Vol 6, No 2 (2020)
Review paper
Published online: 2020-09-04

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Rola odporności wrodzonej w twardzinie układowej

Przemysław Jacek Kotyla1, Olga Gumkowska-Sroka2
DOI: 10.5603//FR.2020.0009
Forum Reumatol 2020;6(2):70-79.


W pracy przedstawiono najnowsze poglądy dotyczące udziału układu odporności wrodzonej w patogenezie twardziny układowej. Szczególną uwagę poświęcono roli receptorów rozpoznających wzorce oraz znaczeniu zjawiska sygnatury interferonu. Wyniki najnowszych badań wskazują także na rosnące znaczenie niektórych populacji komórek odporności wrodzonej jak mastocyty, miofibroblasty oraz komórki NK.

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  1. Jiménez-Dalmaroni MJ, Gerswhin ME, Adamopoulos IE. The critical role of toll-like receptors--From microbial recognition to autoimmunity: A comprehensive review. Autoimmun Rev. 2016; 15(1): 1–8.
  2. otyla P. Systemic Sclerosis : An Autoimmune Disease Without a known pathology and to be conquered. Mosaic of Autoimmunity. . https://doi.org/10.1016/B978-0-12-814307-0.00049-9.
  3. Ptak W, Ptak M, Szczepanik M. Mechanizmy odporności nieswoistej. W: Podstawy immunologii. Wydawnictwo Lekarskie PZWL, Warszawa 2017: 113–134.
  4. Dowson C, Simpson N, Duffy L, et al. Innate Immunity in Systemic Sclerosis. Curr Rheumatol Rep. 2017; 19(1): 2.
  5. Lafyatis R. New Insights into the Mechanisms of Innate Immune Receptor Signalling in Fibrosis. The Open Rheumatology Journal. 2012; 6(1): 72–79.
  6. Grossman C, Dovrish Z, Shoenfeld Y, et al. Do infections facilitate the emergence of systemic sclerosis? Autoimmun Rev. 2011; 10(5): 244–247.
  7. Randone SB, Guiducci S, Cerinic MM. Systemic sclerosis and infections. Autoimmun Rev. 2008; 8(1): 36–40.
  8. Bhattacharyya S, Midwood KS, Yin H, et al. Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma. Adv Wound Care (New Rochelle). 2017; 6(10): 356–369.
  9. Bhattacharyya S, Varga J. Endogenous ligands of TLR4 promote unresolving tissue fibrosis: Implications for systemic sclerosis and its targeted therapy. Immunol Lett. 2018; 195: 9–17.
  10. 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.
  11. Agarwal SK, Wu M, Livingston CK, et al. Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts. Arthritis Res Ther. 2011; 13(1): R3.
  12. Saito F, Tasaka S, Inoue KI, et al. Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice. Am J Respir Cell Mol Biol. 2008; 38(5): 566–571.
  13. Hasegawa M, Sato S, Ihn H, et al. Enhanced production of interleukin-6 (IL-6), oncostatin M and soluble IL-6 receptor by cultured peripheral blood mononuclear cells from patients with systemic sclerosis. Rheumatology (Oxford). 1999; 38(7): 612–617.
  14. 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): 435–446.
  15. Glimcher LH, Murphy KM. Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 2000; 14(14): 1693–1711.
  16. Laurence A, O'Shea JJ. T(H)-17 differentiation: of mice and men. Nat Immunol. 2007; 8(9): 903–905.
  17. Liu X, Mayes MD, Tan FK, et al. Correlation of interferon-inducible chemokine plasma levels with disease severity in systemic sclerosis. Arthritis Rheum. 2013; 65(1): 226–235.
  18. He Z, Zhu Y, Jiang H. Inhibiting toll-like receptor 4 signaling ameliorates pulmonary fibrosis during acute lung injury induced by lipopolysaccharide: an experimental study. Respir Res. 2009; 10: 126.
  19. Luckhardt TR, Coomes SM, Trujillo G, et al. TLR9-induced interferon β is associated with protection from gammaherpesvirus-induced exacerbation of lung fibrosis. Fibrogenesis Tissue Repair. 2011; 4: 18.
  20. Dantas AT, Goncalves SM, Pereira MC, et al. Interferon sans systemic sclerosis: correlation between interferon gamma and interferon lambda 1 (IL-29). Autoimmunity. 2015; 48(7): 429–433.
  21. Wu M, Assassi S. The role of type 1 interferon in systemic sclerosis. Front Immunol. 2013; 4: 266.
  22. Farina GA, York MR, Di Marzio M, et al. Poly(I:C) drives type I IFN- and TGFβ-mediated inflammation and dermal fibrosis simulating altered gene expression in systemic sclerosis. J Invest Dermatol. 2010; 130(11): 2583–2593.
  23. Higgs BW, Liu Z, White B, et al. Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann Rheum Dis. 2011; 70(11): 2029–2036.
  24. O'Sullivan BJ, Pai S, Street S, et al. Immune deficiency or hyperactivity-Nf-kappab illuminates autoimmunity. J Autoimmun. 2008; 31(3): 245–251.
  25. 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): 1396–1402.
  26. Kim D, Peck A, Santer D, et al. Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis. Arthritis Rheum. 2008; 58(7): 2163–2173.
  27. 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): 625–628.
  28. Frantz C, Pezet S, Avouac J, et al. Soluble CD163 as a Potential Biomarker in Systemic Sclerosis. Dis Markers. 2018; 2018: 8509583.
  29. Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014; 5: 491.
  30. 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): 2630–2640.
  31. Huang J, Maier C, Zhang Y, et al. Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. Ann Rheum Dis. 2017; 76(11): 1941–1948.
  32. Knipper JA, Willenborg S, Brinckmann J, et al. Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair. Immunity. 2015; 43(4): 803–816.
  33. Yukawa S, Yamaoka K, Sawamukai N, et al. Dermal mast cell density in fingers reflects severity of skin sclerosis in systemic sclerosis. Mod Rheumatol. 2013; 23(6): 1151–1157.
  34. Hügle T, Hogan V, White KE, et al. Mast cells are a source of transforming growth factor β in systemic sclerosis. Arthritis Rheum. 2011; 63(3): 795–799.
  35. Ruoss SJ, Hartmann T, Caughey GH. Mast cell tryptase is a mitogen for cultured fibroblasts. J Clin Invest. 1991; 88(2): 493–499.
  36. Cairns JA, Walls AF. Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts. J Clin Invest. 1997; 99(6): 1313–1321.
  37. Jordana M, Befus AD, Newhouse MT, et al. Effect of histamine on proliferation of normal human adult lung fibroblasts. Thorax. 1988; 43(7): 552–558.
  38. Dees C, Akhmetshina A, Zerr P, et al. Platelet-derived serotonin links vascular disease and tissue fibrosis. J Exp Med. 2011; 208(5): 961–972.
  39. Tecchio C, Micheletti A, Cassatella MA. Neutrophil-derived cytokines: facts beyond expression. Front Immunol. 2014; 5: 508.
  40. Richter K, Kietzmann T. Reactive oxygen species and fibrosis: further evidence of a significant liaison. Cell Tissue Res. 2016; 365(3): 591–605.
  41. Takemasa A, Ishii Y, Fukuda T. A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice. Eur Respir J. 2012; 40(6): 1475–1482.
  42. Spits H, Artis D, Colonna M, et al. Innate lymphoid cells--a proposal for uniform nomenclature. Nat Rev Immunol. 2013; 13(2): 145–149.
  43. Wohlfahrt T, Usherenko S, Englbrecht M, et al. Type 2 innate lymphoid cell counts are increased in patients with systemic sclerosis and correlate with the extent of fibrosis. Ann Rheum Dis. 2016; 75(3): 623–626.
  44. Roan F, Stoklasek TA, Whalen E, et al. CD4+ Group 1 Innate Lymphoid Cells (ILC) Form a Functionally Distinct ILC Subset That Is Increased in Systemic Sclerosis. J Immunol. 2016; 196(5): 2051–2062.
  45. Hams E, Armstrong ME, Barlow JL, et al. IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis. Proc Natl Acad Sci U S A. 2014; 111(1): 367–372.
  46. Lei L, Zhao C, Qin F, et al. Th17 cells andIL-17 promote the skin and lung inflammation and fibrosis processin a bleomycin-induced murine model of systemic sclerosis. ClinExp Rheumatol. 2016; 34(Suppl 100): 14–22.
  47. Leroy EC. Connective tissue synthesis by scleroderma skin fibroblasts in cell culture. J Exp Med. 1972; 135(6): 1351–1362.
  48. Sappino AP, Masouyé I, Saurat JH, et al. Smooth muscle differentiation in scleroderma fibroblastic cells. Am J Pathol. 1990; 137(3): 585–591.
  49. Beon M, Harley RA, Wessels A, et al. Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis. Clin Exp Rheumatol. 2004; 22(6): 733–742.
  50. Ludwicka A, Ohba T, Trojanowska M, et al. Growth and characterization of fibroblasts obtained from bronchoalveolar lavage of patients with scleroderma. J Rheumatol. 1992; 19(11): 1716–1723.
  51. Distler O, Distler JHW, Scheid A, et al. Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ Res. 2004; 95(1): 109–116.
  52. Staton CA, Valluru M, Hoh L, et al. Angiopoietin-1, angiopoietin-2 and Tie-2 receptor expression in human dermal wound repair and scarring. Br J Dermatol. 2010; 163(5): 920–927.
  53. Distler O, Distler JHW, Scheid A, et al. Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ Res. 2004; 95(1): 109–116.
  54. Manetti M, Neumann E, Milia AF, et al. Severe fibrosis and increased expression of fibrogenic cytokines in the gastric wall of systemic sclerosis patients. Arthritis Rheum. 2007; 56(10): 3442–3447.
  55. Denton CP, Ong VH, Xu S, et al. Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis. Ann Rheum Dis. 2018; 77(9): 1362–1371.
  56. Hashimoto S, Gon Y, Takeshita I, et al. IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase-dependent pathway. J Allergy Clin Immunol. 2001; 107(6): 1001–1008.
  57. Kendall RT, Feghali-Bostwick CA. Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol. 2014; 5: 123.
  58. Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014; 5: 491.
  59. Vivier E, Raulet DH, Moretta A, et al. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nat Immunol. 2002; 3(12): 1142–1149.
  60. Chien Yh, Meyer C, Bonneville M. γδ T cells: first line of defense and beyond. Annu Rev Immunol. 2014; 32: 121–155.
  61. van Bon L, Affandi AJ, Broen J, et al. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med. 2014; 370(5): 433–443.
  62. Marasini B, Cossutta R, Selmi C, et al. Polymorphism of the fractalkine receptor CX3CR1 and systemic sclerosis-associated pulmonary arterial hypertension. Clin Dev Immunol. 2005; 12(4): 275–279.
  63. Dignat-George F, Boulanger CM. The many faces of endothelial microparticles. Arterioscler Thromb Vasc Biol. 2011; 31(1): 27–33.
  64. Guiducci S, Distler JHW, Jüngel A, et al. The relationship between plasma microparticles and disease manifestations in patients with systemic sclerosis. Arthritis Rheum. 2008; 58(9): 2845–2853.
  65. Benyamine A, Magalon J, Cointe S, et al. Increased serum levels of fractalkine and mobilisation of CD34CD45 endothelial progenitor cells in systemic sclerosis. Arthritis Res Ther. 2017; 19(1): 60.
  66. Cui Y, Zheng L, Jiang M, et al. Circulating microparticles in patients with coronary heart disease and its correlation with interleukin-6 and C-reactive protein. Mol Biol Rep. 2013; 40(11): 6437–6442.
  67. Horikawa M, Hasegawa M, Komura K, et al. Abnormal natural killer cell function in systemic sclerosis: altered cytokine production and defective killing activity. J Invest Dermatol. 2005; 125(4): 731–737.
  68. Manetti M, Ibba-Manneschi L, Liakouli V, et al. The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis. Ann Rheum Dis. 2010; 69(3): 598–605.
  69. Terras S, Opitz E, Moritz RKC, et al. Increased serum IL-33 levels may indicate vascular involvement in systemic sclerosis. Ann Rheum Dis. 2013; 72(1): 144–145.
  70. Bertheloot D, Latz E. HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins. Cellular & Molecular Immunology. 2016; 14(1): 43–64.
  71. Zhang YJ, Zhang Q, Yang GJ, et al. Elevated serum levels of interleukin-1β and interleukin-33 in patients with systemic sclerosis in Chinese population. Z Rheumatol. 2018; 77(2): 151–159.
  72. Terras S, Opitz E, Moritz RKC, et al. Increased serum IL-33 levels may indicate vascular involvement in systemic sclerosis. Ann Rheum Dis. 2013; 72(1): 144–145.
  73. Yanaba K, Yoshizaki A, Asano Y, et al. Serum IL-33 levels are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. Clin Rheumatol. 2011; 30(6): 825–830.
  74. Hayakawa H, Hayakawa M, Tominaga SI. Soluble ST2 suppresses the effect of interleukin-33 on lung type 2 innate lymphoid cells. Biochem Biophys Rep. 2016; 5: 401–407.
  75. Vettori S, Cuomo G, Iudici M, et al. Early systemic sclerosis: serum profiling of factors involved in endothelial, T-cell, and fibroblast interplay is marked by elevated interleukin-33 levels. J Clin Immunol. 2014; 34(6): 663–668.
  76. Striz I. Cytokines of the IL-1 family: recognized targets in chronic inflammation underrated in organ transplantations. Clin Sci (Lond). 2017; 131(17): 2241–2256.
  77. Aida-Yasuoka K, Peoples C, Yasuoka H, et al. Estradiol promotes the development of a fibrotic phenotype and is increased in the serum of patients with systemic sclerosis. Arthritis Res Ther. 2013; 15(1): R10.
  78. Racanelli V, Prete M, Musaraj G, et al. Autoantibodies to intracellular antigens: generation and pathogenetic role. Autoimmun Rev. 2011; 10(8): 503–508.
  79. Chen W, Frank M, Jin W, et al. TGF-β Released by Apoptotic T Cells Contributes to an Immunosuppressive Milieu. Immunity. 2001; 14(6): 715–725.