Skip to main content
SpringerLink
Log in

Autoimmunity in Systemic Sclerosis: Overview

  • Chapter
  • First Online:
Systemic Sclerosis

  • 964 Accesses

Abstract

Systemic sclerosis (SSc) is characterized by autoimmunity and tissue fibrosis of several organs. Although the pathogenic relationship between systemic autoimmunity and the clinical manifestations of SSc remains unknown, SSc patients display a variety of abnormal immune activation including the production of disease-specific autoantibodies. Previous studies have demonstrated that immune cells, mainly including T and B cells, play a critical role in systemic autoimmunity and disease expression, though the role of autoimmunity in generating the clinical and pathologic phenotype in SSc remains uncertain. Activation and polarization of T cells can contribute to a profibrotic environment. Oligoclonal T cells, preferentially producing type 2 cytokines, exist in affected tissues and peripheral blood early in the disease course and seem to be participating in the establishment of fibrosis. Similarly, SSc patients have B cell abnormalities characterized by chronic hyper-reactivity of memory B cells, possibly due to CD19 overexpression. CD19 is a crucial regulator of B cell activation. Recent studies demonstrated B cells from SSc patients show an upregulated CD19 signaling pathway that induces SSc-specific autoantibody production in SSc mouse models. Although distinct subsets of autoantibodies do not have a proven pathogenic role, they are selectively associated with unique disease manifestations. Collectively, autoimmunity in SSc is most likely participating in SSc-specific tissue damage. If revealed the mechanisms of autoimmunity in SSc, these knowledge could lead to new disease-modifying therapeutic strategies directed at SSc-specific immune effector pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger Jr TA, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15:202–5.

    CAS  PubMed  Google Scholar 

  2. Furst DE, Clements PJ. Hypothesis for the pathogenesis of systemic sclerosis. J Rheumatol. 1997;24 suppl 48:53–7.

    Google Scholar 

  3. Yoshizaki A, Yanaba K, Iwata Y, Komura K, Ogawa A, Muroi E, et al. Elevated serum interleukin-27 levels in patients with systemic sclerosis: association with T cell, B cell and fibroblast activation. Ann Rheum Dis. 2011;70(1):194–200. doi:10.1136/ard.2009.121053.

    Article  CAS  PubMed  Google Scholar 

  4. Yoshizaki A, Komura K, Iwata Y, Ogawa F, Hara T, Muroi E, et al. Clinical significance of serum HMGB-1 and sRAGE levels in systemic sclerosis: association with disease severity. J Clin Immunol. 2009;29(2):180–9. doi:10.1007/s10875-008-9252-x.

    Article  CAS  PubMed  Google Scholar 

  5. Okano Y. Antinuclear antibody in systemic sclerosis (scleroderma). Rheum Dis Clin N Am. 1996;22(4):709–35.

    Article  CAS  Google Scholar 

  6. Sakkas LI, Chikanza IC, Platsoucas CD. Mechanisms of disease: the role of immune cells in the pathogenesis of systemic sclerosis. Nat Clin Pract Rheumatol. 2006;2(12):679–85.

    Article  CAS  PubMed  Google Scholar 

  7. Kumar PS, Sagar VR. Drying kinetics and physico-chemical characteristics of Osmo-dehydrated Mango, Guava and Aonla under different drying conditions. J Food Sci Technol. 2014;51(8):1540–6. doi:10.1007/s13197-012-0658-3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Sato S, Fujimoto M, Hasegawa M, Takehara K, Tedder TF. Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis. Mol Immunol. 2004;41(12):1123–33. doi:10.1016/j.molimm.2004.06.025.

    Article  CAS  PubMed  Google Scholar 

  9. Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol. 2001;2(9):764–6. doi:10.1038/ni0901-764. ni0901-764 [pii].

    Article  CAS  PubMed  Google Scholar 

  10. Whitfield ML, Finlay DR, Murray JI, Troyanskaya OG, Chi JT, Pergamenschikov A, et al. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A. 2003;100(21):12319–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol. 1992;166(3):255–63.

    Article  CAS  PubMed  Google Scholar 

  12. Kahari VM, Sandberg M, Kalimo H, Vuorio T, Vuorio E. Identification of fibroblasts responsible for increased collagen production in localized scleroderma by in situ hybridization. J Invest Dermatol. 1988;90(5):664–70.

    Article  CAS  PubMed  Google Scholar 

  13. Scharffetter K, Lankat-Buttgereit B, Krieg T. Localization of collagen mRNA in normal and scleroderma skin by in-situ hybridization. Eur J Clin Invest. 1988;18:9–17.

    Article  CAS  PubMed  Google Scholar 

  14. Hoffmann KF, McCarty TC, Segal DH, Chiaramonte M, Hesse M, Davis EM, et al. Disease fingerprinting with cDNA microarrays reveals distinct gene expression profiles in lethal type 1 and type 2 cytokine-mediated inflammatory reactions. FASEB J. 2001;15(13):2545–7. doi:10.1096/fj.01-0306fje.

    CAS  PubMed  Google Scholar 

  15. Higashi-Kuwata N, Makino T, Inoue Y, Takeya M, Ihn H. Alternatively activated macrophages (M2 macrophages) in the skin of patient with localized scleroderma. Exp Dermatol. 2009;18(8):727–9. doi:10.1111/j.1600-0625.2008.00828.x.

    Article  PubMed  Google Scholar 

  16. Sato S, Hasegawa M, Takehara K. Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J Dermatol Sci. 2001;27:140–6.

    Article  CAS  PubMed  Google Scholar 

  17. Bellisai F, Morozzi G, Scaccia F, Chellini F, Simpatico A, Pecetti G, et al. Evaluation of the effect of Bosentan treatment on proinflammatory cytokine serum levels in patients affected by Systemic Sclerosis. Int J Immunopathol Pharmacol. 2011;24(1):261–4.

    CAS  PubMed  Google Scholar 

  18. Duncan MR, Berman B. Stimulation of collagen and glycosaminoglycan production in cultured human adult dermal fibroblasts by recombinant human interleukin 6. J Invest Dermatol. 1991;97(4):686–92.

    Article  CAS  PubMed  Google Scholar 

  19. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004;4(8):583–94. doi:10.1038/nri1412.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Hasegawa M, Fujimoto M, Takehara K, Sato S. Pathogenesis of systemic sclerosis: altered B cell function is the key linking systemic autoimmunity and tissue fibrosis. J Dermatol Sci. 2005;39(1):1–7. doi:10.1016/j.jdermsci.2005.03.013.

    Article  CAS  PubMed  Google Scholar 

  21. Hasegawa M, Fujimoto M, Kikuchi K, Takehara K. 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.

    CAS  PubMed  Google Scholar 

  22. Hasegawa M, Sato S, Fujimoto M, Ihn H, Kikuchi K, Takehara K. Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis. J Rheumatol. 1998;25:308–13.

    CAS  PubMed  Google Scholar 

  23. Needleman BW, Wigley FM, Stair RW. Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor-a, and interferon-g levels in sera from patients with scleroderma. Arthritis Rheum. 1992;35(1):67–72.

    Article  CAS  PubMed  Google Scholar 

  24. Hasegawa M, Sato S, Ihn H, Takehara K. 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. 1999;38(7):612–7.

    Article  CAS  PubMed  Google Scholar 

  25. Mavalia C, Scaletti C, Romagnani P, Carossino AM, Pignone A, Emmi L, et al. Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis. Am J Pathol. 1997;151(6):1751–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  26. Kopf M, Le Gros G, Bachmann M, Lamers MC, Bluethmann H, Kohler G. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature. 1993;362(6417):245–8. doi:10.1038/362245a0.

    Article  CAS  PubMed  Google Scholar 

  27. Sharma SK, MacLean JA, Pinto C, Kradin RL. The effect of an anti-CD3 monoclonal antibody on bleomycin-induced lymphokine production and lung injury. Am J Respir Crit Care Med. 1996;154(1):193–200. doi:10.1164/ajrccm.154.1.8680680.

    Article  CAS  PubMed  Google Scholar 

  28. Salmon-Ehr V, Serpier H, Nawrocki B, Gillery P, Clavel C, Kalis B, et al. Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblast cultures. Potential role in fibrosis. Arch Dermatol. 1996;132(7):802–6.

    Article  CAS  PubMed  Google Scholar 

  29. Postlethwaite AE, Holness MA, Katai H, Raghow R. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J Clin Invest. 1992;90(4):1479–85. doi:10.1172/JCI116015.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Ong C, Wong C, Roberts CR, Teh HS, Jirik FR. Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur J Immunol. 1998;28(9):2619–29.

    Article  CAS  PubMed  Google Scholar 

  31. Huaux F, Liu T, McGarry B, Ullenbruch M, Phan SH. Dual roles of IL-4 in lung injury and fibrosis. J Immunol. 2003;170(4):2083–92.

    Article  CAS  PubMed  Google Scholar 

  32. Aversa G, Punnonen J, Cocks BG, de Waal Malefyt R, Vega Jr F, Zurawski SM, et al. An interleukin 4 (IL-4) mutant protein inhibits both IL-4 or IL-13-induced human immunoglobulin G4 (IgG4) and IgE synthesis and B cell proliferation: support for a common component shared by IL-4 and IL-13 receptors. J Exp Med. 1993;178(6):2213–8.

    Article  CAS  PubMed  Google Scholar 

  33. Fallon PG, Richardson EJ, McKenzie GJ, McKenzie AN. Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J Immunol. 2000;164(5):2585–91.

    Article  CAS  PubMed  Google Scholar 

  34. Rankin AL, Mumm JB, Murphy E, Turner S, Yu N, McClanahan TK, et al. IL-33 induces IL-13-dependent cutaneous fibrosis. J Immunol. 2010;184(3):1526–35. doi:10.4049/jimmunol.0903306.

    Article  CAS  PubMed  Google Scholar 

  35. Kantor TV, Friberg D, Medsger Jr TA, Buckingham RB, Whiteside TL. Cytokine production and serum levels in systemic sclerosis. Clin Immunol Immunopathol. 1992;65(3):278–85.

    Article  CAS  PubMed  Google Scholar 

  36. Fujii H, Hasegawa M, Takehara K, Mukaida N, Sato S. Abnormal expression of intracellular cytokines and chemokine receptors in peripheral blood T lymphocytes from patients with systemic sclerosis. Clin Exp Immunol. 2002;130(3):548–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Valentini G, Baroni A, Esposito K, Naclerio C, Buommino E, Farzati A, et al. Peripheral blood T lymphocytes from systemic sclerosis patients show both Th1 and Th2 activation. J Clin Immunol. 2001;21(3):210–7.

    Article  CAS  PubMed  Google Scholar 

  38. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517. doi:10.1146/annurev.immunol.021908.132710.

    Article  CAS  PubMed  Google Scholar 

  39. Hemdan NY, Birkenmeier G, Wichmann G, Abu El-Saad AM, Krieger T, Conrad K, et al. Interleukin-17-producing T helper cells in autoimmunity. Autoimmun Rev. 2010;9(11):785–92. doi:10.1016/j.autrev.2010.07.003.

    Article  CAS  PubMed  Google Scholar 

  40. 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. doi:10.1186/ar3486.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. 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. doi:10.1002/1529-0131(200011)43:11<2455::AID-ANR12>3.0.CO;2-K.

    Article  CAS  PubMed  Google Scholar 

  42. 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. doi:S0923-1811(08)00043-1 [pii]. 10.1016/j.jdermsci.2008.01.001.

    Article  CAS  PubMed  Google Scholar 

  43. 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. doi:10.1002/art.30159.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Nakashima T, Jinnin M, Yamane K, Honda N, Kajihara I, Makino T, et al. Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J Immunol. 2012;188(8):3573–83. doi:10.4049/jimmunol.1100591.

    Article  CAS  PubMed  Google Scholar 

  45. Mathian A, Parizot C, Dorgham K, Trad S, Arnaud L, Larsen M, et al. Activated and resting regulatory T cell exhaustion concurs with high levels of interleukin-22 expression in systemic sclerosis lesions. Ann Rheum Dis. 2012;71(7):1227–34. doi:10.1136/annrheumdis-2011-200709.

    Article  CAS  PubMed  Google Scholar 

  46. Brembilla NC, Chizzolini C. T cell abnormalities in systemic sclerosis with a focus on Th17 cells. Eur Cytokine Netw. 2012;23(4):128–39. doi:10.1684/ecn.2013.0325.

    CAS  PubMed  Google Scholar 

  47. Fenoglio D, Battaglia F, Parodi A, Stringara S, Negrini S, Panico N, et al. Alteration of Th17 and Treg cell subpopulations co-exist in patients affected with systemic sclerosis. Clin Immunol. 2011;139(3):249–57. doi:10.1016/j.clim.2011.01.013.

    Article  CAS  PubMed  Google Scholar 

  48. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911. doi:10.1016/j.immuni.2009.03.019.

    Article  CAS  PubMed  Google Scholar 

  49. Banica L, Besliu A, Pistol G, Stavaru C, Ionescu R, Forsea AM, et al. Quantification and molecular characterization of regulatory T cells in connective tissue diseases. Autoimmunity. 2009;42(1):41–9. doi:10.1080/08916930802282651.

    Article  CAS  PubMed  Google Scholar 

  50. Antiga E, Quaglino P, Bellandi S, Volpi W, Del Bianco E, Comessatti A, et al. Regulatory T cells in the skin lesions and blood of patients with systemic sclerosis and morphoea. Br J Dermatol. 2010;162(5):1056–63. doi:10.1111/j.1365-2133.2010.09633.x.

    Article  CAS  PubMed  Google Scholar 

  51. Koenen HJ, Smeets RL, Vink PM, van Rijssen E, Boots AM, Joosten I. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood. 2008;112(6):2340–52. doi:10.1182/blood-2008-01-133967.

    Article  CAS  PubMed  Google Scholar 

  52. Osorio F, LeibundGut-Landmann S, Lochner M, Lahl K, Sparwasser T, Eberl G, et al. DC activated via dectin-1 convert Treg into IL-17 producers. Eur J Immunol. 2008;38(12):3274–81. doi:10.1002/eji.200838950.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008;29(1):44–56. doi:10.1016/j.immuni.2008.05.007.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Beriou G, Costantino CM, Ashley CW, Yang L, Kuchroo VK, Baecher-Allan C, et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood. 2009;113(18):4240–9. doi:10.1182/blood-2008-10-183251.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol. 2009;10(8):857–63. doi:10.1038/ni.1767.

    Article  CAS  PubMed  Google Scholar 

  56. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol. 2009;10(8):864–71. doi:10.1038/ni.1770.

    Article  CAS  PubMed  Google Scholar 

  57. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature. 2008;453(7191):106–9. doi:10.1038/nature06881.

    Article  CAS  PubMed  Google Scholar 

  58. Wolk K, Witte E, Witte K, Warszawska K, Sabat R. Biology of interleukin-22. Semin Immunopathol. 2010;32(1):17–31. doi:10.1007/s00281-009-0188-x.

    Article  CAS  PubMed  Google Scholar 

  59. Zhang N, Pan HF, Ye DQ. Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol Cell Biochem. 2011;353(1–2):41–6. doi:10.1007/s11010-011-0772-y.

    Article  CAS  PubMed  Google Scholar 

  60. Sonnenberg GF, Nair MG, Kirn TJ, Zaph C, Fouser LA, Artis D. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J Exp Med. 2010;207(6):1293–305. doi:10.1084/jem.20092054.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med. 2001;345(5):340–50.

    Article  CAS  PubMed  Google Scholar 

  62. Tedder TF, Poe JC, Fujimoto M, Haas KM, Sato S. The CD19-CD21 signal transduction complex of B lymphocytes regulates the balance between health and autoimmune disease: systemic sclerosis as a model system. Curr Dir Autoimmun. 2005;8:55–90.

    Article  CAS  PubMed  Google Scholar 

  63. Matsushita T, Hasegawa M, Yanaba K, Kodera M, Takehara K, Sato S. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum. 2006;54(1):192–201.

    Article  CAS  PubMed  Google Scholar 

  64. Lafyatis R, Kissin E, York M, Farina G, Viger K, Fritzler MJ, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2009;60(2):578–83. doi:10.1002/art.24249.

    Article  PubMed Central  PubMed  Google Scholar 

  65. Jordan S, Distler JH, Maurer B, Huscher D, van Laar JM, Allanore Y, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2013-204522.

    PubMed Central  Google Scholar 

  66. Goodnow CC. Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires. Proc Natl Acad Sci U S A. 1996;93:2264–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Tedder TF. Introduction: response-regulators of B lymphocyte signaling thresholds provide a context for antigen receptor signal transduction. Semin Immunol. 1998;10:259–65.

    Article  CAS  PubMed  Google Scholar 

  68. Tedder TF, Inaoki M, Sato S. The CD19/21 complex regulates signal transduction thresholds governing humoral immunity and autoimmunity. Immunity. 1997;6:107–18.

    Article  CAS  PubMed  Google Scholar 

  69. Bolland S, Ravetch JV. Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity. 2000;13(2):277–85.

    Article  CAS  PubMed  Google Scholar 

  70. Majeti R, Xu Z, Parslow TG, Olson JL, Daikh DI, Killeen N, et al. An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity. Cell. 2000;103(7):1059–70.

    Article  CAS  PubMed  Google Scholar 

  71. Pan C, Baumgarth N, Parnes JR. CD72-deficient mice reveal nonredundant roles of CD72 in B cell development and activation. Immunity. 1999;11(4):495–506.

    Article  CAS  PubMed  Google Scholar 

  72. Inaoki M, Sato S, Weintraub BC, Goodnow CC, Tedder TF. CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes. J Exp Med. 1997;186:1923–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Sato S, Ono N, Steeber DA, Pisetsky DS, Tedder TF. CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity. J Immunol. 1996;157:4371–8.

    CAS  PubMed  Google Scholar 

  74. Sato S, Miller AS, Inaoki M, Bock CB, Jansen PJ, Tang MLK, et al. CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction: altered signaling in CD22-deficient mice. Immunity. 1996;5:551–62.

    Article  CAS  PubMed  Google Scholar 

  75. O’Keefe TL, Williams GT, Davies SL, Neuberger MS. Hyperresponsive B cells in CD22-deficient mice. Science. 1996;274:798–801.

    Article  PubMed  Google Scholar 

  76. Tedder TF, Zhou L-J, Engel P. The CD19/CD21 signal transduction complex of B lymphocytes. Immunol Today. 1994;15:437–42.

    Article  CAS  PubMed  Google Scholar 

  77. Fujimoto M, Poe JC, Hasegawa M, Tedder TF. CD19 regulates intrinsic B lymphocyte signal transduction and activation through a novel mechanism of processive amplification. Immunol Res. 2000;22(2–3):281–98.

    Article  CAS  PubMed  Google Scholar 

  78. Engel P, Zhou L-J, Ord DC, Sato S, Koller B, Tedder TF. Abnormal B lymphocyte development, activation and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity. 1995;3:39–50.

    Article  CAS  PubMed  Google Scholar 

  79. Rickert RC, Rajewsky K, Roes J. Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature. 1995;376:352–5.

    Article  CAS  PubMed  Google Scholar 

  80. Sato S, Steeber DA, Tedder TF. The CD19 signal transduction molecule is a response regulator of B-lymphocyte differentiation. Proc Natl Acad Sci U S A. 1995;92:11558–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Sato S, Steeber DA, Jansen PJ, Tedder TF. CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19. J Immunol. 1997;158:4662–9.

    CAS  PubMed  Google Scholar 

  82. Zhou L-J, Smith HM, Waldschmidt TJ, Schwarting R, Daley J, Tedder TF. Tissue-specific expression of the human CD19 gene in transgenic mice inhibits antigen-independent B lymphocyte development. Mol Cell Biol. 1994;14:3884–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Sato S, Hasegawa M, Fujimoto M, Tedder TF, Takehara K. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol. 2000;165(11):6635–43.

    Article  CAS  PubMed  Google Scholar 

  84. Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum. 2004;50(6):1918–27.

    Article  PubMed  Google Scholar 

  85. Asano N, Fujimoto M, Yazawa N, Shirasawa S, Hasegawa M, Okochi H, et al. B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse. Am J Pathol. 2004;165(2):641–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Famularo G, Giacomelli R, Alesse E, Cifone MG, Morrone S, Boirivant M, et al. Polyclonal B lymphocyte activation in progressive systemic sclerosis. J Clin Lab Immunol. 1989;29(2):59–63.

    CAS  PubMed  Google Scholar 

  87. Fleischmajer R, Perlish JS, Reeves JRT. Cellular infiltrates in scleroderma skin. Arthritis Rheum. 1977;20:975–84.

    Article  CAS  PubMed  Google Scholar 

  88. Fujimoto M, Sato S. B lymphocytes and systemic sclerosis. Curr Opin Rheumatol. 2005;17(6):746–51.

    Article  PubMed  Google Scholar 

  89. Wang J, Watanabe T. Expression and function of Fas during differentiation and activation of B cells. Int Rev Immunol. 1999;18:367–79.

    Article  CAS  PubMed  Google Scholar 

  90. Ogawa F, Shimizu K, Muroi E, Hara T, Hasegawa M, Takehara K, et al. Serum levels of 8-isoprostane, a marker of oxidative stress, are elevated in patients with systemic sclerosis. Rheumatology. 2006;45(7):815–8.

    Article  CAS  PubMed  Google Scholar 

  91. Simonini G, Pignone A, Generini S, Falcini F, Cerinic MM. Emerging potentials for an antioxidant therapy as a new approach to the treatment of systemic sclerosis. Toxicology. 2000;155(1–3):1–15.

    CAS  PubMed  Google Scholar 

  92. Inghilleri S, Morbini P, Oggionni T, Barni S, Fenoglio C. In situ assessment of oxidant and nitrogenic stress in bleomycin pulmonary fibrosis. Histochem Cell Biol. 2006;125(6):661–9.

    Article  CAS  PubMed  Google Scholar 

  93. Manoury B, Nenan S, Leclerc O, Guenon I, Boichot E, Planquois JM, et al. The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis. Respir Res. 2005;6:11–22.

    Article  PubMed Central  PubMed  Google Scholar 

  94. Yoshizaki A, Yanaba K, Ogawa A, Iwata Y, Ogawa F, Takenaka M, et al. The specific free radical scavenger edaravone suppresses fibrosis in the bleomycin-induced and tight skin mouse models of systemic sclerosis. Arthritis Rheum. 2011;63(10):3086–97. doi:10.1002/art.30470.

    Article  CAS  PubMed  Google Scholar 

  95. Mendoza G, Alvarez AI, Pulido MM, Molina AJ, Merino G, Real R, et al. Inhibitory effects of different antioxidants on hyaluronan depolymerization. Carbohydr Res. 2007;342(1):96–102.

    Article  CAS  PubMed  Google Scholar 

  96. Freitas JP, Filipe P, Emerit I, Meunier P, Manso CF, Guerra Rodrigo F. Hyaluronic acid in progressive systemic sclerosis. Dermatology. 1996;192(1):46–9.

    Article  CAS  PubMed  Google Scholar 

  97. Neudecker BA, Stern R, Connolly MK. Aberrant serum hyaluronan and hyaluronidase levels in scleroderma. Br J Dermatol. 2004;150(3):469–76.

    Article  CAS  PubMed  Google Scholar 

  98. Yoshizaki A, Iwata Y, Komura K, Hara T, Ogawa F, Muroi E, et al. Clinical significance of serum hyaluronan levels in systemic sclerosis: association with disease severity. J Rheumatol. 2008;35(9):1825–9. doi:08/13/087 [pii].

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, 113-8655, Bunkyo-ku, Tokyo, Japan

    Ayumi Yoshizaki & Shinichi Sato

Authors
  1. Ayumi Yoshizaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shinichi Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ayumi Yoshizaki .

Editor information

Editors and Affiliations

  1. Department of Dermatology, Kanazawa University, Kanazawa, Ishikawa, Japan

    Kazuhiko Takehara

  2. Department of Dermatology, University of Tsukuba, Tsukuba, Ibaraki, Japan

    Manabu Fujimoto

  3. Department of Allergy and Rheumatology, Nippon Medical School, Tokyo, Tokyo, Japan

    Masataka Kuwana

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Japan

About this chapter

Cite this chapter

Yoshizaki, A., Sato, S. (2016). Autoimmunity in Systemic Sclerosis: Overview. In: Takehara, K., Fujimoto, M., Kuwana, M. (eds) Systemic Sclerosis. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55708-1_2

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-55708-1_2

  • Published:

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-55707-4

  • Online ISBN: 978-4-431-55708-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation