Advertisement

Rheumatology International

, Volume 39, Issue 3, pp 469–478 | Cite as

Circulating S100 proteins effectively discriminate SLE patients from healthy controls: a cross-sectional study

  • Barbora Šumová
  • Lucie Andrés Cerezo
  • Lenka Szczuková
  • Lucie Nekvindová
  • Michal Uher
  • Hana Hulejová
  • Radka Moravcová
  • Mariam Grigorian
  • Karel Pavelka
  • Jiří Vencovský
  • Ladislav Šenolt
  • Jakub ZávadaEmail author
Observational Research
  • 70 Downloads

Abstract

S100 proteins are currently being investigated as potential diagnostic and prognostic biomarkers of several cancers and inflammatory diseases. The aims of this study were to analyse the plasma levels of S100A4, S100A8/9 and S100A12 in patients with incomplete systemic lupus erythematosus (iSLE), in patients with established SLE and in healthy controls (HCs) and to investigate the potential utility of the S100 proteins as diagnostic or activity-specific biomarkers in SLE. Plasma levels were measured by ELISA in a cross-sectional cohort study of 44 patients with SLE, 8 patients with iSLE and 43 HCs. Disease activity was assessed using the SLEDAI-2K. The mean levels of all S100 proteins were significantly higher in SLE patients compared to HCs. In iSLE patients, the levels of S100A4 and S100A12 but not S100A8/9 were also significantly higher compared to HCs. There were no significant differences in S100 levels between the iSLE and SLE patients. Plasma S100 proteins levels effectively discriminated between SLE patients and HCs. The area under the curve (AUC) for S100A4, S100A8/9 and S100A12 plasma levels was 0.989 (95% CI 0.976–1.000), 0.678 (95% CI 0.563–0.792) and 0.807 (95% CI 0.715–0.899), respectively. S100 levels did not differentiate between patients with high and low disease activity. Only the S100A12 levels were significantly associated with SLEDAI-2K and with cSLEDAI-2K. S100 proteins were significantly higher in SLE patients compared HCs and particularly S100A4 could be proposed as a potential diagnostic biomarker for SLE.

Keywords

Biomarkers SLE S100 proteins Disease activity 

Abbreviations

ANA

Anti-nuclear antibodies

anti-dsDNA

Anti-double-stranded DNA antibody

BILAG

British Isles Lupus Assessment Group disease activity index

CI

Confidence interval

c-SLEDAI-2 K

Systemic lupus erythematosus Disease Activity Index 2000 clinical items

DAMPs

Damage-associated molecular patterns

ELISA

Enzyme-linked immunosorbent assay

EMT

Epithelial–mesenchymal transition

GC

Glucocorticoids

HCs

Healthy controls

IF

Immunofluorescence

IS

Immunosuppressants

LIA

Line immunoassay

ROC

Receiver operating characteristic

SD

Standard deviation

SLE

Systemic lupus erythematosus

SLEDAI-2K

Systemic Lupus Erythematosus Disease Activity Index 2000

SLICC/ACR

Systemic Lupus International Collaborating Clinics/American College of Rheumatology

RA

Rheumatoid arthritis

RAGE

The receptor for advanced glycation end product

Notes

Acknowledgements

We would like to thank Milada Lösterová for the excellent work as a study nurse in the management of the study.

Author contributions

Substantial contributions to the conception or design of the work: BS, MG, JZ, LS, LAC, KP, JV. Substantial contributions to the acquisition, analysis, or interpretation of data for the work: BS, HH, JZ, LS, LSz, LN, MU, LAC, JV. Drafting the work or revising it critically for important intellectual content: BS, HH, MG, LS, JZ, LSz, LN, MU, LAC, KP, JV. Final approval of the version to be published: BS, HH, MG, JZ, LS, LSz, LN, MU, LAC, KP, JV. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: BS, HH, MG, JZ, LS, LSz, LN, MU, LAC, KP, JV.

Funding

This study was supported by the project of the Ministry of Health of the Czech Republic for conceptual development of research organization [Grant no. 00023728].

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and bits later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Lisnevskaia L, Murphy G, Isenberg D (2014) Systemic lupus erythematosus. Lancet 384:1878–1888.  https://doi.org/10.1016/S0140-6736(14)60128-8 Google Scholar
  2. 2.
    Ahearn JM, Liu C-C, Kao AH, Manzi S (2012) Biomarkers for systemic lupus erythematosus. Transl Res 159:326–342.  https://doi.org/10.1016/j.trsl.2012.01.021 Google Scholar
  3. 3.
    Tektonidou MG, Ward MM (2011) Validation of new biomarkers in systemic autoimmune diseases. Nat Rev Rheumatol 7:708–717.  https://doi.org/10.1038/nrrheum.2011.157 Google Scholar
  4. 4.
    Aletaha D, Smolen J The simplified disease activity index (SDAI) and the clinical disease activity index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 23:S100-8Google Scholar
  5. 5.
    Herbst R, Liu Z, Jallal B, Yao Y (2012) Biomarkers for systemic lupus erythematosus. Int J Rheum Dis 15:433–444.  https://doi.org/10.1111/j.1756-185X.2012.01764.x Google Scholar
  6. 6.
    Sedaghat F, Notopoulos A (2008) S100 protein family and its application in clinical practice. Hippokratia 12:198–204.  https://doi.org/10.1016/j.amjsurg.2009.11.010 Google Scholar
  7. 7.
    Bresnick AR, Weber DJ, Zimmer DB (2015) S100 proteins in cancer. Nat Rev Cancer 15:96–109.  https://doi.org/10.1038/nrc3893 Google Scholar
  8. 8.
    Chen H (2014) S100 protein family in human cancer. Am J Cancer Res 4:89–115.  https://doi.org/10.1053/j.jvca.2004.07.027 Google Scholar
  9. 9.
    Nordal H, Brun J, Hordvik M et al (2016) Calprotectin (S100A8/A9) and S100A12 are associated with measures of disease activity in a longitudinal study of patients with rheumatoid arthritis treated with infliximab. Scand J Rheumatol 45:274–281.  https://doi.org/10.3109/03009742.2015.1107128 Google Scholar
  10. 10.
    Andrés Cerezo L, Mann H, Pecha O et al (2011) Decreases in serum levels of S100A8/9 (calprotectin) correlate with improvements in total swollen joint count in patients with recent-onset rheumatoid arthritis. Arthritis Res Ther 13:R122.  https://doi.org/10.1186/ar3426 Google Scholar
  11. 11.
    Klingelhöfer J, Šenolt L, Baslund B et al (2007) Up-regulation of metastasis-promoting S100A4 (Mts-1) in rheumatoid arthritis: Putative involvement in the pathogenesis of rheumatoid arthritis. Arthritis Rheumatol 56:779–789.  https://doi.org/10.1002/ART.22398 Google Scholar
  12. 12.
    Šenolt L, Andres Cerezo L, Šumová B et al (2015) High levels of metastasis-inducing S100A4 protein and treatment outcome in early rheumatoid arthritis: data from the PERAC cohort. Biomarkers 20:47–51.  https://doi.org/10.3109/1354750X.2014.989544 Google Scholar
  13. 13.
    Pleštilová L, Mann H, Andrés Cerezo L et al (2014) The metastasis promoting protein S100A4 levels associate with disease activity rather than cancer development in patients with idiopathic inflammatory myopathies. Arthritis Res Ther 16:468.  https://doi.org/10.1186/s13075-014-0468-2 Google Scholar
  14. 14.
    Foell D, Roth J (2004) Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum 50:3762–3771.  https://doi.org/10.1002/art.20631 Google Scholar
  15. 15.
    Foell D, Wittkowski H, Vogl T, Roth J (2006) S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 81:28–37.  https://doi.org/10.1189/jlb.0306170 Google Scholar
  16. 16.
    Bian L, Strzyz P, Jonsson IM et al (2011) S100a4 deficiency is associated with efficient bacterial clearance and protects against joint destruction during staphylococcal infection. J Infect Dis 204:722–730.  https://doi.org/10.1093/infdis/jir369 Google Scholar
  17. 17.
    Donato R, Cannon BR, Sorci G et al (2013) Functions of S100 proteins. Curr Mol Med 13:24–57.  https://doi.org/10.2174/1566524011307010024 Google Scholar
  18. 18.
    Andrés Cerezo L, Remá ková M, Tomčik M et al (2014) The metastasis-associated protein S100A4 promotes the inflammatory response of mononuclear cells via the TLR4 signalling pathway in rheumatoid arthritis. Rheumatol (United Kingdom) 53:1520–1526.  https://doi.org/10.1093/rheumatology/keu031 Google Scholar
  19. 19.
    Tomcik M, Palumbo-Zerr K, Zerr P et al (2014) S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis. Ann Rheum Dis.  https://doi.org/10.1136/annrheumdis-2013-204516 Google Scholar
  20. 20.
    Schneider M, Hansen JL, Sheikh SP (2008) S100A4: a common mediator of epithelial–mesenchymal transition, fibrosis and regeneration in diseases? J Mol Med 86:507–522.  https://doi.org/10.1007/s00109-007-0301-3 Google Scholar
  21. 21.
    Soyfoo MS, Roth J, Vogl T et al (2009) Phagocyte-specific S100A8/A9 protein levels during disease exacerbations and infections in systemic lupus erythematosus. J Rheumatol 36:2190–2194.  https://doi.org/10.3899/jrheum.01302 Google Scholar
  22. 22.
    Tyden H, Lood C, Gullstrand B et al (2013) Increased serum levels of S100A8/A9 and S100A12 are associated with cardiovascular disease in patients with inactive systemic lupus erythematosus. Rheumatology 52:2048–2055.  https://doi.org/10.1093/rheumatology/ket263 Google Scholar
  23. 23.
    Turnier JL, Fall N, Thornton S et al (2017) Urine S100 proteins as potential biomarkers of lupus nephritis activity. Arthritis Res Ther 19:242.  https://doi.org/10.1186/s13075-017-1444-4 Google Scholar
  24. 24.
    Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725.  https://doi.org/10.1002/1529-0131(199709)40:9%3C1725::AID-ART29%3E3.0.CO;2-Y Google Scholar
  25. 25.
    Gladman DD, Ibañez D, Urowitz MB (2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol 29:288–291Google Scholar
  26. 26.
    Abrahamowicz M, Fortin PR, Du Berger R et al (1998) The relationship between disease activity and expert physician’s decision to start major treatment in active systemic lupus erythematosus: a decision aid for development of entry criteria for clinical trials. J Rheumatol 25:277–284Google Scholar
  27. 27.
    Zibert JR, Skov L, Thyssen JP et al (2009) Significance of the S100A4 protein in psoriasis. J Invest Dermatol 130:150–160.  https://doi.org/10.1038/jid.2009.206 Google Scholar
  28. 28.
    Fei F, Qu J, Zhang M et al (2017) S100A4 in cancer progression and metastasis: a systematic review. Oncotarget 8:73219–73239.  https://doi.org/10.18632/oncotarget.18016 Google Scholar
  29. 29.
    Lozano S, Mossad E (2004) Cerebral function monitors during pediatric cardiac surgery: can they make a difference? J Cardiothorac Vasc Anesth 18:645–656.  https://doi.org/10.1053/j.jvca.2004.07.027 Google Scholar
  30. 30.
    Grigorian MS, Tulchinsky EM, Zain S et al (1993) The mts1 gene and control of tumor metastasis. Gene 135:229–238.  https://doi.org/10.1016/0378-1119(93)90070-J Google Scholar
  31. 31.
    Okada H, Danoff TM, Kalluri R, Neilson EG (1997) Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 273:F563–F574Google Scholar
  32. 32.
    Grigorian M, Andresen S, Tulchinsky E et al (2001) Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. J Biol Chem 276:22699–22708.  https://doi.org/10.1074/jbc.M010231200 Google Scholar
  33. 33.
    Orre LM, Panizza E, Kaminskyy VO et al (2013) S100A4 interacts with p53 in the nucleus and promotes p53 degradation. Oncogene 32:5531–5540.  https://doi.org/10.1038/onc.2013.213 Google Scholar
  34. 34.
    Li ZH, Bresnick AR (2006) The S100A4 metastasis factor regulates cellular motility via a direct interaction with myosin-IIA. Cancer Res doi.  https://doi.org/10.1158/0008-5472.CAN-05-3087 Google Scholar
  35. 35.
    Xu H, Li M, Zhou Y et al (2016) S100A4 participates in epithelial-mesenchymal transition in breast cancer via targeting MMP2. Tumor Biol 37:2925–2932.  https://doi.org/10.1007/s13277-015-3709-3 Google Scholar
  36. 36.
    Davies BR, O’Donnell M, Durkan GC et al (2002) Expression of S100A4 protein is associated with metastasis and reduced survival in human bladder cancer. J Pathol 196:292–299.  https://doi.org/10.1002/path.1051 Google Scholar
  37. 37.
    Hemandas AK, Salto-Tellez M, Maricar SH et al (2006) Metastasis-associated protein S100A4—a potential prognostic marker for colorectal cancer. J Surg Oncol 93:498–503.  https://doi.org/10.1002/jso.20460 Google Scholar
  38. 38.
    Chow K-H, Park HJ, George J et al (2017) S100A4 is a biomarker and regulator of glioma stem cells that is critical for mesenchymal transition in glioblastoma. Cancer Res 77:5360–5373.  https://doi.org/10.1158/0008-5472.CAN-17-1294 Google Scholar
  39. 39.
    Haga HJ, Brun JG, Berntzen HB et al (1993) Calprotectin in patients with systemic lupus erythematosus: relation to clinical and laboratory parameters of disease activity. Lupus 2:47–50.  https://doi.org/10.1177/096120339300200108 Google Scholar
  40. 40.
    Lood C, Tydén H, Gullstrand B et al (2016) Platelet-derived S100A8/A9 and cardiovascular disease in systemic lupus erythematosus. Arthritis Rheumatol 68:1970–1980.  https://doi.org/10.1002/art.39656 Google Scholar
  41. 41.
    Tantivitayakul P, Benjachat T, Somparn P et al (2016) Elevated expressions of myeloid-related proteins-8 and -14 are danger biomarkers for lupus nephritis. Lupus 25:38–45.  https://doi.org/10.1177/0961203315598015 Google Scholar
  42. 42.
    Hakkim A, Fürnrohr BG, Amann K et al (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA 107:9813–9818.  https://doi.org/10.1073/pnas.0909927107 Google Scholar
  43. 43.
    Ren Y, Tang J, Mok MY et al (2003) Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus. Arthritis Rheum 48:2888–2897.  https://doi.org/10.1002/art.11237 Google Scholar
  44. 44.
    Muñoz LE, Janko C, Franz S et al (2012) Immune complex formation after exposure of autoantigens on the surface of secondary necrotic cells (SNEC) promotes inflammation in SLE. Ann Rheum Dis 71:A73.1–A73.  https://doi.org/10.1136/annrheumdis-2011-201238.2 Google Scholar
  45. 45.
    Donnelly S, Roake W, Brown S et al (2006) Impaired recognition of apoptotic neutrophils by the C1q/calreticulin and CD91 pathway in systemic lupus erythematosus. Arthritis Rheum 54:1543–1556.  https://doi.org/10.1002/art.21783 Google Scholar
  46. 46.
    Cappione A, Anolik JH, Pugh-Bernard A et al (2005) Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J Clin Invest 115:3205–3216.  https://doi.org/10.1172/JCI24179 Google Scholar
  47. 47.
    Kalaaji M, Mortensen E, Jørgensen L et al (2006) Nephritogenic lupus antibodies recognize glomerular basement membrane-associated chromatin fragments released from apoptotic intraglomerular cells. Am J Pathol 168:1779–1792.  https://doi.org/10.2353/ajpath.2006.051329 Google Scholar
  48. 48.
    Uccellini MB, Avalos AM, Marshak-Rothstein A, Viglianti GA (2009) Toll-like receptor-dependent immune complex activation of B cells and dendritic cells. Humana Press, Totowa, pp 363–380Google Scholar
  49. 49.
    Lood C, Stenström M, Tydén H et al (2011) Protein synthesis of the pro-inflammatory S100A8/A9 complex in plasmacytoid dendritic cells and cell surface S100A8/A9 on leukocyte subpopulations in systemic lupus erythematosus. Arthritis Res Ther 13:R60.  https://doi.org/10.1186/ar3314 Google Scholar
  50. 50.
    Ghosh HS, Cisse B, Bunin A et al (2010) Continuous expression of the transcription factor E2-2 maintains the cell fate of mature plasmacytoid dendritic cells. Immunity 33:905–916.  https://doi.org/10.1016/j.immuni.2010.11.023 Google Scholar
  51. 51.
    Bianchi ME (2006) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81:1–5.  https://doi.org/10.1189/jlb.0306164 Google Scholar
  52. 52.
    Ghavami S, Eshragi M, Ande SR et al (2010) S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3. Cell Res 20:314–331.  https://doi.org/10.1038/cr.2009.129 Google Scholar
  53. 53.
    Gestermann N, Di Domizio J, Lande R et al (2018) Netting neutrophils activate autoreactive B cells in lupus. J Immunol 200:3364–3371.  https://doi.org/10.4049/jimmunol.1700778 Google Scholar
  54. 54.
    Villanueva E, Yalavarthi S, Berthier CC et al (2011) Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol 187:538–552.  https://doi.org/10.4049/jimmunol.1100450 Google Scholar
  55. 55.
    Brinkmann V, Reichard U, Goosmann C et al (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535.  https://doi.org/10.1126/science.1092385 Google Scholar
  56. 56.
    Lande R, Ganguly D, Facchinetti V et al (2012) Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA–peptide complexes in systemic lupus erythematosus. Sci Transl Med 3:1–20.  https://doi.org/10.1126/scitranslmed.3001180.Neutrophils Google Scholar
  57. 57.
    Garcia-Romo GS, Caielli S, Vega B et al (2011) Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 3:73ra20.  https://doi.org/10.1126/scitranslmed.3001201 Google Scholar
  58. 58.
    Hakkim A, Furnrohr BG, Amann K et al (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci 107:9813–9818.  https://doi.org/10.1073/pnas.0909927107 Google Scholar
  59. 59.
    Urban CF, Ermert D, Schmid M et al (2009) Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog 5:e1000639.  https://doi.org/10.1371/journal.ppat.1000639 Google Scholar
  60. 60.
    Richardson BC, Yung RL, Johnson KJ et al (1996) Monocyte apoptosis in patients with active lupus. Arthritis Rheum 39:1432–1434Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of RheumatologyPragueCzech Republic
  2. 2.Department of Rheumatology, First Faculty of MedicineCharles UniversityPragueCzech Republic
  3. 3.Institute of Biostatistics and Analyses, Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  4. 4.Neuro-Oncology Group, Laboratory of Neuroplasticity, Dept. of Neuroscience and Pharmacology, Faculty of Health and Medical ScienceUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations