Pathogenesis of scleroderma: Current ideas

Potekaev N.N.; Vavilov V.V.

doi:https://doi.org/

Close metadata

Recommended articles:

Psoriasis: analysis of comorbid pathology. Russian Journal of Clinical Dermatology and Venereology. 2025;(1):16-21

Hybrid wound coating in rehabilitation of severe thermal burns. (An experimental study). Problems of Balneology, Physiotherapy and Exercise Therapy. 2024;(6-2):40-49

Arterial hypertension is an oxidative stress, as a pathogenetic target for the treatment of chronic cerebrovascular insufficiency. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(1):84-90

Modern methods of correction of age-related changes in the female body. Plastic Surgery and Aesthetic Medicine. 2025;(1):90-96

Sleep deprivation and the development of oxidative stress in animal models. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(3):124-129

Pathogenetic aspects of autoantibody formation to central nervous system structures in patients with encephalitis. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(4):53-58

The main mechanisms of development of cognitive impairment. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(4-2):13-18

Therapeutic potential of quercetin and its derivatives against COVID-19. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(5):44-50

Relationship between oxidative stress patterns and proinflammatory cytokines in patients with polypous rhinosinusitis under the course of therapeutic physical factors. Regenerative Biotechnologies, Preventive, Digital and Predictive Medicine. 2025;(2):42-49

Associations of genetic polymorphisms in key inflammatory response genes with the risk of chronic apical periodontitis development. Russian Journal of Stomatology. 2025;(2):52-56

Abstract:

The causes of collagen hyperproduction in scleroderma presently remain little studied. At the present stage, the pathogenesis of scleroderma is considered as the complex interaction of endothelial cell damage and dysfunction, inflammation, autoimmune reactions, and fibroblast activation. The paper presents current ideas on each component.

Keywords:

scleroderma

adhesion molecules

autoantibodies

collagen

metalloproteinases

transforming growth factor

oxidative stress

Authors:

Potekaev N.N.

Moscow Scientific and Practical Center of Dermatovenerology and Cosmetology, Moscow, Russia

Vavilov V.V.

MNPTsDK Departament zdravookhraneniia Moskvy;
Pervyĭ MGMU im. I.M. Sechenova

Close metadata

References:

Yamamoto T. Autoimmune mechanisms of scleroderma and a role of oxidative stress. Self Nonself 2011; 2: 1: 4-10.
Fleischmajer R., Perlish J.S., Reeves J.R. Cellular infiltrates in scleroderma skin. Arthritis Rheum 1977; 20: 975-984.
Ihn H., Fujimoto M., Sato S. et al. Increased levels of circulating intercellular adhesion molecule-1 in patients with localized scleroderma. J Am Acad Dermatol 1994; 31: 591-595.
Kuwana M., Okazaki Y., Yasuoka H. et al. Defective vasculogenesis in systemic sclerosis. Lancet 2004; 364: 603-610.
Sato S., Ihn H., Soma Y. et al. Antihistone antibodies in patients with localized scleroderma. Arthritis Rheum 1993; 36: 1137-1141.
Leitenberger J.J., Cayce R.L., Haley R.W. et al. Distinct autoimmune syndromes in morphea: a review of 245 adult and pediatric cases. Arch Dermatol 2009; 145: 5: 545-550.
Rodnan G.P., Lipinski E., Rabin B.S., Reichlin M. Eosinophilia and serologic abnormalities in linear localized scleroderma. Arthritis Rheum 1977; 20: 133.
Takeda K., Hatamochi A., Ueki H. et al. Decreased collagenase expression in cultured systemic sclerosis fibroblasts. J Invest Dermatol 1994; 103: 359-363.
Flanga V., Medsger T.A. Jr, Reichlin M. Antinuclear and anti-single-stranded DNA antibodies in morphea and generalized morphea. Arch Dermatol 1987; 123: 350-353.
Ruffatti A., Peserico A., Glorioso S. et al. Anticentromere antibody in localized scleroderma. J Am Acad Dermatol 1986; 15: 637-642.
Sato S., Fujimoto M., Ihn H. et al. Clinical characteristics associated with antihistone antibodies in patients with localized scleroderma. J Am Acad Dermatol 1994; 31: 567-571.
Sato S., Fujimoto M., Hasegawa M., Takehara K. Antiphospholipid antibody in localized scleroderma. Ann Rheum Dis 2003; 62: 771-774.
D'Arpa O., White-Cooper H., Cleveland D.W. et al. Use of molecular cloning methods to map the distribution of epitopes on topoisomerase I (Scl-70) recognized by sera of scleroderma patients. Arthritis Rheum 1990; 33: 1501-1511.
Hayakawa I., Hasegawa M., Takehara K., Sato S. Anti-DNA topoisomerase II autoantibodies in localized scleroderma. Arthritis Rheum 2004; 50: 227-232.
Renaudineau Y., Grunebaum E., Krause I. et al. Anti-endothelial cell antibodies (AECA) in systemic sclerosis-increased sensitivity using different endothelial cell substrates and association with other autoantibodies. Autoimmunity 2001; 33: 171-179.
Rowell N.R., Tate G.M. Failure to demonstrate the lupus anticoagulant in systemic sclerosis. Br J Dermatol 1988; 119: 549.
Hess E.V. Is there a phospholipid specificity of lupus anticoagulants (LAC) in patients with autoimmune and drug induced LAC? J Rheumatol 1998; 25: 200-202.
Oger E., Lernyer C., Dueymes M. et al. Association between IgM anticardiolipin antibodies and deep venous thrombosis in patients without systemic lupus erythematosus. Lupus 1997; 6: 455-461.
Higley H., Persichitte K., Chu S. et al. Immunocytochemical localization and serologic detection of transforming growth factor beta 1. Association with type I procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea, and Raynaud's phenomenon. Arthritis Rheum 1994; 37: 278-288.
Mattila L., Airola K., Ahonen M. et al. Activation of tissue inhibitor of metalloproteinases-3 (TIMP-3) mRNA expression in scleroderma skin fibroblasts. J Invest Dermatol 1998; 110: 4: 416-421.
Massague J. How cells read TGF-beta signals. Nat Rev Mol Cell Biol 2000; 1: 169-178.
Derynck R., Feng X.H. TGF-beta receptor signaling. Biochim Biophys Acta 1997; 1333: F105-F150.
O'Kane S., Ferguson M.W. Transforming growth factor beta and wound healing. Int J Biochem Cell Biol 1997; 29: 63-78.
Shi-Wen X., Holmes P.D., Leask A. et al. Autocrine overexpression of CTGF maintains fibrosis: RDA analysis of fibrosis genes in systemic sclerosis. Exp Cell Res 2000; 25: 213-224.
Shimuzu K., Ogawa F., Akiyama Y. et al. Increased serum levels of N(epsilon)-(hexanoyl)lysine, a new marker of oxidative stress, in systemic sclerosis. J Rheumatol 2008; 35: 2214-2219.
Kubo M., Ihn H., Yamane K., Tamaki K. Up-regulated expression of transforming growth factor Β receptors in dermal fibroblasts in skin sections from patients with localized scleroderma. Arthritis Rheum 2001; 44: 731-734.
Kawakami T., Ihn H., Xu W. et al. Increased expression of TGF- Β receptors by scleroderma fibro-blasts: evidence for contribution of autocrine TGF-Β signaling to scleroderma phenotype. J Invest Dermatol 1998; 110: 47-51.
Ihn H., Yamane K., Kubo M., Tamaki K. Blockade of endogenous transforming growth factor Β signaling prevents up-regulated collagen synthesis in scleroderma fibroblasts: association with increased expression of transforming growth factor Β receptors. Arthritis Rheum 2001; 44: 474-480.
Elovic A.E., Ohyama H., Sauty A. et al. IL-4-dependent regulation of TGFalpha and TGFbeta1 expression in human eosinophils. J Immunol 1998; 160: 6121-6127.
Okano Y. Antinuclear antibody in systemic sclerosis (scleroderma). Rheum Dis Clin North Am 1996; 22: 709-735.
Veldhoen M., Stockinger B. TGF-beta1, a "Jack of all trades": the link with pro-inflammatory IL-17-producing T cells. Trends Immunol 2006; 27: 358-361.
Takehara K., Sato S. Localized scleroderma is an autoimmune disorder. Rheumatology (Oxford) 2005; 44: 3: 274-279.
Serpier H., Gillery P., Salmon-Ehr V. et al. Antagonistic effect of interferon-gamma and interleukin-4 on fibroblast cultures. J Invest Dermatol 1997; 109: 158-162.
Needlemann B.W., Wigley F.M., Stair R.W. Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor α and interferonγ levels in sera from patients with scleroderma. Arthritis Rheum 1985; 28: 775-780.
Murota M., Fujimoto M., Matsushita T. et al. Clinical association of serum interleukin-17 levels in systemic sclerosis: Is systemic sclerosis a Th17 disease? J Dermatol Sci 2008; 50: 240-242.
Yamane K., Ihn H., Kubo M. et al. Increased serum levels of soluble vascular cell adhesion molecule 1 and E-selectin in patients with localized scleroderma. J Am Acad Dermatol 2000; 42: 64-69.
Horstmeyer A., Licht C., Scherr G. et al. Signaling and regulation of collagen I synthesis by ET-1 and TGFΒ1. FEBS J 2005; 272: 6297-6309.
Matsushita T., Hasegawa M., Hamaguchi Y. et al. Longitudinal analysis of serum cytokine concentrations in systemic sclerosis: association of interleukin 12 elevation with spontaneous regression of skin sclerosis. J Rheumatol 2006; 33: 275-284.
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: 140-146.
Koch A.E., Kronfeld-Harrington L.B., Szekanecz Z. et al. In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease. Pathobiology 1993; 61: 239-246.
Hasegawa M., Sato S., Fujimoto M. et al. 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: 308-313.
Kaplanski G., Marin V., Montero-Julian F. et al. IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol 2003; 24: 25-29.
Barnes T.C., Spiller D., Anderson M.E. et al. Endothelial cell activation and apoptosis mediated by neutrophil-dependent interleukin 6 trans-signalling: a novel target for systemic sclerosis? Ann Rheum Dis 2011; 70: 2: 366-372.
Sambo P., Baroni S.S., Luchetti M. et al. Oxidative stress in scleroderma: Maintenance of scleroderma fibroblast phenotype by the constitutive upregulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum 2001; 44: 2653-2664.
Dooley A., Shi-wen X., Aden N. et al. Modulation of collagen type I, fibro- nectin and dermal fibroblast function and activity, in systemic sclerosis by the antioxidant epigallocatechin- 3-gallate. Rheumatology 2010; 49: 2024-2036.
Casciola-Rosen L., Wigley F., Rosen A. Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: Implications for pathogenesis. J Exp Med 1997; 185: 71-79.
Galindo M., Santiago B., Alcami J. et al. Hypoxia induces expression of the chemokines monocyte chemoattractant protein-1 (MCP-1) and IL-8 in human dermal fibroblasts. Clin Exp Immunol 2001; 123: 36-41.
Sambo P., Jannino L., Candela M. Monocytes of patients with systemic sclerosis (scleroderma) spontaneously release in vitro increased amounts of superoxide anion. J Invest Dermatol 1999; 112: 78-84.
Bruckdorfer K.R., Hillary J.B., Bunce T. et al. Increased susceptibility to oxidation of low-density lipoprotein isolated from patients with systemic sclerosis. Arthritis Rheum 1995; 38: 1060-1067.
Ogawa F., Shimuzu K., Hara T. et al. Autoantibody against one of the antioxidant repair enzymes, methionine sulfoxide reductase A, in systemic sclerosis: association with pulmonary fibrosis and vascular damage. Arch Dermatol Res 2010; 302: 27-35.
Shi-wen X., Kennedy L., Renzoni E. et al. Endothelin-1 is a downstream mediator of TGFΒ in fibroblasts. Arthritis Rheum 2007; 56: 4189-4194.
Ogawa F., Shimizu K., Muroi E. et al. Serum levels of 8-isoprostane, a marker of oxidative stress, are elevated in patients with systemic sclerosis. Rheumatology 2006; 45: 815-818.