HSP Reactive T Cells are Anti-Inflammatory and Disease Suppressive in Arthritic Diseases

  • Femke Broere
  • Suzanne E. Berlo
  • Teun Guichelaar
  • Lotte Wieten
  • Ruurd Van Der Zee
  • Willem Van EdenEmail author
Part of the Heat Shock Proteins book series (HESP, volume 5)


Immune responses to certain heat-shock proteins (HSP) develop in virtually all inflammatory diseases; however, the significance of such responses is only now becoming clear. In models of experimental arthritis, HSPs can prevent or arrest inflammatory damage, and in initial clinical trials in patients with chronic inflammatory diseases, including rheumatoid arthritis, HSP peptides have been shown to promote the production of anti-inflammatory cytokines, indicating immunoregulatory potential of HSP. Heat shock proteins, also called stress-proteins, are ubiquitous self-antigens that are over-expressed in inflamed tissues. For some reason, the prokaryotic homologous proteins, present in every bacterial species, are dominantly immunogenic. This is striking, especially given the fact that these proteins have large areas of sequence homologies with the host (mammalian) counterparts. Furthermore, in experimental models of arthritis, immunisation with bacterial heat shock proteins has been seen to lead to inhibition of disease development. In addition oral or nasal administration has similarly been seen to lead to disease inhibition. Based on the experimental evidence collected, it becomes attractive to suppose that the exposure to homologues of these self antigens, as present in for instance the bacterial intestinal flora, has a decisive impact on the regulation of self tolerance at the level of T cells. If so, it becomes attractive to use such proteins or their derivative peptides for modulation of inflammation relevant T cells as an antigen specific immunotherapy approach, without the immediate necessity of defining disease specific auto-antigens


Heat shock proteins arthritis T cells immune regulation 



antigen presenting cells


altered peptide ligands


Bacillus Calmette-Guérin


dendritic cells


disease-modifying anti-rheumatic drugs


experimental autoimmune encephalomyelitis


heat shock proteins


inflammatory bowel disease




major histocompatibility complex


Rheumatoid arthritis


T cell receptor




transforming growth factor-β


toll like receptor


tumor necrosis factor-alpha


  1. Aarts-Riemens, T., Emmelot, M. E., Verdonck, L. F. and Mutis, T. (2008) Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4(+)CD25(–) cells. Eur J Immunol 38, 1381–90.CrossRefPubMedGoogle Scholar
  2. Alamanos, Y. and Drosos, A. A. (2005) Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 4, 130–6.CrossRefPubMedGoogle Scholar
  3. Anderton, S. M., van der Zee, R., Prakken, B., Noordzij, A. and van Eden, W. (1995) Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis. J Exp Med 181, 943–52.CrossRefPubMedGoogle Scholar
  4. Bardos, T., Czipri, M., Vermes, C., Zhang, J., Mikecz, K. and Glant, T. T. (2002a) Continuous nasal administration of antigen is critical to maintain tolerance in adoptively transferred autoimmune arthritis in SCID mice. Clin Exp Immunol 129, 224–31.CrossRefPubMedGoogle Scholar
  5. Bardos, T., Mikecz, K., Finnegan, A., Zhang, J. and Glant, T. T. (2002b) T and B cell recovery in arthritis adoptively transferred to SCID mice: antigen-specific activation is required for restoration of autopathogenic CD4+ Th1 cells in a syngeneic system. J Immunol 168, 6013–21.PubMedGoogle Scholar
  6. Berlo, S. E., Guichelaar, T., Ten Brink, C. B., van Kooten, P. J., Hauet-Broeren, F., Ludanyi, K., van Eden, W., Broeren, C. P. and Glant, T. T. (2006) Increased arthritis susceptibility in cartilage proteoglycan-specific T cell receptor-transgenic mice. Arthritis Rheum 54, 2423–33.CrossRefPubMedGoogle Scholar
  7. Berlo, S. E., van Kooten, P. J., Ten Brink, C. B., Hauet-Broere, F., Oosterwegel, M. A., Glant, T. T., Van Eden, W. and Broeren, C. P. (2005) Naive transgenic T cells expressing cartilage proteoglycan-specific TCR induce arthritis upon in vivo activation. J Autoimmun 25, 172–80.PubMedGoogle Scholar
  8. Bettelli, E., Oukka, M. and Kuchroo, V. K. (2007) T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8, 345–50.CrossRefPubMedGoogle Scholar
  9. Bluestone, J. A. (2005) Regulatory T-cell therapy: is it ready for the clinic? Nat Rev Immunol 5, 343–9.CrossRefPubMedGoogle Scholar
  10. Boots, A. M., Verheijden, G. F., Schoningh, R., van Staveren, C. J., Bos, E., Elewaut, D., de Keyser, F., Veys, E., Joosten, I. and Rijnders, A. W. (1997) Selection of self-reactive peptides within human aggrecan by use of a HLA-DRB1*0401 peptide binding motif. J Autoimmun 10, 569–78.CrossRefPubMedGoogle Scholar
  11. Brand, D. D., Kang, A. H. and Rosloniec, E. F. (2003) Immunopathogenesis of collagen arthritis. Springer Semin Immunopathol 25, 3–18.CrossRefPubMedGoogle Scholar
  12. Broere, F., Wieten, L., Klein Koerkamp, E. I., van Roon, J. A., Guichelaar, T., Lafeber, F. P. and van Eden, W. (2008) Oral or nasal antigen induces regulatory T cells that suppress arthritis and proliferation of arthritogenic T cells in joint draining lymph nodes. J Immunol 181, 899–906.PubMedGoogle Scholar
  13. Carlsen, S., Hansson, A. S., Olsson, H., Heinegard, D. and Holmdahl, R. (1998) Cartilage oligomeric matrix protein (COMP)-induced arthritis in rats. Clin Exp Immunol 114, 477–84.CrossRefPubMedGoogle Scholar
  14. Chen, W., Jin, W., Hardegen, N., Lei, K. J., Li, L., Marinos, N., McGrady, G. and Wahl, S. M. (2003) Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198, 1875–86.CrossRefPubMedGoogle Scholar
  15. Detanico, T., Rodrigues, L., Sabritto, A. C., Keisermann, M., Bauer, M. E., Zwickey, H. and Bonorino, C. (2004) Mycobacterial heat shock protein 70 induces interleukin-10 production: immunomodulation of synovial cell cytokine profile and dendritic cell maturation. Clin Exp Immunol 135, 336–42.CrossRefPubMedGoogle Scholar
  16. Ding, X. Z., Fernandez-Prada, C. M., Bhattacharjee, A. K. and Hoover, D. L. (2001) Over-expression of hsp-70 inhibits bacterial lipopolysaccharide-induced production of cytokines in human monocyte-derived macrophages. Cytokine 16, 210–9.CrossRefPubMedGoogle Scholar
  17. Fleischmann, R. and Yocum, D. (2004) Does safety make a difference in selecting the right TNF antagonist? Arthritis Res Ther 6 Suppl 2, S12–8.CrossRefPubMedGoogle Scholar
  18. Floto, R. A., MacAry, P. A., Boname, J. M., Mien, T. S., Kampmann, B., Hair, J. R., Huey, O. S., Houben, E. N., Pieters, J., Day, C., Oehlmann, W., Singh, M., Smith, K. G. and Lehner, P. J. (2006) Dendritic cell stimulation by mycobacterial Hsp70 is mediated through CCR5. Science 314, 454–8.CrossRefPubMedGoogle Scholar
  19. Gao, B. and Tsan, M. F. (2003) Recombinant human heat shock protein 60 does not induce the release of tumor necrosis factor alpha from murine macrophages. J Biol Chem 278, 22523–9.CrossRefPubMedGoogle Scholar
  20. Gao, B. and Tsan, M. F. (2004) Induction of cytokines by heat shock proteins and endotoxin in murine macrophages. Biochem Biophys Res Commun 317, 1149–54.CrossRefPubMedGoogle Scholar
  21. Glant, T. T., Buzas, E. I., Finnegan, A., Negroiu, G., Cs-Szabo, G. and Mikecz, K. (1998a) Critical roles of glycosaminoglycan side chains of cartilage proteoglycan (aggrecan) in antigen recognition and presentation. J Immunol 160, 3812–9.PubMedGoogle Scholar
  22. Glant, T., Csongor, J. and Szucs, T. (1980) Immunopathologic role of proteoglycan antigens in rheumatoid joint disease. Scand J Immunol 11, 247–52.CrossRefPubMedGoogle Scholar
  23. Glant, T. T., Cs-Szabo, G., Nagase, H., Jacobs, J. J. and Mikecz, K. (1998b) Progressive polyarthritis induced in BALB/c mice by aggrecan from normal and osteoarthritic human cartilage. Arthritis Rheum 41, 1007–18.CrossRefPubMedGoogle Scholar
  24. Glant, T. T., Finnegan, A. and Mikecz, K. (2003) Proteoglycan-induced arthritis: immune regulation, cellular mechanisms, and genetics. Crit Rev Immunol 23, 199–250.CrossRefPubMedGoogle Scholar
  25. Glant, T. T., Mikecz, K., Arzoumanian, A. and Poole, A. R. (1987) Proteoglycan-induced arthritis in BALB/c mice. Clinical features and histopathology. Arthritis Rheum 30, 201–12.CrossRefPubMedGoogle Scholar
  26. Glant, T. T., Mikecz, K., Thonar, E. J. M. A. and Kuettner, K. E. (1992) Immune responses to cartilage proteoglycans in inflammatory animal models and human diseases. In Cartilage Degradation: Basic and Clinical Aspects, Woessner, J. F. and Howell, D. S. eds, pp. 435–73. Marcel Dekker Inc., New York.Google Scholar
  27. Goodstone, N. J., Doran, M. C., Hobbs, R. N., Butler, R. C., Dixey, J. J. and Ashton, B. A. (1996) Cellular immunity to cartilage aggrecan core protein in patients with rheumatoid arthritis and non-arthritic controls. Ann Rheum Dis 55, 40–6.CrossRefPubMedGoogle Scholar
  28. Goronzy, J. J. and Weyand, C. M. (2005) Rheumatoid arthritis. Immunol Rev 204, 55–73.CrossRefPubMedGoogle Scholar
  29. Groux, H., O’Garra, A., Bigler, M., Rouleau, M., Antonenko, S., de Vries, J. E. and Roncarolo, M. G. (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–42.CrossRefPubMedGoogle Scholar
  30. Guerassimov, A., Zhang, Y., Banerjee, S., Cartman, A., Leroux, J. Y., Rosenberg, L. C., Esdaile, J., Fitzcharles, M. A. and Poole, A. R. (1998) Cellular immunity to the G1 domain of cartilage proteoglycan aggrecan is enhanced in patients with rheumatoid arthritis but only after removal of keratan sulfate. Arthritis Rheum 41, 1019–25.CrossRefPubMedGoogle Scholar
  31. Guichelaar, T., ten Brink, C. B., van Kooten, P. J., Berlo, S. E., Broeren, C. P., van Eden, W. and Broere, F. (2008a) Autoantigen-specific IL-10-transduced T cells suppress chronic arthritis by promoting the endogenous regulatory IL-10 response. J Immunol 180, 1373–81.PubMedGoogle Scholar
  32. Guichelaar, T., Ten Brink, C. B., van Kooten, P. J., Berlo, S. E., Lafeber, F. P., Broeren, C. P., van Eden, W. and Broere, F. (2008b) Cartilage proteoglycan-specific T cells as vectors of immunomodulatory biologicals in chronic proteoglycan-induced arthritis. Mol Immunol 45, 3526–35.CrossRefPubMedGoogle Scholar
  33. Hanninen, A. and Harrison, L. C. (2004) Mucosal tolerance to prevent type 1 diabetes: can the outcome be improved in humans? Rev Diabet Stud 1, 113–21.CrossRefPubMedGoogle Scholar
  34. Hollo, K., Glant, T. T., Garzo, M., Finnegan, A., Mikecz, K. and Buzas, E. (2000) Complex pattern of Th1 and Th2 activation with a preferential increase of autoreactive Th1 cells in BALB/c mice with proteoglycan (aggrecan)-induced arthritis. Clin Exp Immunol 120, 167–73.CrossRefPubMedGoogle Scholar
  35. Holmdahl, R. (2000) Experimental models for rheumatoid arthritis. In Rheumatoid Arthritis: Frontiers in Pathogenesis and Treatment, Firestein, G. S., Panayi, G. S. and Wollheim, F. A. eds, pp. 39–51. Oxford, New York.Google Scholar
  36. Hori, S., Nomura, T. and Sakaguchi, S. (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–61.CrossRefPubMedGoogle Scholar
  37. Klareskog, L. and McDevitt, H. (1999) Rheumatoid arthritis and its animal models: the role of TNF-alpha and the possible absence of specific immune reactions. Curr Opin Immunol 11, 657–62.CrossRefPubMedGoogle Scholar
  38. Klippel, J. H. ed (2001) Primer on the Rheumatic Diseases. Arthritis Foundation, Atlanta.Google Scholar
  39. Lee, D. M. and Weinblatt, M. E. (2001) Rheumatoid arthritis. Lancet 358, 903–11.CrossRefPubMedGoogle Scholar
  40. Li, N. L., Zhang, D. Q., Zhou, K. Y., Cartman, A., Leroux, J. Y., Poole, A. R. and Zhang, Y. P. (2000) Isolation and characteristics of autoreactive T cells specific to aggrecan G1 domain from rheumatoid arthritis patients. Cell Res 10, 39–49.CrossRefPubMedGoogle Scholar
  41. Liew, F. Y. (2002) T(H)1 and T(H)2 cells: a historical perspective. Nat Rev Immunol 2, 55–60.CrossRefPubMedGoogle Scholar
  42. Mikecz, K. and Glant, T. T. (1994) Migration and homing of lymphocytes to lymphoid and synovial tissues in proteoglycan-induced murine arthritis. Arthritis Rheum 37, 1395–403.CrossRefPubMedGoogle Scholar
  43. Mikecz, K. and Glant, T. T. (1996) Immunoregulation of proteoglycan-induced arthritis in Balb/c mice. Am J Ther 3, 42–51.CrossRefPubMedGoogle Scholar
  44. Mikecz, K., Glant, T. T., Buzas, E. and Poole, A. R. (1990) Proteoglycan-induced polyarthritis and spondylitis adoptively transferred to naive (nonimmunized) BALB/c mice. Arthritis Rheum 33, 866–76.CrossRefPubMedGoogle Scholar
  45. Mikecz, K., Glant, T. T. and Poole, A. R. (1987) Immunity to cartilage proteoglycans in BALB/c mice with progressive polyarthritis and ankylosing spondylitis induced by injection of human cartilage proteoglycan. Arthritis Rheum 30, 306–18.CrossRefPubMedGoogle Scholar
  46. Miller, S. D., Turley, D. M. and Podojil, J. R. (2007) Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. Nat Rev Immunol 7, 665–77.CrossRefPubMedGoogle Scholar
  47. Motta, A., Schmitz, C., Rodrigues, L., Ribeiro, F., Teixeira, C., Detanico, T., Bonan, C., Zwickey, H. and Bonorino, C. (2007) Mycobacterium tuberculosis heat-shock protein 70 impairs maturation of dendritic cells from bone marrow precursors, induces interleukin-10 production and inhibits T-cell proliferation in vitro. Immunology 121, 462–72.CrossRefPubMedGoogle Scholar
  48. Nepom, G. T. (2001) The role of the DR4 shared epitope in selection and commitment of autoreactive T cells in rheumatoid arthritis. Rheum Dis Clin North Am 27, 305–15.CrossRefPubMedGoogle Scholar
  49. Ochsenkuhn, T., Weber, M. M. and Caselmann, W. H. (1990) Arthritis after Mycobacterium bovis immunotherapy for bladder cancer [letter; comment]. Ann Intern Med 112, 882.PubMedGoogle Scholar
  50. Panjwani, N. N., Popova, L. and Srivastava, P. K. (2002) Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J Immunol 168, 2997–3003.PubMedGoogle Scholar
  51. Pincus, T. and Callahan, L. F. (1989) Reassessment of twelve traditional paradigms concerning the diagnosis, prevalence, morbidity and mortality of rheumatoid arthritis. Scand J Rheumatol Suppl 79, 67–96.CrossRefPubMedGoogle Scholar
  52. Pockley, A. G. (2003) Heat shock proteins as regulators of the immune response. Lancet 362, 469–76.CrossRefPubMedGoogle Scholar
  53. Poole, A. R., Glant, T. T. and Mikecz, K. (1988) Autoimmunity to cartilage collagen and proteoglycan and the development of chronic inflammatory arthritis. In The Control of Tissue Damage, Glaurer, A. M. ed, pp. 55–65. Elsevier Publishers (Biomedical Division), Amsterdam.Google Scholar
  54. Poole, A. R., Ionescu, M., Swan, A. and Dieppe, P. A. (1994) Changes in cartilage metabolism in arthritis are reflected by altered serum and synovial fluid levels of the cartilage proteoglycan aggrecan. Implications for pathogenesis. J Clin Invest 94, 25–33.CrossRefPubMedGoogle Scholar
  55. Prakken, B. J., Albani, S. and van Eden, W. (2007) Translating immunological tolerance into therapy. Eur J Immunol 37, 2360–3.CrossRefGoogle Scholar
  56. Quintana, F. J., Carmi, P., Mor, F. and Cohen, I. R. (2004) Inhibition of adjuvant-induced arthritis by DNA vaccination with the 70-kd or the 90-kd human heat-shock protein: immune cross-regulation with the 60-kd heat-shock protein. Arthritis Rheum 50, 3712–20.CrossRefPubMedGoogle Scholar
  57. Roord, S. T., Zonneveld-Huijssoon, E., Le, T., Yung, G. P., Koffeman, E., Ronaghy, A., Ghahramani, N., Lanza, P., Billetta, R., Prakken, B. J. and Albani, S. (2006) Modulation of T cell function by combination of epitope specific and low dose anticytokine therapy controls autoimmune arthritis. PLoS ONE 1, e87.CrossRefPubMedGoogle Scholar
  58. Rosenberg, L. C. and Buckwalter, J. A. (1986) Cartilage proteoglycans. In Articular Cartilage Biochemistry, Kuettner, K. E., Schleyerbach, R. and Hascall, V. C. eds, pp. 39–57. Raven Press, New York.Google Scholar
  59. Roudier, J. (2000) Association of MHC and rheumatoid arthritis. Association of RA with HLA-DR4: the role of repertoire selection. Arthritis Res 2, 217–20.CrossRefPubMedGoogle Scholar
  60. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. and Toda, M. (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155, 1151–64.PubMedGoogle Scholar
  61. Setoguchi, K., Misaki, Y., Araki, Y., Fujio, K., Kawahata, K., Kitamura, T. and Yamamoto, K. (2000) Antigen-specific T cells transduced with IL-10 ameliorate experimentally induced arthritis without impairing the systemic immune response to the antigen. J Immunol 165, 5980–6.PubMedGoogle Scholar
  62. Silman, A. J. and Pearson, J. E. (2002) Epidemiology and genetics of rheumatoid arthritis. Arthritis Res 4 Suppl 3, S265–72.CrossRefPubMedGoogle Scholar
  63. Stordeur, P. and Goldman, M. (1998) Interleukin-10 as a regulatory cytokine induced by cellular stress: molecular aspects. Int Rev Immunol 16, 501–22.CrossRefPubMedGoogle Scholar
  64. van der Helm-van Mil, A. H., Wesoly, J. Z. and Huizinga, T. W. (2005) Understanding the genetic contribution to rheumatoid arthritis. Curr Opin Rheumatol 17, 299–304.CrossRefPubMedGoogle Scholar
  65. van Eden, W., Thole, J. E., van der Zee, R., Noordzij, A., van Embden, J. D., Hensen, E. J. and Cohen, I. R. (1988) Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature 331, 171–3.CrossRefPubMedGoogle Scholar
  66. van Eden, W., van der Zee, R. and Prakken, B. (2005) Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol 5, 318–30.CrossRefPubMedGoogle Scholar
  67. Van Eden, W. and Waksman, B. H. (2003) Immune regulation in adjuvant-induced arthritis: possible implications for innovative therapeutic strategies in arthritis. Arthritis Rheum 48, 1788–96.CrossRefPubMedGoogle Scholar
  68. van Puijvelde, G. H., van Es, T., van Wanrooij, E. J., Habets, K. L., de Vos, P., van der Zee, R., van Eden, W., van Berkel, T. J. and Kuiper, J. (2007) Induction of oral tolerance to HSP60 or an HSP60-peptide activates T cell regulation and reduces atherosclerosis. Arterioscler Thromb Vasc Biol 27, 2677–83.CrossRefPubMedGoogle Scholar
  69. Verheijden, G. F., Rijnders, A. W., Bos, E., Coenen-de Roo, C. J., van Staveren, C. J., Miltenburg, A. M., Meijerink, J. H., Elewaut, D., de Keyser, F., Veys, E. and Boots, A. M. (1997) Human cartilage glycoprotein-39 as a candidate autoantigen in rheumatoid arthritis. Arthritis Rheum 40, 1115–25.CrossRefPubMedGoogle Scholar
  70. Voll, R. E. and Kalden, J. R. (2005) Do we need new treatment that goes beyond tumor necrosis factor blockers for rheumatoid arthritis? Ann N Y Acad Sci 1051, 799–810.CrossRefPubMedGoogle Scholar
  71. von Herrath, M. G. and Harrison, L. C. (2003) Antigen-induced regulatory T cells in autoimmunity. Nat Rev Immunol 3, 223–32.CrossRefGoogle Scholar
  72. Wang, Y., Gao, B. and Tsan, M. F. (2005) Induction of cytokines by heat shock proteins and concanavalin A in murine splenocytes. Cytokine 32, 149–54.CrossRefPubMedGoogle Scholar
  73. Wauben, M. H., Boog, C. J., van der Zee, R., Joosten, I., Schlief, A. and van Eden, W. (1992) Disease inhibition by major histocompatibility complex binding peptide analogues of disease-associated epitopes: more than blocking alone. J Exp Med 176, 667–77.CrossRefPubMedGoogle Scholar
  74. Wendling, U., Paul, L., van der Zee, R., Prakken, B., Singh, M. and van Eden, W. (2000) A conserved mycobacterial heat shock protein (hsp) 70 sequence prevents adjuvant arthritis upon nasal administration and induces IL-10-producing T cells that cross-react with the mammalian self-hsp70 homologue. J Immunol 164, 2711–7.PubMedGoogle Scholar
  75. Whittall, T., Wang, Y., Younson, J., Kelly, C., Bergmeier, L., Peters, B., Singh, M. and Lehner, T. (2006) Interaction between the CCR5 chemokine receptors and microbial HSP70. Eur J Immunol 36, 2304–14.CrossRefPubMedGoogle Scholar
  76. Wieten, L., Broere, F., Koffeman, E. C., van Kooten, P. J., Hilbers, J. W., de Jong, H., Berlo, S., Prakken, B., Anderton, S. M., van der Zee, R., van Eden, W. Hsp70 peptides are targets for anti-inflammatory T cells in autoimmune arthritis. Submitted for publication.Google Scholar
  77. Yudoh, K., Matsuno, H., Nakazawa, F., Yonezawa, T. and Kimura, T. (2000) Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis. Arthritis Rheum 43, 617–27.CrossRefPubMedGoogle Scholar
  78. Zou, J., Zhang, Y., Thiel, A., Rudwaleit, M., Shi, S. L., Radbruch, A., Poole, R., Braun, J. and Sieper, J. (2003) Predominant cellular immune response to the cartilage autoantigenic G1 aggrecan in ankylosing spondylitis and rheumatoid arthritis. Rheumatology (Oxford) 42, 846–55.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Femke Broere
    • 1
  • Suzanne E. Berlo
    • 1
  • Teun Guichelaar
    • 1
  • Lotte Wieten
    • 1
  • Ruurd Van Der Zee
    • 1
  • Willem Van Eden
    • 2
    Email author
  1. 1.Division of Immunology, Department of Infectious Diseases and Immunology, Faculty of Veterinary MedicineUniversity of UtrechtUtrechtThe Netherlands
  2. 2.Division of Immunology, Department of Infectious Diseases and Immunology, Faculty of Veterinary MedicineUniversity of UtrechtUtrechtThe Netherlands

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