Skip to main content
SpringerLink
Log in

Serum heat shock protein 60 can predict remission of flare-up in juvenile idiopathic arthritis

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

Abstract

Heat shock protein (Hsp) 60 has been implicated in the pathogenesis of various inflammatory and autoimmune diseases. This study aimed to investigate synovial fluid and serum concentrations of Hsp60 and anti-Hsp60 and their relationship with juvenile idiopathic arthritis (JIA). Forty-eight patients with JIA, including 22 oligo-articular, 19 poly-articular, and 7 systemic diseases, and 33 normal controls were enrolled in this study. Synovial fluid and serum Hsp60 and anti-Hsp60 concentrations were measured via ELISA. Serum concentrations of Hsp60 of active and inactive oligo- and poly-articular JIA were significantly higher than those of normal controls. Serum concentration of anti-Hsp60 in active oligo-articular JIA was higher than that of normal controls (49.25 vs. 35.76 ng/mL, p = 0.059). Similarly, serum concentration of anti-Hsp60 in active poly-articular JIA was significantly higher than that of inactive samples (65.05 vs. 26.54 ng/mL, p = 0.008). In addition, serum concentration of Hsp60 correlated with the time required for remission from flare-ups in patients with JIA. Serum concentration of Hsp60 correlated well with time required for remission from flare-ups in patients with JIA, representing a potential disease marker to monitor disease activity.

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

Similar content being viewed by others

Abbreviations

Hsp:

Heat shock protein

JIA:

Juvenile idiopathic arthritis

Treg:

Regulatory T cells

TLR:

Toll-like receptor

CD:

Cluster of differentiation

APC:

Antigen-presenting cells

MyD88:

Myeloid differentiation factor 88

TIR:

Toll/interleukin-1 receptor

TIRAP:

TIR domain-containing adaptor

TRIF:

TIR domain-containing adapter-inducing interferon-β

PBMC:

Peripheral blood-derived mononuclear cells

IL:

Interleukin

IFN:

Interferon

References

  1. Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science (New York, NY) 295(5561):1852–1858

    Article  CAS  Google Scholar 

  2. Bukau B, Weissman J, Horwich A (2006) Molecular chaperones and protein quality control. Cell 125(3):443–451

    Article  PubMed  CAS  Google Scholar 

  3. Beg AA (2002) Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 23(11):509–512

    Article  PubMed  CAS  Google Scholar 

  4. Srivastava P (2002) Roles of heat-shock proteins in innate and adaptive immunity. Nat rev 2(3):185–194

    Article  CAS  Google Scholar 

  5. Zanin-Zhorov A, Bruck R, Tal G, Oren S, Aeed H, Hershkoviz R, Cohen IR, Lider O (2005) Heat shock protein 60 inhibits th1-mediated hepatitis model via innate regulation of th1/th2 transcription factors and cytokines. J Immunol 174(6):3227–3236

    PubMed  CAS  Google Scholar 

  6. Zanin-Zhorov A, Cahalon L, Tal G, Margalit R, Lider O, Cohen IR (2006) Heat shock protein 60 enhances CD4+ CD25+ regulatory t cell function via innate tlr2 signaling. J Clin Investig 116(7):2022–2032

    Article  PubMed  CAS  Google Scholar 

  7. Zanin-Zhorov A, Nussbaum G, Franitza S, Cohen IR, Lider O (2003) T cells respond to heat shock protein 60 via tlr2: activation of adhesion and inhibition of chemokine receptors. FASEB J 17(11):1567–1569

    PubMed  CAS  Google Scholar 

  8. Cohen-Sfady M, Nussbaum G, Pevsner-Fischer M, Mor F, Carmi P, Zanin-Zhorov A, Lider O, Cohen IR (2005) Heat shock protein 60 activates B cells via the tlr4-myd88 pathway. J Immunol 175(6):3594–3602

    PubMed  CAS  Google Scholar 

  9. Arnold-Schild D, Hanau D, Spehner D, Schmid C, Rammensee HG, de la Salle H, Schild H (1999) Cutting edge: receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells. J Immunol 162(7):3757–3760

    PubMed  CAS  Google Scholar 

  10. Theriault JR, Mambula SS, Sawamura T, Stevenson MA, Calderwood SK (2005) Extracellular Hsp70 binding to surface receptors present on antigen presenting cells and endothelial/epithelial cells. FEBS Lett 579(9):1951–1960

    Article  PubMed  CAS  Google Scholar 

  11. Basu S, Binder RJ, Ramalingam T, Srivastava PK (2001) Cd91 is a common receptor for heat shock proteins gp96, Hsp90, Hsp70, and calreticulin. Immunity 14(3):303–313

    Article  PubMed  CAS  Google Scholar 

  12. Wang Y, Kelly CG, Karttunen JT, Whittall T, Lehner PJ, Duncan L, MacAry P, Younson JS, Singh M, Oehlmann W, Cheng G, Bergmeier L, Lehner T (2001) CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity 15(6):971–983

    Article  PubMed  CAS  Google Scholar 

  13. Floto RA, MacAry PA, Boname JM, Mien TS, Kampmann B, Hair JR, Huey OS, Houben EN, Pieters J, Day C, Oehlmann W, Singh M, Smith KG, Lehner PJ (2006) Dendritic cell stimulation by mycobacterial Hsp70 is mediated through CCR5. Science (New York, NY) 314(5798):454–458

    Article  CAS  Google Scholar 

  14. Perschinka H, Wellenzohn B, Parson W, van der Zee R, Willeit J, Kiechl S, Wick G (2007) Identification of atherosclerosis-associated conformational heat shock protein 60 epitopes by phage display and structural alignment. Atherosclerosis 194(1):79–87

    Article  PubMed  Google Scholar 

  15. Xiao Q, Mandal K, Schett G, Mayr M, Wick G, Oberhollenzer F, Willeit J, Kiechl S, Xu Q (2005) Association of serum-soluble heat shock protein 60 with carotid atherosclerosis: clinical significance determined in a follow-up study. Stroke: A Journal of Cerebral Circulation 36(12):2571–2576

    CAS  Google Scholar 

  16. Gaston JS, Life PF, Bailey LC, Bacon PA (1989) In vitro responses to a 65-kilodalton mycobacterial protein by synovial T cells from inflammatory arthritis patients. J Immunol 143(8):2494–2500

    PubMed  CAS  Google Scholar 

  17. van Eden W, Thole JE, van der Zee R, Noordzij A, van Embden JD, Hensen EJ, Cohen IR (1988) Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature 331(6152):171–173

    Article  PubMed  Google Scholar 

  18. Conroy SE, Tucker L, Latchman DS, Isenberg DA (1996) Incidence of anti Hsp90 and 70 antibodies in children with SLE, juvenile dermatomyositis and juvenile chronic arthritis. Clin Exp Rheumatol 14(1):99–104

    PubMed  CAS  Google Scholar 

  19. Elst EF, Klein M, de Jager W, Kamphuis S, Wedderburn LR, van der Zee R, Albani S, Kuis W, Prakken BJ (2008) Hsp60 in inflamed muscle tissue is the target of regulatory autoreactive T cells in patients with juvenile dermatomyositis. Arthritis Rheum 58(2):547–555

    Article  PubMed  CAS  Google Scholar 

  20. Laad AD, Thomas ML, Fakih AR, Chiplunkar SV (1999) Human gamma delta T cells recognize heat shock protein-60 on oral tumor cells. Int J Cancer 80(5):709–714

    Article  PubMed  CAS  Google Scholar 

  21. Thomas ML, Samant UC, Deshpande RK, Chiplunkar SV (2000) Gammadelta T cells lyse autologous and allogenic oesophageal tumours: involvement of heat-shock proteins in the tumour cell lysis. Cancer Immunol Immunother 48(11):653–659

    Article  PubMed  CAS  Google Scholar 

  22. Anthony LS, Wu H, Sweet H, Turnnir C, Boux LJ, Mizzen LA (1999) Priming of CD8+ ctl effector cells in mice by immunization with a stress protein-influenza virus nucleoprotein fusion molecule. Vaccine 17(4):373–383

    Article  PubMed  CAS  Google Scholar 

  23. Blachere NE, Li Z, Chandawarkar RY, Suto R, Jaikaria NS, Basu S, Udono H, Srivastava PK (1997) Heat shock protein–peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med 186(8):1315–1322

    Article  PubMed  CAS  Google Scholar 

  24. Gao B, Tsan MF (2003) Recombinant human heat shock protein 60 does not induce the release of tumor necrosis factor alpha from murine macrophages. J Biol Chem 278(25):22523–22529

    Article  PubMed  CAS  Google Scholar 

  25. Gao B, Tsan MF (2003) Endotoxin contamination in recombinant human heat shock protein 70 (Hsp70) preparation is responsible for the induction of tumor necrosis factor alpha release by murine macrophages. J Biol Chem 278(1):174–179

    Article  PubMed  CAS  Google Scholar 

  26. Osterloh A, Meier-Stiegen F, Veit A, Fleischer B, von Bonin A, Breloer M (2004) Lipopolysaccharide-free heat shock protein 60 activates T cells. J Biol Chem 279(46):47906–47911

    Article  PubMed  CAS  Google Scholar 

  27. Panjwani NN, Popova L, Srivastava PK (2002) Heat shock proteins gp96 and Hsp70 activate the release of nitric oxide by APCS. J Immunol 168(6):2997–3003

    PubMed  CAS  Google Scholar 

  28. van den Broek MF, Hogervorst EJ, Van Bruggen MC, Van Eden W, van der Zee R, van den Berg WB (1989) Protection against streptococcal cell wall-induced arthritis by pretreatment with the 65-kD mycobacterial heat shock protein. J Exp Med 170(2):449–466

    Article  PubMed  Google Scholar 

  29. Thompson SJ, Francis JN, Siew LK, Webb GR, Jenner PJ, Colston MJ, Elson CJ (1998) An immunodominant epitope from mycobacterial 65-kDa heat shock protein protects against pristane-induced arthritis. J Immunol 160(9):4628–4634

    PubMed  CAS  Google Scholar 

  30. Kingston AE, Hicks CA, Colston MJ, Billingham ME (1996) A 71-kD heat shock protein (Hsp) from mycobacterium tuberculosis has modulatory effects on experimental rat arthritis. Clin Exp Immunol 103(1):77–82

    Article  PubMed  CAS  Google Scholar 

  31. Huang JL, Kuo ML, Hung IJ, Wu CJ, Ou LH, Cheng JH (2001) Lowered IL-4-producing t cells and decreased IL-4 secretion in peripheral blood from subjects with juvenile rheumatoid arthritis. Chang Gung Med J 24(2):77–83

    PubMed  CAS  Google Scholar 

  32. Nguyen TT, Zlacka D, Vavrincova P, Sedlacek P, Hromadnikova I (2006) Detection of antibodies against 60-, 65- and 70-kDa heat shock proteins in paediatric patients with various disorders using Western blotting and elisa. Clin Chem Lab Med 44(4):442–449

    Article  PubMed  CAS  Google Scholar 

  33. Zlacka D, Vavrincova P, Hien Nguyen TT, Hromadnikova I (2006) Frequency of anti-Hsp60, -65 and -70 antibodies in sera of patients with juvenile idiopathic arthritis. J Autoimmun 27(2):81–88

    Article  PubMed  CAS  Google Scholar 

  34. Petty RE, Southwood TR, Baum J, Bhettay E, Glass DN, Manners P, Maldonado-Cocco J, Suarez-Almazor M, Orozco-Alcala J, Prieur AM (1998) Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 25(10):1991–1994

    PubMed  CAS  Google Scholar 

  35. Pinals RS, Masi AT, Larsen RA (1981) Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 24(10):1308–1315

    Article  PubMed  CAS  Google Scholar 

  36. Kumaraguru U, Pack CD, Rouse BT (2003) Toll-like receptor ligand links innate and adaptive immune responses by the production of heat-shock proteins. J Leukoc Biol 73(5):574–583

    Article  PubMed  CAS  Google Scholar 

  37. Bulut Y, Michelsen KS, Hayrapetian L, Naiki Y, Spallek R, Singh M, Arditi M (2005) Mycobacterium tuberculosis heat shock proteins use diverse Toll-like receptor pathways to activate pro-inflammatory signals. J Biol Chem 280(22):20961–20967

    Article  PubMed  CAS  Google Scholar 

  38. Quintana FJ, Carmi P, Mor F, Cohen IR (2002) Inhibition of adjuvant arthritis by a DNA vaccine encoding human heat shock protein 60. J Immunol 169(6):3422–3428

    PubMed  CAS  Google Scholar 

  39. de Kleer IM, Kamphuis SM, Rijkers GT, Scholtens L, Gordon G, De Jager W, Hafner R, van de Zee R, van Eden W, Kuis W, Prakken BJ (2003) The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat-shock protein 60 capable of producing the regulatory cytokine interleukin-10. Arthritis Rheum 48(7):2001–2010

    Article  PubMed  Google Scholar 

  40. Kamphuis S, Kuis W, de Jager W, Teklenburg G, Massa M, Gordon G, Boerhof M, Rijkers GT, Uiterwaal CS, Otten HG, Sette A, Albani S, Prakken BJ (2005) Tolerogenic immune responses to novel T-cell epitopes from heat-shock protein 60 in juvenile idiopathic arthritis. Lancet 366(9479):50–56

    Article  PubMed  CAS  Google Scholar 

  41. Prakken BJ, Roord S, van Kooten PJ, Wagenaar JP, van Eden W, Albani S, Wauben MH (2002) Inhibition of adjuvant-induced arthritis by interleukin-10-driven regulatory cells induced via nasal administration of a peptide analog of an arthritis-related heat-shock protein 60 T cell epitope. Arthritis Rheum 46(7):1937–1946

    Article  PubMed  CAS  Google Scholar 

  42. Nguyen TT, Gehrmann M, Zlacka D, Sosna A, Vavrincova P, Multhoff G, Hromadnikova I (2006) Heat shock protein 70 membrane expression on fibroblast-like synovial cells derived from synovial tissue of patients with rheumatoid and juvenile idiopathic arthritis. Scand J Rheumatol 35(6):447–453

    Article  PubMed  CAS  Google Scholar 

  43. Yokota S, Minota S, Fujii N (2006) Anti-Hsp auto-antibodies enhance Hsp-induced pro-inflammatory cytokine production in human monocytic cells via Toll-like receptors. Int Immunol 18(4):573–580

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Science Council, Taiwan (grant no. NSC95-2314-B-182A-172-MY3, to JH).

Competing interests

The author(s) declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, 5 Fu-Hsin Street, Kueishan, Taoyuan, Taiwan

    Chih-Te Charles Wu, Liang-Shiou Ou, Kuo-Wei Yeh, Wen-I Lee & Jing-Long Huang

Authors
  1. Chih-Te Charles Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liang-Shiou Ou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kuo-Wei Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-I Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing-Long Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jing-Long Huang.

Additional information

Wu and Ou contributed equally to this paper.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, CT.C., Ou, LS., Yeh, KW. et al. Serum heat shock protein 60 can predict remission of flare-up in juvenile idiopathic arthritis. Clin Rheumatol 30, 959–965 (2011). https://doi.org/10.1007/s10067-011-1709-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-011-1709-2

Keywords

Search

Navigation