Skip to main content

Advertisement

SpringerLink
Log in

Increased expression of S100A8 and S100A9 in patients with diffuse cutaneous systemic sclerosis. A correlation with organ involvement and immunological abnormalities

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

S100A8 and S100A9 play important roles in immune and inflammatory disorders. The role of the two proteins in systemic sclerosis (SSc) remains unknown. Fifty-seven diffuse cutaneous SSc (dcSSc) patients, 31 limited cutaneous SSc (lcSSc) patients were recruited in the present study. The expression of S100A8 and S100A9 in plasma was measured using an enzyme-linked immunosorbent assay and the mRNA levels in peripheral blood were assessed using reverse transcriptase quantitative PCR. The expression and distribution of S100A8, S100A9, and receptor for advanced glycation end products (RAGE), in skin tissues was analyzed by immunohistochemistry. The plasma concentrations of S100A8 and S100A9 were significantly higher in dcSSc patients than in normal controls and lcSSc patients. Both S100A8 and S100A9 levels were significantly increased in dcSSc patients with lung or kidney involvement. Increased plasma levels of S100A8 and S100A9 in dcSSc patients were associated with several autoantibodies. Transcription levels of S100A8 and S100A9 in peripheral blood were found elevated in both dcSSc and lcSSc patients than normal controls. Immunohistochemistry demonstrated higher S100A8 and S100A9 expression in sclerotic skin than in normal skin. The number of S100A8, S100A9, or RAGE positive fibroblasts was also significantly increased. Highly elevated expression of both S100A8 and S100A9 was found in dcSSc patients. There was close correlation with disease severity and serological abnormalities, suggesting that the two proteins may play important roles in the development of systemic sclerosis.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Yamamoto T (2009) Scleroderma—pathophysiology. Eur J Dermatol : EJD 19(1):14–24. doi:10.1684/ejd.2008.0570

    PubMed  CAS  Google Scholar 

  2. LeRoy EC, Medsger TA Jr (2001) Criteria for the classification of early systemic sclerosis. J Rheumatol 28(7):1573–1576

    PubMed  CAS  Google Scholar 

  3. Gourh P, Arnett FC, Assassi S, Tan FK, Huang M, Diekman L, Mayes MD, Reveille JD, Agarwal SK (2009) Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations. Arthritis Res Ther 11(5):R147. doi:10.1186/ar2821

    Article  PubMed  Google Scholar 

  4. Foell D, Frosch M, Sorg C, Roth J (2004) Phagocyte-specific calcium-binding S100 proteins as clinical laboratory markers of inflammation. Clin Chim Acta Int J Clin Chem 344(1–2):37–51. doi:10.1016/j.cccn.2004.02.023

    Article  CAS  Google Scholar 

  5. Foell D, Wittkowski H, Vogl T, Roth J (2007) S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 81(1):28–37. doi:10.1189/jlb.0306170

    Article  PubMed  CAS  Google Scholar 

  6. Ehrchen JM, Sunderkotter C, Foell D, Vogl T, Roth J (2009) The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol 86(3):557–566. doi:10.1189/jlb.1008647

    Article  PubMed  CAS  Google Scholar 

  7. Perera C, McNeil HP, Geczy CL (2010) S100 Calgranulins in inflammatory arthritis. Immunol Cell Biol 88(1):41–49. doi:10.1038/icb.2009.88

    Article  PubMed  CAS  Google Scholar 

  8. Soyfoo MS, Roth J, Vogl T, Pochet R, Decaux G (2009) Phagocyte-specific S100A8/A9 protein levels during disease exacerbations and infections in systemic lupus erythematosus. J Rheumatol 36(10):2190–2194. doi:10.3899/jrheum.081302

    Article  PubMed  CAS  Google Scholar 

  9. Foell D, Hernandez-Rodriguez J, Sanchez M, Vogl T, Cid MC, Roth J (2004) Early recruitment of phagocytes contributes to the vascular inflammation of giant cell arteritis. J Pathol 204(3):311–316. doi:10.1002/path.1660

    Article  PubMed  CAS  Google Scholar 

  10. Frosch M, Roth J (2008) New insights in systemic juvenile idiopathic arthritis—from pathophysiology to treatment. Rheumatology (Oxford) 47(2):121–125. doi:10.1093/rheumatology/kem271

    Article  CAS  Google Scholar 

  11. Foell D, Wittkowski H, Ren Z, Turton J, Pang G, Daebritz J, Ehrchen J, Heidemann J, Borody T, Roth J, Clancy R (2008) Phagocyte-specific S100 proteins are released from affected mucosa and promote immune responses during inflammatory bowel disease. J Pathol 216(2):183–192. doi:10.1002/path.2394

    Article  PubMed  CAS  Google Scholar 

  12. Tan FK, Zhou X, Mayes MD, Gourh P, Guo X, Marcum C, Jin L, Arnett FC Jr (2006) Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology (Oxford) 45(6):694–702. doi:10.1093/rheumatology/kei244

    Article  CAS  Google Scholar 

  13. Giusti L, Bazzichi L, Baldini C, Ciregia F, Mascia G, Giannaccini G, Del Rosso M, Bombardieri S, Lucacchini A (2007) Specific proteins identified in whole saliva from patients with diffuse systemic sclerosis. J Rheumatol 34(10):2063–2069

    PubMed  CAS  Google Scholar 

  14. Fietta A, Bardoni A, Salvini R, Passadore I, Morosini M, Cavagna L, Codullo V, Pozzi E, Meloni F, Montecucco C (2006) Analysis of bronchoalveolar lavage fluid proteome from systemic sclerosis patients with or without functional, clinical and radiological signs of lung fibrosis. Arthritis Res Ther 8(6):R160. doi:10.1186/ar2067

    Article  PubMed  Google Scholar 

  15. Bargagli E, Olivieri C, Prasse A, Bianchi N, Magi B, Cianti R, Bini L, Rottoli P (2008) Calgranulin B (S100A9) levels in bronchoalveolar lavage fluid of patients with interstitial lung diseases. Inflammation 31(5):351–354. doi:10.1007/s10753-008-9085-z

    Article  PubMed  CAS  Google Scholar 

  16. Kumar RK, Harrison CA, Cornish CJ, Kocher M, Geczy CL (1998) Immunodetection of the murine chemotactic protein CP-10 in bleomycin-induced pulmonary injury. Pathology 30(1):51–56

    Article  PubMed  CAS  Google Scholar 

  17. Preliminary criteria for the classification of systemic sclerosis (scleroderma) (1980) Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 23(5):581–590

    Article  Google Scholar 

  18. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N, Wollheim F (1988) Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 15(2):202–205

    PubMed  CAS  Google Scholar 

  19. Clements PJ, Lachenbruch PA, Seibold JR, Zee B, Steen VD, Brennan P, Silman AJ, Allegar N, Varga J, Massa M et al (1993) Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 20(11):1892–1896

    PubMed  CAS  Google Scholar 

  20. Sato S, Ihn H, Kikuchi K, Takehara K (1994) Antihistone antibodies in systemic sclerosis. Association with pulmonary fibrosis. Arthritis Rheum 37(3):391–394

    Article  PubMed  CAS  Google Scholar 

  21. Wynn TA (2007) Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 117(3):524–529. doi:10.1172/JCI31487

    Article  PubMed  CAS  Google Scholar 

  22. Ho KT, Reveille JD (2003) The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 5(2):80–93

    Article  PubMed  CAS  Google Scholar 

  23. Walker JG, Ahern MJ, Smith MD, Coleman M, Pile K, Rischmueller M, Cleland L, Roberts-Thomson PJ (2003) Scleroderma renal crisis: poor outcome despite aggressive antihypertensive treatment. Intern Med J 33(5–6):216–220

    Article  PubMed  CAS  Google Scholar 

  24. Denton CP, Black CM (2004) Scleroderma—clinical and pathological advances. Best Pract Res Clin Rheumatol 18(3):271–290. doi:10.1016/j.berh.2004.03.001

    PubMed  CAS  Google Scholar 

  25. Steen VD, Medsger TA Jr (2000) Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 43(11):2437–2444. doi:10.1002/1529-0131(200011)43:11<2437::AID-ANR10>3.0.CO;2-U

    Article  PubMed  CAS  Google Scholar 

  26. Hesselstrand R, Scheja A, Shen GQ, Wiik A, Akesson A (2003) The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology (Oxford) 42(4):534–540

    Article  CAS  Google Scholar 

  27. Denton CP, Shi-Wen X, Sutton A, Abraham DJ, Black CM, Pearson JD (1998) Scleroderma fibroblasts promote migration of mononuclear leucocytes across endothelial cell monolayers. Clin Exp Immunol 114(2):293–300

    Article  PubMed  CAS  Google Scholar 

  28. Hussein MR, Hassan HI, Hofny ER, Elkholy M, Fatehy NA, Abd Elmoniem AE, Ezz El-Din AM, Afifi OA, Rashed HG (2005) Alterations of mononuclear inflammatory cells, CD4/CD8+ T cells, interleukin 1beta, and tumour necrosis factor alpha in the bronchoalveolar lavage fluid, peripheral blood, and skin of patients with systemic sclerosis. J Clin Pathol 58(2):178–184. doi:10.1136/jcp.2004.019224

    Article  PubMed  CAS  Google Scholar 

  29. Yoshizaki A, Komura K, Iwata Y, Ogawa F, Hara T, Muroi E, Takenaka M, Shimizu K, Hasegawa M, Fujimoto M, Sato S (2009) Clinical significance of serum HMGB-1 and sRAGE levels in systemic sclerosis: association with disease severity. J Clin Immunol 29(2):180–189. doi:10.1007/s10875-008-9252-x

    Article  PubMed  CAS  Google Scholar 

  30. He M, Kubo H, Ishizawa K, Hegab AE, Yamamoto Y, Yamamoto H, Yamaya M (2007) The role of the receptor for advanced glycation end-products in lung fibrosis. Am J Physiol Lung Cell Mol Physiol 293(6):L1427–L1436. doi:10.1152/ajplung.00075.2007

    Article  PubMed  CAS  Google Scholar 

  31. Morbini P, Villa C, Campo I, Zorzetto M, Inghilleri S, Luisetti M (2006) The receptor for advanced glycation end products and its ligands: a new inflammatory pathway in lung disease? Modern pathology. An Off J US Can Acad Pathol Inc 19(11):1437–1445. doi:10.1038/modpathol.3800661

    CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the grants from the National Natural Science Foundation of China, grant number 81270120 and 81072463; the Science and Technology Committee of Shanghai Municipality, grant number 11410701800 and 10JC1402100; and US NIH NIAID UO1 (1U01AI090909).

Disclosures

None.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Huashan Hospital, Fudan University, No. 12, Middle Wulumuqi Road, Shanghai, 200040, People’s Republic of China

    Xue Xu, Xiao-xia Zhu, Min-rui Liang, Yu Xue & He-jian Zou

  2. Division of Dermatology, Huashan Hospital, Fudan University, No. 12, Middle Wulumuqi Road, Shanghai, 200040, People’s Republic of China

    Wen-yu Wu

  3. Division of Rheumatology, Shanghai Traditional Chinese Medicine-Integrated Hospital, No. 230, Baoding Road, Shanghai, 200433, People’s Republic of China

    Wen-zheng Tu

  4. State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, No. 220, Handan Road, Shanghai, 200433, People’s Republic of China

    Hai-yan Chu & Jiu-cun Wang

Authors
  1. Xue Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wen-yu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen-zheng Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hai-yan Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao-xia Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Min-rui Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jiu-cun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. He-jian Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jiu-cun Wang or He-jian Zou.

Additional information

Xue Xu and Wen-yu Wu contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, X., Wu, Wy., Tu, Wz. et al. Increased expression of S100A8 and S100A9 in patients with diffuse cutaneous systemic sclerosis. A correlation with organ involvement and immunological abnormalities. Clin Rheumatol 32, 1501–1510 (2013). https://doi.org/10.1007/s10067-013-2305-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-013-2305-4

Keywords

Search

Navigation