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Early Systemic Sclerosis: Serum Profiling of Factors Involved in Endothelial, T-cell, and Fibroblast Interplay is Marked by Elevated Interleukin-33 Levels

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Abstract

Purpose

To assess the serum profile of factors involved in endothelial, T-cell, and fibroblast interplay in patients with Raynaud’s phenomenon (RP) associated with nailfold vodeocapillaroscopy (NVC) scleroderma findings and/or systemic sclerosis (SSc) marker autoantibodies, recently labeled as early SSc patients.

Methods

Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), CCL2, CXCL8, IL-13, IL-33, and transforming growth factor-β (TGF-β) were measured in 24 early SSc patients, 48 definite SSc patients, and 24 osteoarthritis/fibromyalgia controls by multiplex suspension immunoassay. All SSc patients were investigated for the presence/absence of preclinical and clinical organ involvement, SSc marker autoantibodies, and NVC abnormalities.

Results

Serum sICAM-1, CCL2, CXCL8, and IL-13 were increased in all SSc patients as compared to controls, and paralleled the severity of the disease subset (early SSc < limited cutaneous SSc < diffuse cutaneous SSc; p < 0.0001). Surprisingly, IL-33 was significantly higher in early SSc patients as compared to both controls (p < 0.01) and definite SSc patients (p < 0.05). In early SSc there were no differences in the investigated markers according to the functional and serological features assessed.

Conclusions

Our study suggests that an endothelial, T-cell and fibroblast activation can be present in patients with early SSc and it is associated with a distinct profile of circulating factors involved in the cross-talk of these cells. The marked increase of IL-33 in early SSc patients suggests new routes of investigation of cell-cell dynamics in target tissues predating overt disease manifestations, thus opening to new therapeutic approaches.

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References

  1. Gu YS, Kong J, Cheema GS, Keen CL, Wick G, Gershwin ME. The immunobiology of systemic sclerosis. Semin Arthritis Rheum. 2008;38:132–60.

    Article  CAS  PubMed  Google Scholar 

  2. Fleischmajer R, Perlish JS. The pathophysiology of the fibrosis in scleroderma skin. Prog Clin Biol Res. 1984;154:381–404.

    CAS  PubMed  Google Scholar 

  3. Greenblatt MB, Aliprantis AO. The immune pathogenesis of scleroderma: context is everything. Curr Rheumatol Rep. 2013;15:297.

    Article  PubMed Central  PubMed  Google Scholar 

  4. De Palma R, D’Aiuto E, Vettori S, Cuoppolo PP, Abbate G, Valentini G. Peripheral T cells from early systemic sclerosis patients kill autologous fibroblasts in co-culture: is T-cell response aimed to play a protective role? Rheumatology (Oxford). 2010;49:1257–66.

    Article  Google Scholar 

  5. Valentini G, Cuomo G, Abignano G, Petrillo A, Vettori S, Capasso A, et al. Early systemic sclerosis: assessment of clinical and pre-clinical organ ivolvement in patients with different disease features. Rheumatology (Oxford). 2011;50:317–23.

    Article  Google Scholar 

  6. Valentini G, Marcoccia A, Cuomo G, Vettori S, Iudici M, Bondanini F, et al. Early systemic sclerosis: marker autoantibodies and videocapillaroscopy patterns are each associated with distinct clinical, functional and cellular activation markers. Arthritis Res Ther. 2013;15:R63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23:581–90

    Google Scholar 

  8. Van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against rheumatism collaborative initiative. Arthritis Rheum. 2013;65:2737–47.

    Article  PubMed  Google Scholar 

  9. LeRoy EC, Black CM, Fleichmajer R, Jablonksa S, Krieg T, Medsger Jr TA, et al. Scleroderma (systemic sclerosis). Classification, subset and pathogenesis. J Rheumatol. 1988;15:202–5.

    CAS  PubMed  Google Scholar 

  10. Cappelli S, Bellando Randone S, Martinovic D, Tamas MM, Pasalic K, Allanore Y, et al. “To be or not to be,” ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum. 2012;41:589–98.

    Article  PubMed  Google Scholar 

  11. Yoshizaki A, Yanaba K, Iwata Y, Komura K, Ogawa A, Akiyama Y, et al. Cell adhesion molecole regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model. J Immunol. 2010;185:2502–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Codullo V, Baldwin HM, Singh MD, Fraser AR, Wilson C, Gilmour A, et al. An investigation of the inflammatory cytokine and chemokine network in systemic sclerosis. Ann Rheum Dis. 2011;70:1115–21.

    Article  CAS  PubMed  Google Scholar 

  13. Fuschiotti P. Role of IL-13 in systemic sclerosis. Cytokine. 2011;56:544–9.

    Article  CAS  PubMed  Google Scholar 

  14. 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;184:1526–35.

    Article  CAS  PubMed  Google Scholar 

  15. Varga J, Whitfield ML. Transforming growth factor-beta in systemic sclerosis (scleroderma). Front Biosci (Schol Ed). 2009;1:226–35.

    Article  Google Scholar 

  16. Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S. Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumatol. 2005;24:111–6.

    Article  PubMed  Google Scholar 

  17. Denton CP, Bickerstaff MC, Shiwen X, Carulli MT, Haskard DO, Dubois RM, et al. Serial circulating adhesion molecule levels reflect disease severity in systemic sclerosis. Br J Rheumatol. 1995;34:1048–54.

    Article  CAS  PubMed  Google Scholar 

  18. Snowden N, Coupes B, Herrick A, Illingworth K, Jayson MI, Brenchley PE. Plasma TGF-beta in systemic sclerosis: a cross sectional study. Ann Rheum Dis. 1994;53:763–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Dziadzio M, Smith RE, Abraham DJ, Black CM, Denton CP. Circulating levels of active transforming growth factor beta1 are reduced in diffuse cutaneous systemic sclerosis and correlate inversely with the modified Rodnan skin score. Rheumatology (Oxford). 2005;44:1518–24.

    Article  CAS  Google Scholar 

  20. Wolf SI, Howat S, Abraham DJ, Pearson JD, Lawson C. Agonistic anti-ICAM-1 antibodies in scleroderma: activation of endothelial pro-inflammatory cascade. Vasc Pharmacol. 2013;59:19–26.

    Article  CAS  Google Scholar 

  21. Mehrad B, Keane MP, Strieter RM. Chemokines as mediators of angiogenesis. Thromb Haemost. 2007;97:755–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Wynn T. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;241:199–210.

    Article  Google Scholar 

  23. Van de Veerdonk FL, Netea MG. New insights in the immunobiology of IL-1 family members. Front Immunol. 2013;4:167.

    PubMed Central  PubMed  Google Scholar 

  24. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479–90.

    Article  CAS  PubMed  Google Scholar 

  25. Chackarian AA, Oldham ER, Murphy EE, Schimtz J, Pflanz S, Kastelein RA, et al. IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. J Immunol. 2007;179:2551–5.

    Google Scholar 

  26. Manetti M, Guiducci S, Ceccarelli C, Romano E, Bellando-Randone S, Conforti ML, et al. Increased circulating levels of interleukin 33 in sistemic sclerosis correlate with early disease stage and microvascular involvement. Ann Rheum Dis. 2011;70:1876–8.

    Article  CAS  PubMed  Google Scholar 

  27. Terras S, Opitz E, Moritz RKC, Höxtermann S, Gambichler T, Kreuter A. Increased serum IL-33 levels may indicate vascular involvement in systemic sclerosis. Ann Rheum Dis. 2013;72:144–5.

    Article  CAS  PubMed  Google Scholar 

  28. Manetti M, Ibba-Manneschi L, Liakouli V, Guiducci S, Milia AF, Benelli G, et al. The IL1-like cytokine IL-33 and its receptor ST2 are abnormally espresse in the affected skin and visceral organs of patients with systemic sclerosis. Ann Rheum Dis. 2010;69:598–605.

    Article  CAS  PubMed  Google Scholar 

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Financial Support

This study was supported by a grant of the Italian Foundation for Arthritis Research (FIRA).

Conflict of Interest

All authors of this article declare they have no competing interests.

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Authors and Affiliations

  1. Rheumatology Unit, Second University of Naples, Via S. Pansini 5, 80131, Naples, Italy

    Serena Vettori, Giovanna Cuomo, Michele Iudici, Virginia D’Abrosca, Veronica Giacco & Gabriele Valentini

  2. Clinical Immunology Unit, Second University of Naples, via Pansini 5, 80131, Naples, Italy

    Giusi Barra & Raffaele De Palma

Authors
  1. Serena Vettori
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  2. Giovanna Cuomo
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  3. Michele Iudici
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  4. Virginia D’Abrosca
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  5. Veronica Giacco
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  6. Giusi Barra
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  7. Raffaele De Palma
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  8. Gabriele Valentini
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Correspondence to Serena Vettori.

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Vettori, S., Cuomo, G., Iudici, M. et al. Early Systemic Sclerosis: Serum Profiling of Factors Involved in Endothelial, T-cell, and Fibroblast Interplay is Marked by Elevated Interleukin-33 Levels. J Clin Immunol 34, 663–668 (2014). https://doi.org/10.1007/s10875-014-0037-0

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  • DOI: https://doi.org/10.1007/s10875-014-0037-0

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