Pathophysiology of scleroderma: an update
U.-F. Haustein,
U. Anderegg,
Corresponding Author
U.-F. Haustein
University of Leipzig, Department of Dermatology, Liebigstrasse 21, 04103 Leipzig, Germany
*Corresponding author. Tel.: +49 341 9718600; fax: +49 341 9718609.Search for more papers by this authorU. Anderegg
University of Leipzig, Department of Dermatology, Liebigstrasse 21, 04103 Leipzig, Germany
Search for more papers by this authorU.-F. Haustein,
U. Anderegg,
Corresponding Author
U.-F. Haustein
University of Leipzig, Department of Dermatology, Liebigstrasse 21, 04103 Leipzig, Germany
*Corresponding author. Tel.: +49 341 9718600; fax: +49 341 9718609.Search for more papers by this authorU. Anderegg
University of Leipzig, Department of Dermatology, Liebigstrasse 21, 04103 Leipzig, Germany
Search for more papers by this authorAbstract
Objectives To review the pathophysiological background of systemic sclerosis in relation to the main, components involved: microvascular system, immunological system and fibroblasts of the connective tissue.
Background Although many particular aspects of the pathophysiology of systemic sclerosis have been investigated in recent years, the complexity of the pathogenesis and the important links between the components involved remain unclear.
Methods Literature review.
Results and conclusion Scleroderma is a connective tissue disorder resulting in a progressive fibrosis of skin and internal organs. The genetic background is not clear. The microvascular system is one of the first targets involved (damage of capillaries, enhanced expression of adhesion molecules interacting with lymphocytes, perivascular infiltrates as starting points for tissue fibrosis). The immune system is unbalanced (selection of T-cell subpopulations, elevated serum levels of several cytokines, occurrence of autoantigens to topoisomerase I, centromeric proteins and RNA polymerases). As far as autoimmunity is concerned the triggering autoantigen is still unknown. Development of connective tissue fibrosis is prominent (sub-populations of fibroblasts with disturbed regulation of collagen turnover by TGF-β, CTGF and collagen receptors (α1β1, α2β2)). Investigation of pathophysiology of scleroderma is effected by monitoring the serum levels for soluble mediators, by cell culture studies of affected and non-affected fibroblasts and EC, by studying environmentally induced forms of scleroderma and by studies using animal models.
References
- 1 LeRoy EC, Black CM, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988; 15: 202–205.
- 2 Black CM. The aetiopathogenesis of systemic sclerosis. J Intern Med 1993; 234: 3–8.
- 3 Kahari VM. Activation of dermal connective tissue in scleroderma. Ann Intern Med 1994; 25: 511–518.
- 4 Jimenez S, Feldman G, Bashey R, et al. Co-ordinate disease in the expression of type II and type III collagen genes in progressive systemic sclerosis fibroblasts. Biochem J 1986; 237: 837–843.
- 5 Haustein UF, Herrmann K. Environmental scleroderma. Clin Dermatol 1994; 12: 467–473.
- 6 Black CM, Welsh KI. Genetics of scleroderma. Clin Dermatol 1994; 12: 337–347.
- 7 Morel PA, Chang HJ, Wilson JW, et al. Severe systemic sclerosis with anti-topoisomerase I antibodies Is associated with an HLA-DRw 11 allele. Human Immunol 1994; 40: 101–110.
- 8 Laing TJ, Gillespie BW, Toth MB, et al. Racial differences in scleroderma among woman in Michigan. Arthritis Rheum 1997; 40: 734–742.
- 9 Takeuchi F, Kuwata S, Nakano K, et al. Association of TAP1 and TAP2 with systemic sclerosis in Japanese. Clin Exp Rheumatol 1996; 14: 513–521.
- 10 Vargas-Alarcón G, Granados J, Ibañez de Kasep, G, et al. Association of HLA-DR5 (DR11) with systemic sclerosis (scleroderma) in Mexican patients. Clin Exp Rheumatol 1995; 13: 11–16.
- 11 Reveille JD. Molecular genetics of systemic sclerosis. Curr Opin Rheumatol 1995; 7: 522–528.
- 12 Arnett FC. HLA and autoimmunity in scleroderma (systemic sclerosis). Int Rev Immunol 1995; 12: 107–128.
- 13 Wolff DJ, White Needleman B, Wasserman SS, et al. Spontaneous and clastogen induced chromosomal breakage in scleroderma. J Rheumatol 1991; 18: 837–840.
- 14 Maricq H. Comparison of quantitative and semiquantitative estimates of nailfold capillary abnormalities in scleroderma spectrum disorders. Microvasc Res 1986; 32: 271–276.
- 15 Scheja A, Akesson A, Niewierowicz I, et al. Computer based quantitative analysis of capillary abnormalities in systemic sclerosis and its relation to plasma concentration of von Will-ebrand factor. Ann Rheum Dis 1996; 55: 52–56.
- 16 Kahaleh MB. The vascular endothelium in scleroderma. Int Rev Immunol 1995; 12: 227–245.
- 17 Carvalho D, Savage COS, Black CM, et al. IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro. J Clin Invest 1996; 97: 111–119.
- 18 Salojin KV, LeTonquèze M, Saraux A, et al. Anticndothelial cell antibodies: useful markers of systemic sclerosis. Am J Med 1997; 102: 178–185.
- 19 Stein CM, Tanner SB, Awad JA, et al. Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma. Arthritis Rheum 1996; 39: 1146–1150.
- 20 Murrell DF. A radical proposal for the pathogenesis of scleroderma. J Am Acad Dermatol 1993; 28: 78–85.
- 21 Herrick AL, Illingworth K, Blann A, et al. Von Willebrand factor, thrombomodulin, thromboxane, β-thromboglobulin and markers of fibrinolysis in primary Raynaud's phenomenon and systemic sclerosis. Ann Rheum Dis 1996; 55: 122–127.
- 22 Sgonc R, Gruschwitz MS, Dietrich H, et al. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest 1996; 98: 785–792.
- 23 Haustein UF, Scheel H, Siegemund A, et al. Parameter der Gefäßfunktion bei der progressiven Sklerodermie. Hautarzt 1993; 44: 717–722.
- 24 Sollberg S, Peltonen J, Uitto J, Jimenez SA. Elevated expression of β1 and β2 integrins, intercellular adhesion molecule I, and endothelial leukocyte adhesion molecule I in the skin of patients with systemic sclerosis of recent onset. Arthritis Rheum 1992; 35: 290–298.
- 25 Prescott RJ, Freemont AJ, Jones CJ, et al. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992; 166: 255–263.
- 26 Gruschwitz MS, Hornstein OP, von den Driesch, P. Correlation of soluble adhesion molecules in the peripheral blood of scleroderma patients with their in situ expression and with disease activity. Arthritis Rheum 1995; 18: 184–189.
- 27 Fritzler MJ, Hart DA. Altered regulation of fibrolysis in scleroderma and potential for thrombolytic therapy. In: P Glas-Greenwalt, editor. Fibrinolysis in disease - molecular and hemovascular aspects of fibrinolysis. Boca Raton , FL : CRC Press, 1996; 35: 245–252.
- 28 Venneker GT, van den Hoogen, FHJ, Boerbooms AMT, et al. Aberrant expression of membrane cofactor protein and decay-accelerating factor in the endothelium of patients with systemic sclerosis. Labor Invest 1994; 70: 830–835.
- 29 Needleman-White B, Wigley FM, Stair RW. Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor α, and interferon-γ levels in sera from patients with scleroderma. Arthritis Rheum 1992; 35: 67–72.
- 30 Yurovsky VV, The repertoire of T-cell receptors in systemic sclerosis. Crit Rev Immunol 1995; 15: 155–165.
- 31 White B. Immunologic aspects of scleroderma. Curr Opin Rheumatol 1995; 7: 541–545.
- 32 Fritzler MJ. Autoantibodies in scleroderma. J Dermatol 1993; 20: 257–268.
- 33 Jimenez SA, Batuman O. Immunopathogenesis of systemic sclerosis: possible role of retroviruses. Autoimmunity 1993; 16: 225–233.
- 34 Haustein UF, Pustowoit B, Krusche U, et al. Antibodies to retrovirus proteins in scleroderma. Acta Dermato-Venereol (Stockh) 1993; 73: 116–118.
- 35 Jaffee BD, Claman HN. Chronic graft versus host disease as a model for scleroderma, I. Description of the model systems. Cell Immunol 1983; 77: 1–12.
- 36 LeRoy EC. The control of fibrosis in systemic sclerosis: a strategy involving extracellular matrix, cytokines, and growth factors. J Dermatol 1994; 21: 1–4.
- 37 Postlethwaite AE. Connective tissue metabolism including cytokine in scleroderma. Curr Opin Rheumatol 1995; 7: 535–540.
- 38 Feghali CA, Bost KL, Boulware DW, et al. Control of IL-6 expression-and response in fibroblasts from patients with systemic sclerosis. Autoimmunity 1994; 17: 309–318.
- 39 Abraham D, Lupoli S, McWhirter A, et al. Expression and function of surface antigens on scleroderma fibroblasts. Arthritis Rheum 1991, 34: 1164–1172.
- 40 Gruschwitz MS, Vieth G. Up-regulation of class II major histocompatibility complex and intercellular adhesion molecule 1 expression on scleroderma fibroblasts and endothelial cell by interferon-γ and tumor necrosis factor α in the early disease stage. Arthritis Rheum 1997; 40, 540–550.
- 41 Kähäri VM, Sandberg M, Kalimo H, et al. Identification of fibroblasts responsible for increased collagen production in localized scleroderma by in situ hybridization. J Invest Dermatol 1988; 90: 664–670.
- 42 Kahaleh MB, Yin T. Enhanced expression of high-affinity interleukin-2 receptors in scleroderma: possible role for IL-6. Clin Immunol Immunopathol 1992; 62: 97–102.
- 43 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: 328–332.
- 44 Bruns M, Hofmann, C, Herrmann K, Haustein UF. Serum levels of soluble IL-2 receptor, soluble ICAM-1, TNF-alpha, interleukin-4 and interleukin-6 in scleroderma. J Eur Acad Dermatol Venereol 1997; 8: 222–228.
- 45 Fagundus DM, LeRoy EC. Cytokines and systemic sclerosis. Clin Dermatol 1994; 12: 407–417.
- 46 Higley H, Persichitte K, Chu S, et al. Immunocytochemical localization and serologic detection of transforming growth factor β 1. Arthritis Rheum 1994; 37: 278–288.
- 47 Rossi P, Karsenty G, Roberts AB, el al. A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by TGFβ. Cell 1988; 52: 405–414.
- 48 Slack JL, Liska D, Bornstein P. Regulation of expression of the type 1 collagen genes. Am J Med Genet 1993; 45: 140–151.
- 49 Igarashi A, Nashiro K, Kikuchi K, et al. Significant correlation between connective tissue growth factor gene expression and skin sclerosis in tissue sections from patients with systemic sclerosis. J Invest Dermatol 1995; 105: 280–284.
- 50 Kikuchi K, Kadono T, Furue M, et al. Tissue inhibitor of metalloproteinase 1 (TIMP-1) may be an autocrine growth factor in scleroderma fibroblasts. J Invest Dermatol 1997; 108: 281–284.
- 51 Feghali CA, Boulware DW, Ferriss JA, et al. Expression of c-myc, c-myb, and c-sis in fibroblasts from affected and unaffected skin of patients with systemic sclerosis. Autoimmunity 1993; 16: 167–171.
- 52 Sollberg S, Mauch C, Eckes B, et al. The fibroblast in systemic sclerosis. Clin Dermatol 1994; 12: 279–285.
- 53 Varga J, Bashey RI. Regulation of connective tissue synthesis in systemic sclerosis. Int Rev Immunol 1995; 12: 187–199.
- 54 Peltonen J, Kahari I, Uitto J, et al. Increased expression of type VI collagen genes in systemic sclerosis. Arthritis Rheum 1990; 33: 1829–1835.
- 55 Westergren-Thorsson G, Cöster L, Akesson A, et al. Altered dermatan sulfate proteoglycan synthesis in fibroblast cultures established from skin of patients with systemic sclerosis. J Rheumatol 1996; 23: 1398–1406.
- 56 Takeda K, Hatamochi A, Ueki H, et al. Decreased collagenase expression in cultured systemic sclerosis fibroblasts. J Invest Dermatol 1994; 103: 359–363.
- 57 LeRoy EC. Increased collagen synthesis by scleroderma fibroblasts in vitro. J Clin Invest 1974; 54: 880–889.
- 58 Botstein GR, Sherer GK, LeRoy EC. Fibroblast selection in scleroderma: an alternative model of fibrosis. Arthritis Rheum 1982; 26: 186–195.
- 59 Mauch C, Kozlowska E, Eckes B, Krieg T. Altered regulation of collagen metabolism in scleroderma fibroblasts grown within three-dimensional collagen gels. Exp Dermatol 1992; 1: 185–190.
- 60 Eckes B, Mauch C, Hiippe G, Krieg T. Down-regulation of collagen synthesis in fibroblasts within three-dimensional collagen lattices involves transcriptional and posttranscriptional mechanism. FEBS Lett 1993; 318: 129–133.
- 61 Kozlowska E, Sollberg S, Mauch C, et al. Decreased expression of alpha2 betal integrin in scleroderma fibroblasts. Exp Dermatol 1996; 5: 57–63.
- 62 Osada K, Seishima M, Kitajima Y, et al. Decreased integrin α2, but normal response to TGF-β in scleroderma fibroblasts. J Dermatol Sci 1995; 9: 169–175.
- 63 Border WA, Noble NA. TGFβ in tissue fibrosis. N Engl J Med 1994; 331: 1286–1292.
- 64 Christner PJ, Peters J, Hawkins D, et al. The tight skin 2 mouse. An animal model displaying cutaneous fibrosis and mononuclear cell infiltration. Arthritis Rheum 1995; 38: 1791–1798.
Citing Literature
