(5):827–51.PubMedCentralPubMedCrossRef

28.•

Haroon M., et al. Certain class I HLA alleles and haplotypes implicated in susceptibility play a role in determining specific features of the psoriatic arthritis phenotype. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2014-205461. This GWAS study reports that specific HLA alleles are associated with specific forms of PsA.

29.

Winchester R et al. HLA associations reveal genetic heterogeneity in psoriatic arthritis and in the psoriasis phenotype. Arthritis Rheum. 2012;64(4):1134–44.PubMedCrossRef

30.

McHugh K, Bowness P. The link between HLA-B27 and SpA—new ideas on an old problem. Rheumatology (Oxford). 2012;51(9):1529–39.CrossRef

31.

Capon F et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum Genet. 2007;122(2):201–6.PubMedCrossRef

32.

Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol. 2009;129(6):1339–50.PubMedCrossRef

33.

Huffmeier U et al. Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat Genet. 2010;42(11):996–9.PubMedCentralPubMedCrossRef

34.

Chan JR et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med. 2006;203(12):2577–87.PubMedCentralPubMedCrossRef

35.

van der Fits L et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol. 2009;182(9):5836–45.PubMedCrossRef

36.

Wiekowski MT et al. Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J Immunol. 2001;166(12):7563–70.PubMedCrossRef

37.

Sherlock JP et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat + CD3 + CD4-CD8- entheseal resident T cells. Nat Med. 2012;18(7):1069–76.PubMedCrossRef

38.

Murphy CA et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198(12):1951–7.PubMedCentralPubMedCrossRef

39.

Nakae S et al. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol. 2003;171(11):6173–7.PubMedCrossRef

40.

Ruutu M et al. Beta-glucan triggers spondylarthritis and Crohn’s disease-like ileitis in SKG mice. Arthritis Rheum. 2012;64(7):2211–22.PubMedCrossRef

41.

Benham H et al. Interleukin-23 mediates the intestinal response to microbial beta-1,3-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis Rheumatol. 2014;66(7):1755–67.PubMedCrossRef

42.

Lories RJ et al. Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis. Arthritis Rheum. 2007;56(2):489–97.PubMedCrossRef

43.

Jacques P et al. Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Ann Rheum Dis. 2014;73(2):437–45.PubMedCrossRef

44.

Nograles KE et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol. 2008;159(5):1092–102.PubMedCentralPubMed

45.

Liang SC et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006;203(10):2271–9.PubMedCentralPubMedCrossRef

46.

Raychaudhuri SP, Raychaudhuri SK, Genovese MC. IL-17 receptor and its functional significance in psoriatic arthritis. Mol Cell Biochem. 2012;359(1-2):419–29.PubMedCrossRef

47.

Paulissen SM et al. Synovial fibroblasts directly induce Th17 pathogenicity via the cyclooxygenase/prostaglandin E2 pathway, independent of IL-23. J Immunol. 2013;191(3):1364–72.PubMedCrossRef

48.

Yago T et al. IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-alpha antibody: a novel mechanism of osteoclastogenesis by IL-17. J Cell Biochem. 2009;108(4):947–55.PubMedCrossRef

49.

Kotake S et al. Role of osteoclasts and interleukin-17 in the pathogenesis of rheumatoid arthritis: crucial ‘human osteoclastology’. J Bone Miner Metab. 2012;30(2):125–35.PubMedCrossRef

50.

Res PC 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(11), e14108.PubMedCentralPubMedCrossRef

51.

Ortega C 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(2):435–43.PubMedCrossRef

52.

Lin AM et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol. 2011;187(1):490–500.PubMedCentralPubMedCrossRef

53.

Zaba LC et al. Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells. J Invest Dermatol. 2009;129(1):79–88.PubMedCentralPubMedCrossRef

54.

Zaba LC 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(5):1022-10 e1–395.PubMedCrossRef

55.•

Menon B et al. Interleukin-17 + CD8+ T cells are enriched in the joints of patients with psoriatic arthritis and correlate with disease activity and joint damage progression. Arthritis Rheumatol. 2014;66(5):1272–81. The first study reporting the presence of Tc17 cells in the synovial fluid of patients with PsA but not RA.

56.

Leipe J et al. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum. 2010;62(10):2876–85.PubMedCrossRef

57.•

Langley RG et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med. 2014;371(4):326–38. This paper reports the results of the first phase III clinical trial of a monoclonal antibody blocking IL-17A in PsO.

58.

Leonardi C et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366(13):1190–9.PubMedCrossRef

59.

Mease PJ et al. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med. 2014;370(24):2295–306.PubMedCrossRef

60.

McInnes IB et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis. 2014;73(2):349–56.PubMedCrossRef

61.

Russell CB et al. Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17 receptor monoclonal antibody. J Immunol. 2014;192(8):3828–36.PubMedCrossRef

62.

Borgato L et al. The T cell receptor repertoire in psoriatic synovitis is restricted and T lymphocytes expressing the same TCR are present in joint and skin lesions. J Rheumatol. 2002;29(9):1914–9.PubMed

63.

Costello PJ, Winchester RJ, Curran SA, Peterson KS, Kane DJ, Bresnihan B, et al. Psoriatic arthritis joint fluids are characterised by CD8 and CD4 T cell clonal expansions appear antigen driven. J Immunol. 2001;166(4):2878–86.PubMedCrossRef

64.••

Belasco J et al. Comparative genomic profiling of synovium versus skin lesions in psoriatic arthritis. Arthritis Rheumatol. 2015;67(4):934–44. This study reports differences between gene expression profiles between the skin and synovial tissue of patients with PsO and PsA suggesting the presence of underlying differences in the pathogenesis of these diseases.

65.

Morar N et al. HIV-associated psoriasis: pathogenesis, clinical features, and management. Lancet Infect Dis. 2010;10(7):470–8.PubMedCrossRef

66.

Munoz-Perez MA et al. Dermatological findings correlated with CD4 lymphocyte counts in a prospective 3 year study of 1161 patients with human immunodeficiency virus disease predominantly acquired through intravenous drug abuse. Br J Dermatol. 1998;139(1):33–9.PubMedCrossRef

67.

Huber M et al. IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis. J Clin Invest. 2013;123(1):247–60.PubMedCentralPubMedCrossRef

68.

Pantelyushin S et al. Rorgammat + innate lymphocytes and gammadelta T cells initiate psoriasiform plaque formation in mice. J Clin Invest. 2012;122(6):2252–6.PubMedCentralPubMedCrossRef

69.

Keijsers RR et al. In vivo induction of cutaneous inflammation results in the accumulation of extracellular trap-forming neutrophils expressing RORgammat and IL-17. J Invest Dermatol. 2014;134(5):1276–84.PubMedCrossRef

70.

Noordenbos T et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum. 2012;64(1):99–109.PubMedCrossRef

71.

Yen HR et al. Tc17 CD8 T cells: functional plasticity and subset diversity. J Immunol. 2009;183(11):7161–8.PubMedCentralPubMedCrossRef

72.

Mukasa R et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity. 2010;32(5):616–27.PubMedCentralPubMedCrossRef

73.

Satoh T et al. The development of IL-17/IFN-gamma-double producing CTLs from Tc17 cells is driven by epigenetic suppression of Socs3 gene promoter. Eur J Immunol. 2012;42(9):2329–42.PubMedCrossRef

74.

Cantini G et al. A critical role for regulatory T cells in driving cytokine profiles of Th17 cells and their modulation of glioma microenvironment. Cancer Immunol Immunother. 2011;60(12):1739–50.PubMedCrossRef

75.

Evans HG et al. TNF-alpha blockade induces IL-10 expression in human CD4+ T cells. Nat Commun. 2014;5:3199.PubMedCentralPubMed

76.

Huber S et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3(−) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity. 2011;34(4):554–65.PubMedCentralPubMedCrossRef

77.

Leonardi CL 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(9625):1665–74.PubMedCrossRef

78.

McInnes IB et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013;382(9894):780–9.PubMedCrossRef

79.

Papp KA 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(9625):1675–84.PubMedCrossRef

80.

Ritchlin C et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis. 2014;73(6):990–9.PubMedCentralPubMedCrossRef

81.

Papp KA et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366(13):1181–9.PubMedCrossRef

82.•

McInnes IB, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, improves active psoriatic arthritis: 24-week efficacy and safety data from a phase 3 randomized, multicenter, double-blind, placebo-controlled study using subcutaneous dosing. ACR 2014 Meeting Abstract, http://acrabstracts.org/abstracts/secukinumab-a-human-anti-interleukin-17a-monoclonal-antibody-improves-active-psoriatic-arthritis-24-week-efficacy-and-safety-data-from-a-phase-3-randomized-multicenter-double-blind-placebo-contr/ This abstract from the ACR 2014 meeting reports the results of the first phase III clinical trial of a monoclonal antibody blocking IL-17A in PsA. This abstract from the ACR 2014 meeting reports the results of the first phase III clinical trial of a monoclonal antibody blocking IL-17A in PsA.

Titel: Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis
verfasst von: L. E. Durham
B. W. Kirkham
L. S. Taams
Publikationsdatum: 01.08.2015
Verlag: Springer US
Erschienen in: Current Rheumatology Reports / Ausgabe 8/2015
Print ISSN: 1523-3774
Elektronische ISSN: 1534-6307
DOI: https://doi.org/10.1007/s11926-015-0529-9

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