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Scleroderma pp 199–208Cite as

Autoantibodies in Pathogenesis

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Abstract

Scleroderma or systemic sclerosis (SSc) is a systemic autoimmune disease characterized by a distinct, proliferative vasculopathy associated with skin thickening and fibrosis within internal organs and is associated with a unique autoimmune response. While vascular damage is almost universal in scleroderma, disease expression is heterogeneous in terms of phenotypic characteristics and disease course. Nevertheless, clear clinical subtypes can be discerned. The limited cutaneous form of scleroderma (lcSSc) is characterized by skin thickening on the distal limbs, face and neck, and an increased prevalence of isolated pulmonary hypertension and ischemic digital loss. In contrast, the diffuse form of the disease also involves more proximal skin and affects visceral organs, including the lung, heart, gastrointestinal tract, skeletal muscle and kidneys, with attendant negative effects on mortality.

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References

  1. Maes L, Blockmans D, Verschueren P, et al. Anti-PM/Scl-100 and anti-RNA-polymerase III antibodies in scleroderma. Clin Chim Acta. 2010;411(13–14):965–71.

    Article  PubMed  CAS  Google Scholar 

  2. Steen VD, Powell DL, Medsger Jr TA. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum. 1988;31(2):196–203.

    Article  PubMed  CAS  Google Scholar 

  3. Weiner ES, Earnshaw WC, Senecal JL, Bordwell B, Johnson P, Rothfield NF. Clinical associations of anticentromere antibodies and antibodies to topoisomerase I. A study of 355 patients. Arthritis Rheum. 1988;31(3):378–85.

    Article  PubMed  CAS  Google Scholar 

  4. Dick T, Mierau R, Bartz-Bazzanella P, et al. Coexistence of antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis. Ann Rheum Dis. 2002;61(2):121–7.

    Article  PubMed  CAS  Google Scholar 

  5. Harvey GR, McHugh NJ. Serologic abnormalities in systemic sclerosis. Curr Opin Rheumatol. 1999;11(6):495–502.

    Article  PubMed  CAS  Google Scholar 

  6. Rothfield NF. Autoantibodies in scleroderma. Rheum Dis Clin North Am. 1992;18(2):483–98.

    PubMed  CAS  Google Scholar 

  7. Reimer G, Steen VD, Penning CA, Medsger Jr TA, Tan EM. Correlates between autoantibodies to nucleolar antigens and clinical features in patients with systemic sclerosis (scleroderma). Arthritis Rheum. 1988;31(4):525–32.

    Article  PubMed  CAS  Google Scholar 

  8. Henry PA, Atamas SP, Yurovsky VV, Luzina I, Wigley FM, White B. Diversity and plasticity of the anti-DNA topoisomerase I autoantibody response in scleroderma. Arthritis Rheum. 2000;43(12):2733–42.

    Article  PubMed  CAS  Google Scholar 

  9. Kuwana M, Kaburaki J, Mimori T, Kawakami Y, Tojo T. Longitudinal analysis of autoantibody response to topoisomerase I in systemic sclerosis. Arthritis Rheum. 2000;43(5):1074–84.

    Article  PubMed  CAS  Google Scholar 

  10. Sato S, Hamaguchi Y, Hasegawa M, Takehara K. Clinical significance of anti-topoisomerase I antibody levels determined by ELISA in ­systemic sclerosis. Rheumatology (Oxford). 2001;40(10):1135–40.

    Article  CAS  Google Scholar 

  11. Hu PQ, Fertig N, Medsger Jr TA, Wright TM. Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Arthritis Rheum. 2003;48(5):1363–73.

    Article  PubMed  CAS  Google Scholar 

  12. Anthony RM, Ravetch JV. A novel role for the IgG Fc glycan: the anti-inflammatory activity of sialylated IgG Fcs. J Clin Immunol. 2010;30(Suppl 1):S9–14.

    Article  PubMed  CAS  Google Scholar 

  13. Casciola-Rosen L, Nagaraju K, Plotz P, et al. Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy. J Exp Med. 2005;201(4):591–601.

    Article  PubMed  CAS  Google Scholar 

  14. Zhou X, Tan FK, Xiong M, et al. Systemic sclerosis (scleroderma): specific autoantigen genes are selectively overexpressed in scleroderma fibroblasts. J Immunol. 2001;167(12):7126–33.

    PubMed  CAS  Google Scholar 

  15. Howard OM, Dong HF, Yang D, et al. Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. J Exp Med. 2002;196(6):781–91.

    Article  PubMed  CAS  Google Scholar 

  16. Andrade F, Roy S, Nicholson D, Thornberry N, Rosen A, Casciola-Rosen L. Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis. Immunity. 1998;8(4):451–60.

    Article  PubMed  CAS  Google Scholar 

  17. Casciola-Rosen L, Andrade F, Ulanet D, Wong WB, Rosen A. Cleavage by granzyme B is strongly predictive of autoantigen status: implications for initiation of autoimmunity. J Exp Med. 1999;190(6):815–26.

    Article  PubMed  CAS  Google Scholar 

  18. Ulanet DB, Torbenson M, Dang CV, Casciola-Rosen L, Rosen A. Unique conformation of cancer autoantigen B23 in hepatoma: a mechanism for specificity in the autoimmune response. Proc Natl Acad Sci USA. 2003;100(21):12361–6.

    Article  PubMed  CAS  Google Scholar 

  19. Schachna L, Wigley FM, Morris S, Gelber AC, Rosen A, Casciola-Rosen L. Recognition of Granzyme B-generated autoantigen fragments in scleroderma patients with ischemic digital loss. Arthritis Rheum. 2002;46(7):1873–84.

    Article  PubMed  CAS  Google Scholar 

  20. Ulanet DB, Flavahan NA, Casciola-Rosen L, Rosen A. Selective cleavage of nucleolar autoantigen B23 by granzyme B in differentiated vascular smooth muscle cells: insights into the association of specific autoantibodies with distinct disease phenotypes. Arthritis Rheum. 2004;50(1):233–41.

    Article  PubMed  CAS  Google Scholar 

  21. Rosenthal AK, McLaughlin JK, Linet MS, Persson I. Scleroderma and malignancy: an epidemiological study. Ann Rheum Dis. 1993;52(7):531–3.

    Article  PubMed  CAS  Google Scholar 

  22. Rosenthal AK, McLaughlin JK, Gridley G, Nyren O. Incidence of cancer among patients with systemic sclerosis. Cancer. 1995;76(5):910–4.

    Article  PubMed  CAS  Google Scholar 

  23. Shah AA, Rosen A, Hummers L, Wigley F, Casciola-Rosen L. Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies. Arthritis Rheum. 2010;62(9):2787–95.

    Article  PubMed  Google Scholar 

  24. Henault J, Tremblay M, Clement I, Raymond Y, Senecal JL. Direct binding of anti-DNA topoisomerase I autoantibodies to the cell surface of fibroblasts in patients with systemic sclerosis. Arthritis Rheum. 2004;50(10):3265–74.

    Article  PubMed  CAS  Google Scholar 

  25. Henault J, Robitaille G, Senecal JL, Raymond Y. DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemic sclerosis patients. Arthritis Rheum. 2006;54(3):963–73.

    Article  PubMed  CAS  Google Scholar 

  26. Robitaille G, Christin MS, Clement I, Senecal JL, Raymond Y. Nuclear autoantigen CENP-B transactivation of the epidermal growth factor receptor via chemokine receptor 3 in vascular smooth muscle cells. Arthritis Rheum. 2009;60(9):2805–16.

    Article  PubMed  CAS  Google Scholar 

  27. 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):2163–73.

    Article  PubMed  CAS  Google Scholar 

  28. 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.

    PubMed  CAS  Google Scholar 

  29. Sgonc R. The vascular perspective of systemic sclerosis: of chickens, mice and men. Int Arch Allergy Immunol. 1999;120(3):169–76.

    Article  PubMed  CAS  Google Scholar 

  30. Jimenez SA, Christner PJ. Murine animal models of systemic sclerosis. Curr Opin Rheumatol. 2002;14(6):671–80.

    Article  PubMed  CAS  Google Scholar 

  31. Saito E, Fujimoto M, Hasegawa M, et al. CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J Clin Invest. 2002;109(11):1453–62.

    PubMed  CAS  Google Scholar 

  32. Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol. 2001;1(2):147–53.

    Article  PubMed  CAS  Google Scholar 

  33. Renaudineau Y, Revelen R, Levy Y, et al. Anti-endothelial cell antibodies in systemic sclerosis. Clin Diagn Lab Immunol. 1999;6(2):156–60.

    PubMed  CAS  Google Scholar 

  34. Worda M, Sgonc R, Dietrich H, et al. In vivo analysis of the apoptosis-inducing effect of anti-endothelial cell antibodies in systemic sclerosis by the chorionallantoic membrane assay. Arthritis Rheum. 2003;48(9):2605–14.

    Article  PubMed  CAS  Google Scholar 

  35. Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest. 1996;98(3):785–92.

    Article  PubMed  CAS  Google Scholar 

  36. Chizzolini C, Raschi E, Rezzonico R, et al. Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis. Arthritis Rheum. 2002;46(6):1602–13.

    Article  PubMed  CAS  Google Scholar 

  37. Fineschi S, Goffin L, Rezzonico R, et al. Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll-like receptor 4. Arthritis Rheum. 2008;58(12):3913–23.

    Article  PubMed  CAS  Google Scholar 

  38. Ronda N, Raschi E, Testoni C, et al. Anti-fibroblast antibodies in systemic sclerosis. Isr Med Assoc J. 2002;4(11 Suppl):858–64.

    PubMed  CAS  Google Scholar 

  39. Ronda N, Gatti R, Giacosa R, et al. Antifibroblast antibodies from systemic sclerosis patients are internalized by fibroblasts via a caveolin-linked pathway. Arthritis Rheum. 2002;46(6):1595–601.

    Article  PubMed  CAS  Google Scholar 

  40. Tamby MC, Humbert M, Guilpain P, et al. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J. 2006;28(4):799–807.

    Article  PubMed  CAS  Google Scholar 

  41. Terrier B, Tamby MC, Camoin L, et al. Identification of target antigens of antifibroblast antibodies in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;177(10):1128–34.

    Article  PubMed  CAS  Google Scholar 

  42. Kodera T, Tan FK, Sasaki T, Arnett FC, Bona CA. Association of 5’-untranslated region of the fibrillin-1 gene with Japanese scleroderma. Gene. 2002;297(1–2):61–7.

    Article  PubMed  CAS  Google Scholar 

  43. Tan FK, Arnett FC, Antohi S, et al. Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin-1, in patients with scleroderma and other connective tissue diseases. J Immunol. 1999;163(2):1066–72.

    PubMed  CAS  Google Scholar 

  44. Tan FK, Arnett FC, Reveille JD, et al. Autoantibodies to fibrillin 1 in systemic sclerosis: ethnic differences in antigen recognition and lack of correlation with specific clinical features or HLA alleles. Arthritis Rheum. 2000;43(11):2464–71.

    Article  PubMed  CAS  Google Scholar 

  45. Tan FK, Wang N, Kuwana M, et al. Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations. Arthritis Rheum. 2001;44(4):893–901.

    Article  PubMed  CAS  Google Scholar 

  46. Brinckmann J, Hunzelmann N, El-Hallous E, et al. Absence of autoantibodies against correctly folded recombinant fibrillin-1 protein in systemic sclerosis patients. Arthritis Res Ther. 2005;7(6):R1221–6.

    Article  PubMed  CAS  Google Scholar 

  47. Wallis DD, Tan FK, Kielty CM, Kimball MD, Arnett FC, Milewicz DM. Abnormalities in fibrillin 1-containing microfibrils in dermal fibroblast cultures from patients with systemic sclerosis (scleroderma). Arthritis Rheum. 2001;44(8):1855–64.

    Article  PubMed  CAS  Google Scholar 

  48. Yuan X, Downing AK, Knott V, Handford PA. Solution structure of the transforming growth factor beta-binding protein-like module, a domain associated with matrix fibrils. EMBO J. 1997;16(22):6659–66.

    Article  PubMed  CAS  Google Scholar 

  49. Loeys BL, Gerber EE, Riegert-Johnson D, et al. Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci Transl Med. 2010;2(23):23ra20.

    Article  PubMed  CAS  Google Scholar 

  50. Sato S, Hayakawa I, Hasegawa M, Fujimoto M, Takehara K. Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis. J Invest Dermatol. 2003;120(4):542–7.

    Article  PubMed  CAS  Google Scholar 

  51. Nishijima C, Hayakawa I, Matsushita T, et al. Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis. Clin Exp Immunol. 2004;138(2):357–63.

    Article  PubMed  CAS  Google Scholar 

  52. 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.

    Article  PubMed  CAS  Google Scholar 

  53. Classen JF, Henrohn D, Rorsman F, et al. Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. Arthritis Rheum. 2009;60(4):1137–44.

    Article  PubMed  CAS  Google Scholar 

  54. Loizos N, Lariccia L, Weiner J, et al. Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor alpha in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum. 2009;60(4):1145–51.

    Article  PubMed  CAS  Google Scholar 

  55. Goldblatt F, Gordon TP, Waterman SA. Antibody-mediated gastrointestinal dysmotility in scleroderma. Gastroenterology. 2002;123(4):1144–50.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Kimberly Doering BS & Antony Rosen MB, ChB, BSc (Hons)

Authors
  1. Kimberly Doering BS
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  2. Antony Rosen MB, ChB, BSc (Hons)
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Correspondence to Antony Rosen MB, ChB, BSc (Hons) .

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Editors and Affiliations

  1. Feinberg School of Medicine, Northwestern University, E. Huron Street 240, Chicago, 60611-2909, Illinois, USA

    John Varga

  2. Royal Free and University College, Medical School, University College London, Rowland Street, London, NW3 2PF, United Kingdom

    Christopher P. Denton

  3. School of Medicine, Div. Rheumatology, Johns Hopkins University, Eastern Avenue 5200, Baltimore, 21224, Maryland, USA

    Fredrick M. Wigley

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Doering, K., Rosen, A. (2012). Autoantibodies in Pathogenesis. In: Varga, J., Denton, C., Wigley, F. (eds) Scleroderma. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-5774-0_17

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  • DOI: https://doi.org/10.1007/978-1-4419-5774-0_17

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