Advertisement

Fibrosis and Immune Dysregulation in Systemic Sclerosis

  • Yahya Argobi
  • Gideon P. Smith
Chapter
Part of the Molecular and Translational Medicine book series (MOLEMED)

Abstract

Systemic sclerosis is a rare connective tissue disease of unclear etiology characterized by cutaneous and internal organ sclerosis. It has a complex pathogenesis believed to include vascular abnormalities with accompanying autoimmunity leading to tissue sclerosis. This chapter summarizes the current knowledge about systemic sclerosis pathogenesis and reviews the role of immune imbalance and its relationship with vascular damage and sustained sclerosis. Systemic sclerosis is unlike other connective tissue diseases in that immunosuppressive drugs alone are usually insufficient to control the disease and developing treatments for the other aspects, i.e., vasculopathy and fibrosis, is paramount in systemic sclerosis. Over the past decade, studies on animals and humans have revealed valuable information about systemic sclerosis molecular mechanisms. In addition, there have been a number of clinical trials targeting specific cytokines and signaling pathways involved in systemic sclerosis that have helped eliminate potential therapeutic pathways from consideration. Combining the findings from these disparate studies should help narrow the search for novel therapies.

Keywords

Systemic sclerosis Scleroderma Sclerosis Fibrosis Connective tissue 

Abbreviations

ACEi

Angiotensin-converting enzyme inhibitor

AP-1

Transcription factor activator protein-1

ARA

RNA polymerase III antibody

AT1R

Angiotensin II type 1 receptor

ATX

Autotaxin

BAFF

B-cell-activating factor

BLM

Bleomycin

cGVHD

Chronic graft-versus-host disease

Col3a1

Type III collagen

CTGF

Connective tissue growth factor

CTLA-4

T lymphocyte-associated antigen 4

DAMPs

Damage-associated molecular patterns

ECM

Extracellular matrix

ET-1

Endothelin-1

ETAR

Endothelin-1 type A receptor

Fli1

Friend leukemia integration 1

FN-1

Fibronectin

Fra-2

Fos-related antigen-2

IFN

Interferon

ILD

Interstitial lung disease

IPF

Idiopathic pulmonary fibrosis

JAKs

Janus kinases

Klf5

Kruppel-like factor 5

LPA

Lysophosphatidic acid

MMP

Metalloproteinases

mRSS

Modified Rodnan skin score

PAI-1

Plasminogen activator inhibitor-1

PDGF

Platelet-derived growth factor

PDGFR

Platelet-derived growth factor receptor

PPAR-

Peroxisome proliferator-activated receptor gamma

ROS

Reactive oxygen species

RP

Raynaud’s phenomenon

RXR

Retinoid X receptor

Scl-70

Topoisomerase 1

SMA

Smooth muscle actin

SSc

Systemic sclerosis

STATs

Transducers and activators of transcription

TGF-B

Transforming growth factor-B

Th

T helper cell

TLRs

Toll-like receptors

TNF

Tumor necrosis factor

Treg

Regulatory T cell

TSK-1

Tight skin 1

TSK-2

Tight skin 2

uPAR

Urokinase-type plasminogen activator receptor

VCAM-1

Vascular cell adhesion molecule-1

VEGF

Vascular endothelial growth factor

References

  1. 1.
    Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24(2):165–70.PubMedCrossRefGoogle Scholar
  2. 2.
    Cappelli L, Wigley FM. Management of Raynaud phenomenon and digital ulcers in scleroderma. Rheum Dis Clin N Am. 2015;41(3):419–38.CrossRefGoogle Scholar
  3. 3.
    Baron M. Targeted therapy in systemic sclerosis. Rambam Maimonides Med J. 2016;7(4):e0030.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Stern EP, Denton CP. The pathogenesis of systemic sclerosis. Rheum Dis Clin N Am. 2015;41(3):367–82.CrossRefGoogle Scholar
  5. 5.
    Feghali Bostwick C, Medsger TA Jr, Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum. 2003;48(7):1956–63.PubMedCrossRefGoogle Scholar
  6. 6.
    Makino T, Jinnin M. Genetic and epigenetic abnormalities in systemic sclerosis. J Dermatol. 2016;43(1):10–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Murdaca G, Contatore M, Gulli R, et al. Genetic factors and systemic sclerosis. Autoimmun Rev. 2016;15(5):427–32.PubMedCrossRefGoogle Scholar
  8. 8.
    Salazar G, Mayes MD. Genetics, epigenetics and genomics of systemic sclerosis. Rheum Dis Clin N Am. 2015;41(3):345–66.CrossRefGoogle Scholar
  9. 9.
    Marangoni RG, Varga J, Tourtellotte WG. Animal models of scleroderma: recent progress. Curr Opin Rheumatol. 2016;28(6):561–70. An excellent review of recent systemic sclerosis animal modelsPubMedCrossRefGoogle Scholar
  10. 10.
    Asano Y. Recent advances in animal models of systemic sclerosis. J Dermatol. 2016;43(1):19–28.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Yamamoto T, Takagawa S, Katayama I, et al. Animal model of sclerotic skin I: local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol. 1999;112:456–62.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhou CF, Zhou DC, Zhang JX, et al. Bleomycin-induced epithelial–mesenchymal transition in sclerotic skin of mice: possible role of oxidative stress in the pathogenesis. Toxicol Appl Pharmacol. 2014;277(3):250–8.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Do NN, Eming SA. Skin fibrosis: models and mechanisms. Curr Res Transl Med. 2016;64(4):185–93.PubMedCrossRefGoogle Scholar
  14. 14.
    Ishikawa H, Takeda K, Okamoto A, et al. Induction of autoimmunity in a bleomycin-induced murine model of experimental systemic sclerosis: an important role for CD4+ T cells. J Invest Dermatol. 2009;129:1688–95.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Ohgo S, Hasegawa S, Hasebe Y, et al. Bleomycin inhibits adipogenesis and accelerates fibrosis in the subcutaneous adipose layer through TGF-β1. Exp Dermatol. 2013;22(11):769–71.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Smith GP, Chan ES. Molecular pathogenesis of skin fibrosis: insight from animal models. Curr Rheumatol Rep. 2010;12(1):26–33.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Fleischmajer R, Jacobs L, Schwartz E, Sakai LY. Extracellular microfibrils are increased in localized and systemic scleroderma skin. Lab Investig. 1991;64:791–8.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Lemaire R, Farina G, Kissin E, et al. Mutant fibrillin 1 from tight skin mice increases extracellular matrix incorporation of microfibril-associated glycoprotein 2 and type I collagen. Arthritis Rheum. 2004;50(3):915–26.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Christner PJ, Peters J, Hawkins D, et al. The tight skin 2 mouse. An animal model of scleroderma displaying cutaneous fibrosis and mononuclear cell infiltration. Arthritis Rheum. 1995;38:1791–8.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Long KB, Li Z, Burgwin CM, et al. The Tsk2/+ mouse fibrotic phenotype is due to a gain-of-function mutation in the PIIINP segment of the Col3a1 gene. J Invest Dermatol. 2015;135(3):718–27.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Gentiletti J, McCloskey LJ, Artlett CM, et al. Demonstration of autoimmunity in the tight skin-2 mouse: a model for scleroderma. J Immunol. 2005;175(4):2418–26.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Miao CG, Yang YY, He X, et al. Wnt signaling in liver fibrosis: progress, challenges and potential directions. Biochimie. 2013;95(12):2326–35.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    He W, Dai C, Li Y, et al. Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol. 2009;20:765–76.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Konigshoff M, Kramer M, Balsara N, et al. WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest. 2009;119:772–87.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Bergmann C, Distler JH. Canonical Wnt signaling in systemic sclerosis. Lab Investig. 2016;96:151–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Lam AP, Gottardi CJ. β-catenin signaling: a novel mediator of fibrosis and potential therapeutic target. Curr Opin Rheumatol. 2011;23(6):562–7.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Manetti M, Rosa I, Milia AF, et al. Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: a new model of experimental scleroderma? Ann Rheum Dis. 2014;73:1700–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Eferl R, Hasselblatt P, Rath M, et al. Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1. Proc Natl Acad Sci U S A. 2008;105:10525–30.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Maurer B, Busch N, Jungel A, et al. Transcription factor fos-related antigen-2 induces progressive peripheral vasculopathy in mice closely resembling human systemic sclerosis. Circulation. 2009;120:2367–76.PubMedCrossRefGoogle Scholar
  30. 30.
    Reich N, Maurer B, Akhmetshina A, et al. The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis Rheum. 2010;62:280–90.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Venalis P, Kuma Novics G, Schulze-Koops H, et al. Cardiomyopathy in murine models of systemic sclerosis. Arthritis Rheumatol. 2015;67:508–16.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Noda S, Asano Y, Nishimura S, et al. Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis. Nat Commun. 2014;5:5797.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Asano Y. Double heterozygous mice for Klf5 and Fli1 genes: a new animal model of systemic sclerosis recapitulating its three cardinal pathological features. Med Mol Morphol. 2015;48(3):123–8. This promising recent mouse model recapitulates the main three features of SSc and could be useful to study SSc pathogenesis and to develop novel therapeutic agentsPubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Matucci Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013;65(8):1953–62.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Chora I, Guiducci S, Manetti M, et al. Vascular biomarkers and correlation with peripheral vasculopathy in systemic sclerosis. Autoimmun Rev. 2015;14(4):314–22.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Jing J, Dou TT, Yang JQ, et al. Role of endothelin-1 in the skin fibrosis of systemic sclerosis. Eur Cytokine Netw. 2015;26(1):10–4. This study suggests that overproduction of endothelin-1 (ET-1) underlies endothelial injury in SScPubMedPubMedCentralGoogle Scholar
  37. 37.
    Kim HS, Park MK, Kim HY, et al. Capillary dimension measured by computer-based digitalized image correlated with plasma endothelin-1 levels in patients with systemic sclerosis. Clin Rheumatol. 2010;29:247–54.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Sulli A, Soldano S, Pizzorni C, et al. Raynaud’s phenomenon and plasma endothelin: correlations with capillaroscopic patterns in systemic sclerosis. J Rheumatol. 2009;36:1235–9.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis. Arthritis Rheum. 2004;50(12):3985–93.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Matucci Cerinic M, Denton CP, Furst DE, et al. Bosentan treatment of digital ulcers related to systemic sclerosis. Ann Rheum Dis. 2011;70(1):32–8.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Riemekasten G, Philippe A, Näther M, et al. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann Rheum Dis. 2011;70(3):530–6.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Cabral-Marques O, Riemekasten G. Vascular hypothesis revisited: role of stimulating antibodies against angiotensin and endothelin receptors in the pathogenesis of systemic sclerosis. Autoimmun Rev. 2016;15(7):690–4.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Distler O, Del Rosso A, Giacomelli R, et al. Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers. Arthritis Res. 2002;4(6):R11.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Maurer B, Distler A, Suliman YA, et al. Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis. Ann Rheum Dis. 2014;73(10):1880–7. The is study shows that VEGF induces fibrosis in inflammatory and non-inflammatory stages of SScPubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Derrett Smith EC, Dooley A, Gilbane AJ, et al. Endothelial injury in a transforming growth factor β-dependent mouse model of scleroderma induces pulmonary arterial hypertension. Arthritis Rheum. 2013;65(11):2928–39.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Koca SS, Ozgen M, Dagli AF, et al. The protective effects of bevacizumab in bleomycin-induced experimental scleroderma. Adv Clin Exp Med. 2016;25(2):249–53.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Fielding CA, Jones GW, McLoughlin RM, et al. Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity. 2014;40(1):40–50.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Nishijima C, Hayakawa I, Matsushita T, et al. Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis. Clin Exp Immunol. 2004;138:357–63.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Sato S, Hayakawa I, Hasegawa M, et al. Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis. J Invest Dermatol. 2003;120:542–7.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Lu J, Liu Q, Wang L, et al. Increased expression of latent TGF-β-binding protein 4 affects the fibrotic process in scleroderma by TGF-β/SMAD signaling. Lab Investig. 2017;97:591–601.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Liu T, Yang YN. Expression of connective tissue growth factor in skin lesions in patients with scleroderma. Sichuan Da Xue Xue Bao Yi Xue Ban. 2008;39(6):953–6.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Lemaire R, Burwell T, Sun H, et al. Resolution of skin fibrosis by neutralization of the antifibrinolytic function of plasminogen activator inhibitor 1. Arthritis Rheumatol. 2016;68(2):473–83.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Avila JJ, Lympany PA, Pantelidis P, et al. Fibronectin gene polymorphisms associated with fibrosing alveolitis in systemic sclerosis. Am J Respir Cell Mol Biol. 1999;20(1):106–12.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Bhattacharyya S, Wei J, Varga J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol. 2011;8(1):42–54.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Zhu L, Gao D, Yang J, et al. Characterization of the phenotype of high collagen-producing fibroblast clones in systemic sclerosis, using a new modified limiting-dilution method. Clin Exp Dermatol. 2012;37(4):395–403.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Liu T, Zhang J. Detection of V, III and I type collagens of dermal tissues in skin lesions of patients with systemic sclerosis and its implication. J Huazhong Univ Sci Technolog Med Sci. 2008;28(5):599–603.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Martin P, Teodoro WR, Velosa AP, et al. Abnormal collagen V deposition in dermis correlates with skin thickening and disease activity in systemic sclerosis. Autoimmun Rev. 2012;11(11):827–35.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Rudnicka L, Varga J, Christiano AM, et al. Elevated expression of type VII collagen in the skin of patients with systemic sclerosis. Regulation by transforming growth factor-beta. J Clin Invest. 1994;93(4):1709–15.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Chanoki M, Ishii M, Kobayashi H, et al. Increased expression of lysyl oxidase in skin with scleroderma. Br J Dermatol. 1995;133(5):710–5.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Liu T, Hu XD. Transdifferentiation of fibroblasts into myofibroblasts in the skin lesion of systemic sclerosis: role of transforming growth factor β1 and its signal transduction. Nan Fang Yi Ke Da Xue Xue Bao. 2011;31(11):1840–5.PubMedGoogle Scholar
  61. 61.
    Gilbane AJ, Denton CP, Holmes AM. Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells. Arthritis Res Ther. 2013;15(3):215. ReviewPubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Ho YY, Lagares D, Tager AM, et al. Fibrosis – a lethal component of systemic sclerosis. Nat Rev Rheumatol. 2014;10(7):390–402.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Lafyatis R. Transforming growth factor β – at the centre of systemic sclerosis. Nat Rev Rheumatol. 2014;10(12):706–19.PubMedCrossRefGoogle Scholar
  64. 64.
    Varga J, Whitfield ML. Transforming growth factor-beta in systemic sclerosis (scleroderma). Front Biosci (Schol Ed). 2009;1:226–35.CrossRefGoogle Scholar
  65. 65.
    Mutlu GM, Budinger GR, Wu M, et al. Proteasomal inhibition after injury prevents fibrosis by modulating TGF-β1 signalling. Thorax. 2012;67(2):139–46.PubMedCrossRefGoogle Scholar
  66. 66.
    Tsujino K, Reed NI, Atakilit A, et al. Transforming growth factor- plays divergent roles in modulating vascular remodeling, inflammation, and pulmonary fibrosis in a murine model of scleroderma. Am J Physiol Lung Cell Mol Physiol. 2017;312(1):L22–31.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083–92.PubMedCrossRefGoogle Scholar
  68. 68.
    Richeldi L, du Bois RM, Raghu G, et al. INPULSIS trial investigators efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071–82.PubMedCrossRefGoogle Scholar
  69. 69.
    Conte E, Gili E, Fagone E, et al. Effect of pirfenidone on proliferation, TGF-β-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts. Eur J Pharm Sci. 2014;58:13–9.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Khanna D, Albera C, Fischer A, et al. An open-label, phase II study of the safety and tolerability of pirfenidone in patients with scleroderma-associated interstitial lung disease: the LOTUSS trial. J Rheumatol. 2016;43(9):1672–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Rodríguez-Castellanos M, Tlacuilo-Parra A, Sánchez-Enríquez S, et al. Pirfenidone gel in patients with localized scleroderma: a phase II study. Arthritis Res Ther. 2015;16(6):510.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Huang J, Beyer C, Palumbo-Zerr K, et al. Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis. 2016;75(5):883–90.PubMedCrossRefGoogle Scholar
  73. 73.
    Shi-Wen X, Leask A, Abraham D. Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis. Cytokine Growth Factor Rev. 2008;19(2):133–44.PubMedCrossRefGoogle Scholar
  74. 74.
    Abraham D. Connective tissue growth factor: growth factor, matricellular organizer, fibrotic biomarker or molecular target for anti-fibrotic therapy in SSc? Rheumatology (Oxford). 2008;47(Suppl 5):v8–9.CrossRefGoogle Scholar
  75. 75.
    Chen CC, Chen N, Lau LF. The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts. J Biol Chem. 2001;276:10443–52.PubMedCrossRefGoogle Scholar
  76. 76.
    Fan WH, Pech M, Karnovsky MJ. Connective tissue growth factor (CTGF) stimulates vascular smooth muscle cell growth and migration in vitro. Eur J Cell Biol. 2000;79:915–23.PubMedCrossRefGoogle Scholar
  77. 77.
    Sato S, Nagaoka T, Hasegawa M, et al. Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. J Rheumatol. 2000;27:149–54.PubMedGoogle Scholar
  78. 78.
    Chujo S, Shirasaki F, Kawara S, et al. Connective tissue growth factor causes persistent Proα2(I) collagen gene expression induced by transforming growth factor-β in a mouse fibrosis model. J Cell Physiol. 2005;203:447–56.PubMedCrossRefGoogle Scholar
  79. 79.
    Xiao R, Liu FY, Luo JY, et al. Effect of small interfering RNA on the expression of connective tissue growth factor and type I and III collagen in skin fibroblasts of patients with systemic sclerosis. Br J Dermatol. 2006;155(6):1145–53.PubMedCrossRefGoogle Scholar
  80. 80.
    Trojanowska M. Role of PDGF in fibrotic diseases and systemic sclerosis. Rheumatology (Oxford). 2008;47(Suppl 5):v2–4.CrossRefGoogle Scholar
  81. 81.
    Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22(10):1276–312.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Iwayama T, Olson LE. Involvement of PDGF in fibrosis and scleroderma: recent insights from animal models and potential therapeutic opportunities. Curr Rheumatol Rep. 2013;15(2):304.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Ludwicka A, Ohba T, Trojanowska M, et al. Elevated levels of platelet derived growth factor and transforming growth factor-beta 1 in bronchoalveolar lavage fluid from patients with scleroderma. J Rheumatol. 1995;22(10):1876–83.PubMedGoogle Scholar
  84. 84.
    Liu T, Zhang J, Zhang J, et al. RNA interference against platelet-derived growth factor receptor α mRNA inhibits fibroblast transdifferentiation in skin lesions of patients with systemic sclerosis. PLoS One. 2013;8(4):e60414. PDGF is critical in fibroblast transdifferentiation in skin lesions of patients with systemic sclerosisPubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med. 2006;354(25):2667–76.PubMedCrossRefGoogle Scholar
  86. 86.
    Makino K, Makino T, Stawski L, et al. Blockade of PDGF receptors by crenolanib has therapeutic effect in patient fibroblasts and in preclinical models of systemic sclerosis. J Invest Dermatol. 2017. pii: S0022-202X(17)31418-5.Google Scholar
  87. 87.
    Maurer B, Reich N, Juengel A, et al. Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis. Ann Rheum Dis. 2012;71:1382–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Gordon JK, Martyanov V, Magro C, et al. Nilotinib (Tasigna™) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial. Arthritis Res Ther. 2015;17:213.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Chan ES, Fernandez P, Merchant AA, et al. Adenosine A2A receptors in diffuse dermal fibrosis: pathogenic role in human dermal fibroblasts and in a murine model of scleroderma. Arthritis Rheum. 2006;54:2632–42.PubMedCrossRefGoogle Scholar
  90. 90.
    Lazzerini PE, Natale M, Gianchecchi E, et al. Adenosine A2A receptor activation stimulates collagen production in sclerodermic dermal fibroblasts either directly and through a cross-talk with the cannabinoid system. J Mol Med (Berl). 2012;90(3):331–42.CrossRefGoogle Scholar
  91. 91.
    Fernandez P, Trzaska S, Wilder T, et al. Pharmacological blockade of A2A receptors prevents dermal fibrosis in a model of elevated tissue adenosine. Am J Pathol. 2008;172:1675–82. Pharmacological blockade of A2A receptors may be a useful therapeutic agent in SScPubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Fernández P, Perez-Aso M, Smith G, et al. Extracellular generation of adenosine by the ectonucleotidases CD39 and CD73 promotes dermal fibrosis. Am J Pathol. 2013;183(6):1740–6.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Stoddard NC, Chun J. Promising pharmacological directions in the world of lysophosphatidic acid signaling. Biomol Ther (Seoul). 2015;23(1):1–11.CrossRefGoogle Scholar
  94. 94.
    Llona-Minguez S, Ghassemian A, Helleday T. Lysophosphatidic acid receptor (LPAR) modulators: the current pharmacological toolbox. Prog Lipid Res. 2015;58:51–75.PubMedCrossRefGoogle Scholar
  95. 95.
    Tager AM, LaCamera P, Shea BS, et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med. 2008;14:45–54.PubMedCrossRefGoogle Scholar
  96. 96.
    Pradere JP, Klein J, Gres S, et al. LPA1 receptor activation promotes renal interstitial fibrosis. J Am Soc Nephrol. 2007;18:3110–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Castelino FV, Seiders J, Bain G, et al. Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma. Arthritis Rheum. 2011;63(5):1405–15.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Castelino FV, Bain G, Pace VA, et al. An autotaxin/lysophosphatidic acid/interleukin-6 amplification loop drives scleroderma fibrosis. Arthritis Rheumatol. 2016;68(12):2964–74. LPA1 antagonist is a very promising drug in SSc treatmentPubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Wei J, Bhattacharyya S, Jain M, et al. Regulation of matrix remodeling by peroxisome proliferator-activated receptor-γ: a novel link between metabolism and fibrogenesis. Open Rheumatol J. 2012;6:103–15.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Wei J, Bhattacharyya S, Varga J. Peroxisome proliferator-activated receptor gamma: innate protection from excessive fibrogenesis and potential therapeutic target in systemic sclerosis. Curr Opin Rheumatol. 2010;22(6):671–6.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Wei J, Ghosh AK, Sargent JL, et al. PPARgamma downregulation by TGFss in fibroblast and impaired expression and function in systemic sclerosis: a novel mechanism for progressive fibrogenesis. PLoS One. 2010;5(11):e13778.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Yun Z, Maecker HL, Johnson RS, et al. Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell. 2002;2(3):331–41.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Simon MF, Daviaud D, Pradere JP, et al. Lysophosphatidic acid inhibits adipocyte differentiation via lysophosphatidic acid 1 receptor-dependent down-regulation of peroxisome proliferator-activated receptor gamma2. J Biol Chem. 2005;280(15):14656–62.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Tan JT, McLennan SV, Song WW, et al. Connective tissue growth factor inhibits adipocyte differentiation. Am J Physiol Cell Physiol. 2008;295(3):C740–51.PubMedCrossRefGoogle Scholar
  105. 105.
    Meng L, Zhou J, Sasano H, et al. Tumor necrosis factor alpha and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma: mechanism of desmoplastic reaction. Cancer Res. 2001;61(5):2250–5.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Yamasaki S, Nakashima T, Kawakami A, et al. Cytokines regulate fibroblast-like synovial cell differentiation to adipocyte-like cells. Rheumatology. 2004;43(4):448–52.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    McIntyre TM, Pontsler AV, Silva AR, et al. Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARgamma agonist. Proc Natl Acad Sci U S A. 2003;100(1):131–6.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Zheng S, Chen A. Disruption of transforming growth factor-beta signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-gamma in rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2007;292(1):G113–23.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Wei J, Zhu H, Komura K, et al. A synthetic PPAR-γ agonist triterpenoid ameliorates experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses. Ann Rheum Dis. 2014;73(2):446–54.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Ruzehaji N, Frantz C, Ponsoye M, et al. Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis. Ann Rheum Dis. 2016;75(12):2175–83.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Lakota K, Wei J, Carns M, et al. Levels of adiponectin, a marker for PPAR-gamma activity, correlate with skin fibrosis in systemic sclerosis: potential utility as biomarker? Arthritis Res Ther. 2012;14(3):R102.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Kapoor M, McCann M, Liu S, et al. Loss of peroxisome proliferator-activated receptor gamma in mouse fibroblasts results in increased susceptibility to bleomycin-induced skin fibrosis. Arthritis Rheum. 2009;60(9):2822–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Kawai T, Masaki T, Doi S, et al. PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta. Lab Investig. 2009;89(1):47–58.PubMedCrossRefGoogle Scholar
  114. 114.
    Wei J, Ghosh AK, Sargent JL, et al. PPARγ downregulation by TGFß in fibroblast and impaired expression and function in systemic sclerosis: a novel mechanism for progressive fibrogenesis. PLoS One. 2010;5(11):e13778.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Wu M, Melichian DS, Chang E, et al. Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-gamma. Am J Pathol. 2009;174(2):519–33. In this study, rosiglitazone attenuated the severity of dermal sclerosis, collagen accumulation, decreased tissue myofibroblasts and downregulated TGF-β in lesional skin. Its already in the market for treating DM, and could be useful in SScPubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Thomas RM, Worswick S, Aleshin M. Retinoic acid for treatment of systemic sclerosis and morphea: a literature review. Dermatol Ther. 2017;30(2):e12455.CrossRefGoogle Scholar
  117. 117.
    Ohta A, Uitto J. Procollagen gene expression by scleroderma fibroblasts in culture. Inhibition of collagen production and reduction of pro alpha 1(I) and pro alpha 1(III) collagen messenger RNA steady-state levels by retinoids. Arthritis Rheum. 1987;30(4):404–11.PubMedCrossRefGoogle Scholar
  118. 118.
    Toyama T, Asano Y, Akamata K, et al. Tamibarotene ameliorates bleomycin-induced dermal fibrosis by modulating phenotypes of fibroblasts, endothelial cells, and immune cells. J Invest Dermatol. 2016;136(2):387–98.PubMedCrossRefGoogle Scholar
  119. 119.
    Martin SF. Adaptation in the innate immune system and heterologous innate immunity. Cell Mol Life Sci. 2014;71(21):4115–30.PubMedCrossRefGoogle Scholar
  120. 120.
    Fullard N, O’Reilly S. Role of innate immune system in systemic sclerosis. Semin Immunopathol. 2015;37(5):511–7.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Dowson C, Simpson N, Duffy L, et al. Innate immunity in systemic sclerosis. Curr Rheumatol Rep. 2017;19(1):2.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Bhattacharyya S, Kelley K, Melichian DS, et al. Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma. Am J Pathol. 2013;182(1):192–205.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Takahashi T, Asano Y, Ichimura Y, et al. Amelioration of tissue fibrosis by toll-like receptor 4 knockout in murine models of systemic sclerosis. Arthritis Rheumatol. 2015;67(1):254–65.PubMedCrossRefGoogle Scholar
  124. 124.
    Fang F, Marangoni RG, Zhou X, et al. TLR9 signaling is augmented in systemic sclerosis and elicits TGF-β-dependent fibroblast activation. Arthritis Rheumatol. 2016;68(8):1989–2002.PubMedCrossRefGoogle Scholar
  125. 125.
    Sakoguchi A, Nakayama W, Jinnin M, et al. The expression profile of the toll-like receptor family in scleroderma dermal fibroblasts. Clin Exp Rheumatol. 2014;32(6 Suppl 86):S-4-9.PubMedGoogle Scholar
  126. 126.
    O’Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev. 2009;61(2):177–97.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Ledeboer A, Mahoney JH, Milligan ED, Martin D, Maier SF, Watkins LR. Spinal cord glia and interleukin-1 do not appear to mediate persistent allodynia induced by intramuscular acidic saline in rats. J Pain. 2006;7(10):757–67.  https://doi.org/10.1016/j.jpain.2006.04.001.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Awasthi S. Toll-like receptor-4 modulation for cancer immunotherapy. Front Immunol. 2014;5:328.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Wu M, Assassi S. The role of type 1 interferon in systemic sclerosis. Front Immunol. 2013;4:266.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Eloranta ML, Franck-Larsson K, Lövgren T, et al. Type I interferon system activation and association with disease manifestations in systemic sclerosis. Ann Rheum Dis. 2010;69(7):1396–402.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Bălănescu P, Lădaru A, Bălănescu E, et al. IL-17, IL-6 and IFN-γ in systemic sclerosis patients. Rom J Intern Med. 2015;53(1):44–9.PubMedGoogle Scholar
  132. 132.
    Dantas AT, Gonçalves SM, Pereira MC, et al. Interferons and systemic sclerosis: correlation between interferon gamma and interferon-lambda 1 (IL-29). Autoimmunity. 2015;48(7):429–33.PubMedCrossRefGoogle Scholar
  133. 133.
    Christmann RB, Sampaio-Barros P, Stifano G, et al. Association of Interferon- and transforming growth factor β-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol. 2014;66(3):714–25.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Solans R, Bosch JA, Esteban I, et al. Systemic sclerosis developing in association with the use of interferon alpha therapy for chronic viral hepatitis. Clin Exp Rheumatol. 2004;22(5):625–8.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Black CM, Silman AJ, Herrick AI, et al. Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1999;42(2):299–305.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Khamashta M, Merrill JT, Werth VP, et al. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016;75(11):1909–16.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Goldberg A, Geppert T, Schiopu E, et al. Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study. Arthritis Res Ther. 2014;16(1):R57.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Guo X, Higgs BW, Bay-Jensen AC, et al. Suppression of T cell activation and collagen accumulation by an anti-IFNAR1 mAb, anifrolumab, in adult patients with systemic sclerosis. J Invest Dermatol. 2015;135(10):2402–9.PubMedCrossRefGoogle Scholar
  139. 139.
    Stifano G, Christmann RB. Macrophage involvement in systemic sclerosis: do we need more evidence? Curr Rheumatol Rep. 2016;18(1):2.PubMedCrossRefGoogle Scholar
  140. 140.
    Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Ishikawa O, Ishikawa H. Macrophage infiltration in the skin of patients with systemic sclerosis. J Rheumatol. 1992;19(8):1202–6.PubMedGoogle Scholar
  142. 142.
    Higashi-Kuwata N, Jinnin M, Makino T, et al. Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis. Arthritis Res Ther. 2010;12(4):R128.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Mathes AL, Christmann RB, Stifano G, et al. Global chemokine expression in systemic sclerosis (SSc): CCL19 expression correlates with vascular inflammation in SSc skin. Ann Rheum Dis. 2014;73(10):1864–72.PubMedCrossRefGoogle Scholar
  144. 144.
    Bandinelli F, Del Rosso A, Gabrielli A, et al. CCL2, CCL3 and CCL5 chemokines in systemic sclerosis: the correlation with SSc clinical features and the effect of prostaglandin E1 treatment. Clin Exp Rheumatol. 2012;30(2 Suppl 71):S44–9.PubMedGoogle Scholar
  145. 145.
    Clements PJ, Lachenbruch PA, Seibold JR, et al. Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol. 1993;20(11):1892–6.PubMedGoogle Scholar
  146. 146.
    Chizzolini C, Boin F. The role of the acquired immune response in systemic sclerosis. Semin Immunopathol. 2015;37(5):519–28.PubMedCrossRefGoogle Scholar
  147. 147.
    Maddur MS, Sharma M, Hegde P, et al. Human B cells induce dendritic cell maturation and favour Th2 polarization by inducing OX-40 ligand. Nat Commun. 2014;5:4092.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Sakkas LI, Bogdanos DP. Systemic sclerosis: new evidence re-enforces the role of B cells. Autoimmun Rev. 2016;15(2):155–61.PubMedCrossRefGoogle Scholar
  149. 149.
    Yoshizaki A. B lymphocytes in systemic sclerosis: abnormalities and therapeutic targets. J Dermatol. 2016;43(1):39–45.PubMedCrossRefGoogle Scholar
  150. 150.
    Yoshizaki A, Iwata Y, Komura K, et al. CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin- induced scleroderma. Am J Pathol. 2008;172:1650–63.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Schiopu E, Chatterjee S, Hsu V, et al. Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: a phase I, randomized, placebo-controlled, escalating single-dose study. Arthritis Res Ther. 2016;18(1):131.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Streicher K, Morehouse CA, Groves CJ, et al. The plasma cell signature in autoimmune disease. Arthritis Rheumatol. 2014;66(1):173–84.PubMedCrossRefGoogle Scholar
  153. 153.
    Mackay F, Browning JL. BAFF: a fundamental survival factor for B cells. Nat Rev Immunol. 2002;2(7):465–75.PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Matsushita T, Fujimoto M, Hasegawa M, et al. BAFF antagonist attenuates the development of skin fibrosis in tight-skin mice. J Invest Dermatol. 2007;127(12):2772–80.PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    François A, Gombault A, Villeret B, et al. B cell activating factor is central to bleomycin- and IL- 17-mediated experimental pulmonary fibrosis. J Autoimmun. 2015;56:1–11.PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Yoshizaki A, Miyagaki T, DiLillo DJ, et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature. 2012;491:264–8.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Matsushita T, Hamaguchi Y, Hasegawa M, et al. Decreased levels of regulatory B cells in patients with systemic sclerosis: association with autoantibody production and disease activity. Rheumatology (Oxford). 2016;55(2):263–7.PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Hasegawa M, Hamaguchi Y, Yanaba K, et al. B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am J Pathol. 2006;169:954–66.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Jordan S, Distler JH, Maurer B, EUSTAR Rituximab study group, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2015;74(6):1188–94. This study showed promising therapeutic effect of RTX on skin and lung sclerosis in SSc patientsPubMedCrossRefGoogle Scholar
  160. 160.
    O’Reilly S, Cant R, Ciechomska M, et al. Interleukin-6: a new therapeutic target in systemic sclerosis? Clin Trans Immunol. 2013;2(4):e4.CrossRefGoogle Scholar
  161. 161.
    Saito M, Yoshida K, Hibi M, et al. Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J Immunol. 1992;148(12):4066–71.PubMedPubMedCentralGoogle Scholar
  162. 162.
    Nishimoto N, Sasai M, Shima Y, et al. Improvement in Castleman’s disease by humanized anti-interleukin-6 receptor antibody therapy. Blood. 2000;95(1):56–61.PubMedGoogle Scholar
  163. 163.
    Hirano T, Matsuda T, Turner M, et al. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988;18(11):1797–801.PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Taniguchi T, Asano Y, Fukasawa T, et al. Critical contribution of the interleukin-6/signal transducer and activator of transcription 3 axis to vasculopathy associated with systemic sclerosis. J Dermatol. 2017;  https://doi.org/10.1111/1346-8138.13827.PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    O’Reilly S, Ciechomska M, Cant R, et al. Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-β (TGF-β) signaling promoting SMAD3 activation and fibrosis via gremlin protein. J Biol Chem. 2014;289(14):9952–60.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Khan K, Xu S, Nihtyanova S, et al. Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann Rheum Dis. 2012;71(7):1235–42.PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Sakkas LI. Spotlight on tocilizumab and its potential in the treatment of systemic sclerosis. Drug Des Dev Ther. 2016;10:2723–8.CrossRefGoogle Scholar
  168. 168.
    De Lauretis A, Sestini P, Pantelidis P, et al. Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis. J Rheumatol. 2013;40(4):435–46.PubMedCrossRefPubMedCentralGoogle Scholar
  169. 169.
    Desallais L, Avouac J, Frechet M, et al. Targeting IL-6 by both passive or active immunization strategies prevents bleomycin-induced skin fibrosis. Arthritis Res Ther. 2014;16:R157.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387(10038):2630–40. Tocilizumab is safe and well-tolerated in SSc patients, and showed some improvement in skin and lung fibrosisPubMedCrossRefPubMedCentralGoogle Scholar
  171. 171.
    Xing X, Yang J, Yang X, et al. IL-17A induces endothelial inflammation in systemic sclerosis via the ERK signaling pathway. PLoS One. 2013;8:e85032.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004;4(8):583–94.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Kalogerou A, Gelou E, Mountantonakis S, et al. Early T cell activation in the skin from patients with systemic sclerosis. Ann Rheum Dis. 2005;64(8):1233–5.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Almeida I, Silva SV, Fonseca AR, et al. T and NK cell phenotypic abnormalities in systemic sclerosis: a cohort study and a comprehensive literature review. Clin Rev Allergy Immunol. 2015;49(3):347–69.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Roumm AD, Whiteside TL, Medsger TA Jr, et al. Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum. 1984;27(6):645–53.CrossRefGoogle Scholar
  176. 176.
    Hussein MR, Hassan HI, Hofny ER, et al. Alterations of mononuclear inflammatory cells, CD4/CD8+ T cells, interleukin 1beta, and tumour necrosis factor alpha in the bronchoalveolar lavage fluid, peripheral blood, and skin of patients with systemic sclerosis. J Clin Pathol. 2005;58(2):178–84.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Fuschiotti P, Larregina AT, Ho J, et al. Interleukin-13-producing CD8+ T cells mediate dermal fibrosis in patients with systemic sclerosis. Arthritis Rheum. 2013;65(1):236–46.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Tiev KP, Abriol J, Burland MC, et al. T cell repertoire in patients with stable scleroderma. Clin Exp Immunol. 2005;139(2):348–54.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Wells AU, Lorimer S, Majumdar S, et al. Fibrosing alveolitis in systemic sclerosis: increase in memory T-cells in lung interstitium. Eur Respir J. 1995;8(2):266–71.PubMedCrossRefGoogle Scholar
  180. 180.
    O’Reilly S, Hügle T, van Laar JM. T cells in systemic sclerosis: a reappraisal. Rheumatology (Oxford). 2012;51(9):1540–9.CrossRefGoogle Scholar
  181. 181.
    Huang XL, Wang YJ, Yan JW, et al. Role of anti-inflammatory cytokines IL-4 and IL-13 in systemic sclerosis. Inflamm Res. 2015;64(3–4):151–9.PubMedCrossRefGoogle Scholar
  182. 182.
    MacDonald KG, Dawson NA, Huang Q, et al. Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis. J Allergy Clin Immunol. 2015;135(4):946–e9.PubMedCrossRefGoogle Scholar
  183. 183.
    Sato S, Fujimoto M, Hasegawa M, et al. Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis. Rheumatology (Oxford). 2004;43(10):1261–6.CrossRefGoogle Scholar
  184. 184.
    Ponsoye M, Frantz C, Ruzehaji N, et al. Treatment with abatacept prevents experimental dermal fibrosis and induces regression of established inflammation-driven fibrosis. Ann Rheum Dis. 2016;75(12):2142–9.PubMedCrossRefGoogle Scholar
  185. 185.
    Chakravarty EF, Martyanov V, Fiorentino D, et al. Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis. Arthritis Res Ther. 2015;17:159. Abatacept is a very promising drug in SSc treatmentPubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Liang HE, Reinhardt RL, Bando JK, et al. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat Immunol. 2011;13(1):58–66.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Kelly-Welch AE, Hanson EM, Boothby MR, et al. Interleukin-4 and interleukin-13 signaling connections maps. Science. 2003;300(5625):1527–8.PubMedCrossRefGoogle Scholar
  188. 188.
    Hasegawa M, Fujimoto M, Kikuchi K, et al. Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis. J Rheumatol. 1997;24(2):328–32.PubMedGoogle Scholar
  189. 189.
    Lee KS, Ro YJ, Ryoo YW, et al. Regulation of interleukin-4 on collagen gene expression by systemic sclerosis fibroblasts in culture. J Dermatol Sci. 1996;12(2):110–7.PubMedCrossRefGoogle Scholar
  190. 190.
    Kodera T, McGaha TL, Phelps R, et al. Disrupting the IL-4 gene rescues mice homozygous for the tight-skin mutation from embryonic death and diminishes TGF-beta production by fibroblasts. Proc Natl Acad Sci U S A. 2002;99(6):3800–5.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Ong C, Wong C, Roberts CR, et al. Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur J Immunol. 1998;28(9):2619–29.PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Kanellakis P, Ditiatkovski M, Kostolias G, et al. A pro-fibrotic role for interleukin-4 in cardiac pressure overload. Cardiovasc Res. 2012;95(1):77–85.PubMedCrossRefGoogle Scholar
  193. 193.
    Wills-Karp M, Finkelman FD. Untangling the complex web of IL-4- and IL-13-mediated signaling pathways. Sci Sig. 2008;1(51):pe55.Google Scholar
  194. 194.
    Riccieri V, Rinaldi T, Spadaro A, et al. Interleukin-13 in systemic sclerosis: relationship to nailfold capillaroscopy abnormalities. Clin Rheumatol. 2003;22(2):102–6.PubMedCrossRefGoogle Scholar
  195. 195.
    Lu J, Zhu Y, Feng W, et al. Platelet-derived growth factor mediates interleukin-13-induced collagen I production in mouse airway fibroblasts. J Biosci. 2014;39(4):693–700.PubMedCrossRefGoogle Scholar
  196. 196.
    Lee CG, Homer RJ, Zhu Z, et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta (1). J Exp Med. 2001;194(6):809–21.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Matsushita M, Yamamoto T, Nishioka K. Upregulation of interleukin-13 and its receptor in a murine model of bleomycin-induced scleroderma. Int Arch Allergy Immunol. 2004;135(4):348–56.PubMedCrossRefGoogle Scholar
  198. 198.
    Bournia VK, Evangelou K, Sfikakis PP. Therapeutic inhibition of tyrosine kinases in systemic sclerosis: a review of published experience on the first 108 patients treated with imatinib. Semin Arthritis Rheum. 2013;42(4):377–90.PubMedCrossRefGoogle Scholar
  199. 199.
    Singh D, Kane B, Molfino NA, et al. A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354) in subjects with asthma. BMC Pulm Med. 2010;10:3.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    O’Connor W Jr, Esplugues E, Huber S. The role of TH17-associated cytokines in health and disease. J Immunol Res. 2014;2014:936270.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Shabgah AG, Fattahi E, Shahneh FZ. Interleukin-17 in human inflammatory diseases. Postepy Dermatol Alergol. 2014;31(4):256–61.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Radstake TR, van Bon L, Broen J, et al. The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFβ and IFNγ distinguishes SSc phenotypes. PLoS One. 2009;4(6):e5903.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Yang X, Yang J, Xing X, et al. Increased frequency of Th17 cells in systemic sclerosis is related to disease activity and collagen overproduction. Arthritis Res Ther. 2014;16:R4.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Liu M, Yang J, Xing X, et al. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Lei L, Zhao C, Qin F, et al. Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis. Clin Exp Rheumatol. 2016;34(Suppl 100(5)):14–22. IL-17A plays a key role in tissue fibrosis. Anti-IL-17A could be very useful in SSc treatment, large randomized studies are neededPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Yahya Argobi
    • 1
  • Gideon P. Smith
    • 2
  1. 1.King Khalid UniversityAbhaSaudi Arabia
  2. 2.Department of DermatologyMGHBostonUSA

Personalised recommendations