IL-17 and Th17 cells in systemic sclerosis: a comprehensive review

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T cells (especially T helper cells) seem to be strongly associated with systemic sclerosis pathogenesis. Th17-IL-17 axis was proved to be involved in the pathogenesis of multiple autoimmune diseases. By performing a comprehensive research of the literature indexed in PubMed database, the current review summarizes current knowledge related to Th17 and IL-17 in systemic sclerosis. While there is promising data suggesting inhibition of Tregulatory and Th1 signals on one hand and promotion of Th17 and Th2 signals on the other, studies that include prospective and integrated analysis of Tregulatory, Th17, Th1, Th2 (cells and derived cytokines) on the same cohort of Ssc patients are warranted.

1. GRAEBER KE, OLSEN NJ. Th17 cell cytokine secretion profile in host defense and autoimmunity. Inflamm Res. 2012; 61 (2):87-96.

2. HYMOWITZ SG, FILVAROFF EH, YIN JP, LEE J, CAI L, RISSER P, 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; 20:5332–41.

3. TANASESCU C, BĂLĂNESCU E, BĂLĂNESCU P, OLTEANU R, BADEA C, GRANCEA C, et al. IL-17 in cutaneous lupus erythematosus. Eur J Intern Med. 2010; 21 (3):202-7.

4. BLAUVELT A. T-helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis. J Invest Dermatol. 2008; 128 (5):1064-7.

5. CHEN DY, CHEN YM, LAN JL, LIN CC, CHEN HH, HSIEH CW. Potential role of Th17cells in the pathogenesis of adult-onset Still’s disease. Rheumatology (Oxford). 2010; 49 (12):2305-12.

6. DE NITTO D, SARRA M, CUPI ML, PALLONE F, MONTELEONE G. Targeting IL-23 and Th17-cytokines in inflammatory bowel diseases. Curr Pharm Des. 2010; 16 (33):3656-60.

7. ZHANG L, LI YG, LI YH, QI L, LIU XG, YUAN CZ, et al. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS One. 2012; 7 (4):e31000.

8. RAYCHAUDHURI SP, RAYCHAUDHURI SK. IL-23/IL-17 axis in spondyloarthritis-bench to bedside. Clin Rheumatol. 2016; 35 (6):1437-41.

9. LUBRANO E, PERROTTA FM. Secukinumab for ankylosing spondylitis and psoriatic arthritis. Ther Clin Risk Manag. 2016; 12:1587-92.

10. KURASAWA K, HIROSE K, SANO H, ENDO H, SHINKAI H, NAWATA Y, et al. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum. 2000; 43 (11):2455-63.

11. MURATA M, FUJIMOTO M, MATSUSHITA T, HAMAGUCHI Y, HASEGAWA M, TAKEHARA K, et al. Clinical association of serum interleukin-17 levels in systemic sclerosis: is systemic sclerosis a Th17 disease? J Dermatol Sci. 2008; 50(3):240-2.

12. GOURH P, ARNETT FC, ASSASSI S, TAN FK, HUANG M, DIEKMAN L, et al. Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations. Arthritis Res Ther, 2009; 11 (5):R147.

13. HIGGS BW, ZHU W, RICHMAN L, FIORENTINO DF, GREENBERG SA, JALLAL B, et al. Identification of activated cytokine pathways in the blood of systemic lupus erythematosus, myositis, rheumatoid arthritis, and scleroderma patients. Int J Rheum Dis. 2012; 15 (1):25-35.

14. TOROK KS, KURZINSKI K, KELSEY C, YABES J, MAGEE K, VALLEJO AN, et al. Peripheral blood cytokine and chemokine profiles in juvenile localized scleroderma: T-helper cell-associated cytokine profiles. Semin Arthritis Rheum. 2015; 45 (3):284-93.

15. OLEWICZ-GAWLIK A, DANCZAK-PAZDROWSKA A, KUZNAR-KAMINSKA B, GORNOWICZ-POROWSKA J, KATULSKA K, TRZYBULSKA D, et al. Interleukin-17 and interleukin-23: importance in the pathogenesis of lung impairment in patients with systemic sclerosis. Int J Rheum Dis. 2014; 17 (6):664-70.

16. BĂLĂNESCU P, LĂDARU A, BĂLĂNESCU E, NICOLAU A, BĂICUŞ C, DAN GA. IL-17, IL-6 and IFN-γ in Systemic Sclerosis Patients. Rom J Intern Med. 2015; 53 (1):44-9.

17. OKAMOTO Y, HASEGAWA M, MATSUSHITA T, HAMAGUCHI Y, HUU DL, IWAKURA Y, et al. Potential roles of interleukin-17A in the development of skin fibrosis in mice. Arthritis Rheum. 2012; 64 (11):3726-35.

18. LEI L, HE ZY, ZHAO C, SUN XJ, ZHONG XN. Elevated frequencies of CD4(+) IL-21(+) T, CD4(+) IL-21R(+) T and IL-21 (+) Th17 cells, and increased levels of IL-21 in bleomycin-induced mice may be associated with dermal and pulmonary inflammation and fibrosis. Int J Rheum Dis. 2016; 19 (4):392-404.

19. LEI L, ZHONG XN, HE ZY, ZHAO C, SUN XJ. IL-21 induction of CD4+ T cell differentiation into Th17 cells contributes to bleomycin-induced fibrosis in mice. Cell Biol Int. 2015; 39 (4):388-99.

20. RADSTAKE TR, VAN BON L, BROEN J, HUSSIANI A, HESSELSTRAND R, WUTTGE DM, et al. The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFbeta and IFNgamma distinguishes SSc phenoltypes. PLoS One. 2009; 4 (6):e5903.

21. FENOGLIO D, BATTAGLIA F, PARODI A, STRINGARA S, NEGRINI S, PANICO N, RIZZI M, et al. Alteration of Th17 and Treg cell subpopulations co-exist in patients affected with systemic sclerosis. Clin Immunol. 2011; 139 (3):249-57.

22. PAPP G, HORVATH IF, BARATH S, GYIMESI E, SIPKA S, SZODORAY P, et al. Altered T-cell and regulatory cell repertoire in patients with diffuse cutaneous systemic sclerosis. Scand J Rheumatol. 2011; 40 (3):205-10.

23. TRUCHETET ME, BREMBILLA NC, MONTANARI E, ALLANORE Y, CHIZZOLINI C. Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease. Arthritis Res Ther. 2011; 13(5):R166.

24. ALMANZAR G, KLEIN M, SCHMALZING M, HILLIGARDT D, EL HAJJ N, KNEITZ H, et al. Disease manifestation and inflammatory activity as modulators of Th17/Treg balance and RORC/FoxP3 Methylation in Systemic Sclerosis. Int Arch Allergy Immunol. 2016; 171(2):141-54.

25. RODRÍGUEZ-REYNA TS, FURUZAWA-CARBALLEDA J, CABIEDES J, FAJARDO-HERMOSILLO LD, MARTÍNEZ-REYES C, DÍAZ-ZAMUDIO M, et al. Th17 peripheral cells are increased in diffuse cutaneous systemic sclerosis compared with limited illness: a cross-sectional study. Rheumatol Int. 2012; 32 (9):2653-60.

26. LIU X, GAO N, LI M, XU D, HOU Y, WANG Q, et al. Elevated levels of CD4(+)CD25(+)FoxP3(+) T cells in systemic sclerosis patients contribute to the secretion of IL-17 and immunosuppression dysfunction. PLoS One. 2013; 8 (6):e64531.

27. FURUZAWA-CARBALLEDA J, ORTÍZ-ÁVALOS M, LIMA G, JURADO-SANTA CRUZ F, LLORENTE L. Subcutaneous administration of polymerized type I collagen downregulates interleukin (IL)-17A, IL-22 and transforming growth factor-β1 expression, and increases FoxP3-expressing cells in localized scleroderma. Clin Exp Dermatol. 2012; 37 (6):599-609.

28. NAKASHIMA T, JINNIN M, YAMANE K, HONDA N, KAJIHARA I, MAKINO T, MASUGUCHI S, et al. Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J Immunol. 2012; 188 (8):3573-83.

29. LONATI PA, BREMBILLA NC, MONTANARI E, FONTAO L, GABRIELLI A, VETTORI S, et al. High IL-17E and low IL-17C dermal expression identifies a fibrosis-specific motif common to morphea and systemic sclerosis. PLoS One. 2014; 9 (8):e105008.

30. BREMBILLA NC, MONTANARI E, TRUCHETET ME, RASCHI E, MERONI P, CHIZZOLINI C. Th17 cells favor inflammatory responses while inhibiting type I collagen deposition by dermal fibroblasts: differential effects in healthy and systemic sclerosis fibroblasts. Arthritis Res Ther. 2013; 15 (5):R151.

31. FRECH TM, REVELO MP, DRAKOS SG, MURTAUGH MA, MARKEWITZ BA, SAWITZKE AD, LI DY. Vascular leak is a central feature in the pathogenesis of systemic sclerosis. J Rheumatol 2012; 39:1385-91.

32. LIU M, YANG J, XING X, CUI X, LI M. Interleukin-17A promotes functional activation of systemic sclerosis patient-derived dermal vascular smooth muscle cells by extracellular-regulated protein kinases signalling pathway. Arthritis Res Ther. 2014; 16 (6):4223.

33. XING X, YANG J, YANG X, WEI Y, ZHU L, GAO D, et al. IL-17A induces endothelial inflammation in systemic sclerosis via the ERK signaling pathway. PLoS One. 2013; 8 (12):e85032.

34. YANG X, YANG J, XING X, WAN L, LI M. Increased frequency of Th17 cells in systemic sclerosis is related to disease activity and collagen overproduction. Arthritis Res Ther. 2014; 16 (1):R4.

35. ZHOU Y, HOU W, XU K, HAN D, JIANG C, MOU K, et al. The elevated expression of Th17-related cytokines and receptors is associated with skin lesion severity in early systemic sclerosis. Hum Immunol. 2015; 76 (1):22-9.

36. MELONI F, SOLARI N, CAVAGNA L, MOROSINI M, MONTECUCCO CM, FIETTA AM. Frequency of Th1, Th2 and Th17 producing T lymphocytes in bronchoalveolar lavage of patients with systemic sclerosis. Clin Exp Rheumatol. 2009; 27 (5):765-72.

37. ROLLA G, FUSARO E, NICOLA S, BUCCA C, PERONI C, PARISI S, et al. Th-17 cytokines and interstitial lung involvement in systemic sclerosis. J Breath Res. 2016; 10 (4):046013.

38. HSU E, SHI H, JORDAN RM, LYONS-WEILER J, PILEWSKI JM, FEGHALI-BOSTWICK CA. Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. Arthritis Rheum. 2011; 63 (3):783-94.

39. FAVA A, CIMBRO R, WIGLEY FM, LIU QR, ROSEN A, BOIN F. Frequency of circulating topoisomerase-I-specific CD4 T cells predicts presence and progression of interstitial lung disease in scleroderma. Arthritis Res Ther. 2016; 18 (1):9.

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