Skip to main content Accessibility help
×
Home
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 3
  • Print publication year: 2005
  • Online publication date: August 2009

16 - Heat Shock Proteins Regulate Inflammation by Both Molecular and Network Cross-Reactivity

Summary

Introduction

Heat shock proteins were initially identified as heterogeneous families of stress-induced proteins characterised by their chaperone activity [1]. Subsequently, they were identified as immunodominant antigens recognised by the host immune system following microbial infection [2] or during the course of autoimmune disease [3–6]. Recently, the role of heat shock proteins as endogenous activators of the innate and adaptive immune system has been unveiled [7]. In this chapter we discuss the relevance of heat shock proteins and their immune activities to the regulation of inflammation and autoimmune disease. We shall see that the regulatory activities of heat shock proteins on inflammation involve two types of cross-reactivity: molecular cross-reactivity exists between microbial and self-heat shock proteins and network cross-reactivity exists between different self-heat shock proteins.

Inflammation activates heat shock protein–specific T cells

Although the injection of incomplete Freund's adjuvant (IFA) to BALB/c mice induces local inflammation, Anderton and colleagues demonstrated that the injection of IFA also induces T cells reactive with the mammalian 60-kDa heat shock protein (Hsp60) [8]. These Hsp60-reactive T cells were TCRαβ+, CD4+ and major histocompatibility complex (MHC) class II-restricted [8]. Notably, Hsp60-specific cells could only be found in the local lymph nodes draining the site of IFA injection, and they were not present in distant lymph nodes. Hsp60-specific T cells are not only induced but also recruited to the site of inflammation [8].

References
Hartl, F U and Hayer-Hartl, M.Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 2002, 295: 1852–1858
Young, D B, Ivanyi, J, Cox, J H and Lamb, J R.The 65kDa antigen of mycobacteria – a common bacterial protein?Immunol Today 1987, 8: 215–219
Gaston, J S.Heat shock proteins and arthritis – new readers start here. Autoimmunity 1997, 26: 33–42
Dhillon, V, Latchman, D and Isenberg, D.Heat shock proteins and systemic lupus erythematosus. Lupus 1991, 1: 3–8
Lehner, T.The role of heat shock protein, microbial and autoimmune agents in the aetiology of Behcet's disease. Int Rev Immunol 1997, 14: 21–32
Abulafia-Lapid, R, Elias, D, Raz, I, Keren-Zur, Y, Atlan, H and Cohen, I R.T cell proliferative responses to type 1 diabetes patients and healthy individuals to human Hsp60 and its peptides. J Autoimmunity 1999, 12: 121–129
Beg, A A.Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 2002, 23: 509–512
Anderton, S M, Zee, R and Goodacre, J A.Inflammation activates self hsp60-specific T cells. Eur J Immunol 1993, 23: 33–38
Mor, F and Cohen, I R.T cells in the lesion of experimental autoimmune encephalomyelitis. Enrichment for reactivities to myelin basic protein and to heat shock proteins. J Clin Invest 1992, 90: 2447–2455
Birnbaum, G and Kotilinek, L.Heat shock or stress proteins and their role as autoantigens in multiple sclerosis. Ann NY Acad Sci 1997, 835: 157–167
Birnbaum, G.Stress proteins: their role in the normal central nervous system and in disease states, especially multiple sclerosis. Springer Semin Immunopathol 1995, 17: 107–118
Gao, Y L, Brosnan, C F and Raine, C S.Experimental autoimmune encephalomyelitis. Qualitative and semiquantitative differences in heat shock protein 60 expression in the central nervous system. J Immunol 1995, 154: 3548–3556
Pockley, A G.Heat shock proteins, heat shock protein reactivity and allograft rejection. Transplantation 2001, 71: 1503–1507
Wauben M H M, Wagenaar-Hilbers J P A and van Eden W. Adjuvant arthritis. In Cohen, I. R. and Miller, A. (Eds.) Autoimmune Disease Models. Academic Press, Inc., New York 1994, pp 201–216
Elias D. The NOD mouse: a model for autoimmune insulin-dependent diabetes. In Cohen, I. R. and Miller, A. (Eds.) Autoimmune Disease Models. Academic Press, Inc., New York 1994, pp 147–161
Feldmann, M, Brennan, F M and Maini, R N.Rheumatoid arthritis. Cell 1996, 85: 307–310
Tisch, R and McDevitt, H.Insulin-dependent diabetes mellitus. Cell Biol Int 1996, 85: 291–297
Eden, W, Holoshitz, J, Nevo, Z, Frenkel, A, Klajman, A and Cohen, I R.Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc Natl Acad Sci USA 1985, 82: 5117–5120
Billingham, M E J, Carney, S, Butler, R and Colston, M J.A mycobacterial 65-kd heat shock protein induces antigen-specific suppression of adjuvant arthritis, but is not itself arthritogenic. J Exp Med 1990, 171: 339–344
Hogervorst, E J, Schouls, L, Wagenaar, J P, Boog, C J, Spaan, W J, Embden, J D and Eden, W.Modulation of experimental autoimmunity: treatment of adjuvant arthritis by immunization with a recombinant vaccinia virus. Infect Immun 1991, 59: 2029–2035
Ragno, S, Colston, M J, Lowrie, D B, Winrow, V R, Blake, D R and Tascon, R.Protection of rats from adjuvant arthritis by immunization with naked DNA encoding for mycobacterial heat shock protein 65. Arthritis Rheum 1997, 40: 277–283
Anderton, S M, Zee, R, Prakken, B, Noordzij, A and Eden, W.Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis. J Exp Med 1995, 181: 943–952
Thompson, S J, Francis, J N, Siew, L K, Webb, G R, Jenner, P J, Colston, M J and Elson, C J.An immunodominant epitope from mycobacterial 65-kDa heat shock protein protects against pristane-induced arthritis. J Immunol 1998, 160: 4628–4634
Eden, W, Zee, R, Paul, A G A, Prakken, B J, Wendling, U, Anderton, S M and Wauben, M H M.Do heat shock proteins control the balance of T-cell regulation in inflammatory diseases?Immunol Today 1998, 19: 303–307
Quintana, F J, Carmi, P, Mor, F and Cohen, I R.Inhibition of adjuvant arthritis by a DNA vaccine encoding human heat shock protein 60. J Immunol 2002, 169: 3422–3428
Quintana, F J, Carmi, P, Mor, F and Cohen, I R.DNA fragments of the human 60-kDa heat shock protein (HSP60) vaccinate against adjuvant arthritis: identification of a regulatory HSP60 peptide. J Immunol 2003, 171: 3533–3541
Ragno, S, Winrow, V R, Mascagni, P, Lucietto, P, Di Pierro, F, Morris, C J and Blake, D R.A synthetic 10-kD heat shock protein (hsp10) from Mycobacterium tuberculosis modulates adjuvant arthritis. Clin Exp Immunol 1996, 103: 384–390
Kingston, A E, Hicks, C A, Colston, M J and Billingham, M E J.A 71-kD heat shock protein (hsp) from Mycobacterium tuberculosis has modulatory effects on experimental rat arthritis. Clin Exp Immunol 1996, 103: 77–82
Wendling, U, Paul, L, Zee, R, Prakken, B, Singh, M and Eden, W.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 2000, 164: 2711–2717
Tanaka, S, Kimura, Y, Mitani, A, Yamamoto, G, Nishimura, H, Spallek, R, Singh, M, Noguchi, T and Yoshikai, Y.Activation of T cells recognizing an epitope of heat-shock protein 70 can protect against rat adjuvant arthritis. J Immunol 1999, 163: 5560–5565
Quintana, F J, Carmi, P, Mor, F and Cohen, I R.Inhibition of adjuvant-unduced as 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. Arth Rheum 2004, 50: 3712–3720
Macht, L M, Elson, C J, Kirwan, J R, Gaston, J S H, Lamont, A G, Thompson, J M and Thompson, S J.Relationship between disease severity and responses by blood mononuclear cells from patients with rheumatoid arthritis to human heat-shock protein 60. Immunology 2000, 99: 208–214
Roon, J A G, Eden, W, Roy, J L A M, Lafeber, F J P G and Bijlsma, J W J.Stimulation of suppressive T cell responses by human but not bacterial 60-kD heat shock protein in synovial fluid of patients with rheumatoid arthritis. J Clin Invest 1997, 100: 459–463
Prakken, A B, Eden, W, Rijkers, G T, Kuis, W, Toebes, E A, Graeff-Meeder, E R, Zee, R and Zegers, B J.Autoreactivity to human Hsp60 predicts disease remission in oligoarticular juvenile rheumatoid arthritis. Arthritis Rheum 1996, 39: 1826–1832
Kanagawa, O, Martin, S M, Vaupel, B A, Carrasco-Marin, E and Unanue, E R.Autoreactivity of T cells from nonobese diabetic mice: an I-Ag7-dependent reaction. Proc Natl Acad Sci USA 1998, 95: 1721–1724
Quintana, F J and Cohen, I R.Autoantibody patterns in diabetes-prone NOD mice and in standard C57BL/6 mice. J Autoimmunity 2001, 17: 191–197
Wegmann, D R, Norbury-Glaser, M and Daniel, D.Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur J Immunol 1994, 24: 1853–1857
Tisch, R, Yang, X D, Singer, S M, Liblau, R S, Fugger, L and McDevitt, H O.Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 1993, 366: 72–75
Elias, D, Markovits, D, Reshef, T, Zee, R and Cohen, I R.Induction and therapy of autoimmune diabetes in the non-obese diabetic mouse by a 65-kDa heat shock protein. Proc Natl Acad Sci USA 1990, 87: 1576–1580
Elias, D, Reshef, T, Birk, O S, Zee, R, Walker, M D and Cohen, I R.Vaccination against autoimmune mouse diabetes with a T cell epitope of the human 65-kDa heat shock protein. Proc Natl Acad Sci USA 1991, 88: 3088–3091
Elias, D and Cohen, I R.Peptide therapy for diabetes in NOD mice. Lancet 1994, 343: 704–706
Elias, D, Meilin, A, Ablamunits, V, Birk, O S, Carmi, P, Konen-Waisman, S and Cohen, I R.Hsp60 peptide therapy of NOD mouse diabetes induces a Th2 cytokine burst and downregulates autoimmunity to various β-cell antigens. Diabetes 1997, 46: 758–764
Bockova, J, Elias, D and Cohen, I R.Treatment of NOD diabetes with a novel peptide of the Hsp60 molecule induces Th2-type antibodies. J Autoimmunity 1997, 10: 323–329
Yasunami, R and Bach, J F.Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. Eur J Immunol 1988, 18: 481–484
Ablamunits, V, Quintana, F, Reshef, T, Elias, D and Cohen, I R.Acceleration of autoimmune diabetes by cyclophosphamide is associated with an enhanced IFN-γ secretion pathway. J Autoimmunity 1999, 13: 383–392
Quintana, F J, Carmi, P and Cohen, I R.DNA vaccination with heat shock protein 60 inhibits cyclophosphamide-accelerated diabetes. J Immunol 2002, 169: 6030–6035
Abulafia-Lapid, R, Gillis, D, Yosef, O, Atlan, H and Cohen, I R.T cells and autoantibodies to human HSP70 in Type 1 diabetes in children. J Autoimmunity 2003: 313–321
Horváth, L, Cervenak, L, Oroszlán, M, Proháska, Z, Uray, K, Hudecz, F, Baranyi, É, Madácsy, L, Singh, M, Romics, L, Füst, G and Pánczél, P.Antibodies against different epitopes of heat shock protein 60 in children with type 1 diabetes mellitus. Immunol Lett 2002, 80: 155–162
Raz, I, Elias, D, Avron, A, Tamir, M, Metzger, M and Cohen, I R.Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet 2001, 358: 1749–1753
Hemmi, H, Takeuchi, O, Kawai, T, Kaisho, T, Sato, S, Sanjo, H, Matsumoto, M, Hoshino, K, Wagner, H, Takeda, K and Akira, S.A Toll-like receptor recognizes bacterial DNA. Nature 2000, 408: 740–745
Krieg, A M.CpG motifs in bacterial DNA and their immune effects. Ann Rev Immunol 2002, 20: 709–760
Quintana, F J, Rotem, A, Carmi, P and Cohen, I R.Vaccination with empty plasmid DNA or CpG oligonucleotide inhibits diabetes in nonobese diabetic mice: modulation of spontaneous 60-kDa heat shock protein autoimmunity. J Immunol 2000, 165: 6148–6155
Akdis, C A and Blaser, K.Mechanisms of interleukin-10-mediated immune suppression. Immunology 2001, 103: 131–136
Kumaraguru, U, Pack, C D and Rouse, B T.Toll-like receptor ligand links innate and adaptive immune responses by the production of heat-shock proteins. J Leuk Biol 2003, 73: 574–583
Boccaccio, G L, Mor, F and Steinman, L.Non-coding plasmid DNA induces IFN-γ in vivo and suppresses autoimmune encephalomyelitis. Int Immunol 1999, 11: 289–296
Rachmilewitz, D, Karmeli, F, Takabayashi, K, Hayashi, T, Leider-Trejo, L, Lee, J, Leoni, L M and Raz, E.Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 2002, 122: 1428–1441
Zeuner, R A, Ishii, K J, Lizak, M J, Gursel, I, Yamada, H, Klinman, D M and Verthelyi, D.Reduction of CpG-induced arthritis by suppressive oligodeoxynucleotides. Arthritis Rheum 2002, 46: 2219–2224
Zeuner, R A, Verthelyi, D, Gursel, M, Ishii, K J and Klinman, D M.Influence of stimulatory and suppressive DNA motifs on host susceptibility to inflammatory arthritis. Arthritis Rheum 2003, 48: 1701–1707
Serreze, D V, Hamaguchi, K and Leiter, E H.Immunostimulation circumvents diabetes in NOD/Lt mice. J Autoimmunity 1989, 2: 759–776
Tian, J, Zekzer, D, Hanssen, L, Lu, Y, Olcott, A and Kaufman, D L.Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J Immunol 2001, 167: 1081–1089
Sai, P and Rivereau, A S.Prevention of diabetes in the nonobese diabetic mouse by oral immunological treatments. Comparative efficiency of human insulin and two bacterial antigens, lipopolysacharide from Escherichia coli and glycoprotein extract from Klebsiella pneumoniae. Diabetes Metab 1996, 22: 341–348
Iguchi, M, Inagawa, H, Nishizawa, T, Okutomi, T, Morikawa, A, Soma, G I and Mizuno, D.Homeostasis as regulated by activated macrophage. V. Suppression of diabetes mellitus in non-obese diabetic mice by LPSw (a lipopolysaccharide from wheat flour). Chem Pharm Bull (Tokyo) 1992, 40: 1004–1006
Li, Z, Ménoret, A and Srivastava, P.Roles of heat-shock proteins in antigen presentation and cross-presentation. Cur Opin Immunol 2002, 14: 45–51
Srivastava, P.Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2002, 2: 185–194
Vabulas, R M, Braedel, S, Hilf, N, Singh-Jasuja, H, Herter, S, Ahmad-Nejad, P, Kirschning, C J, Da Costa, C, Rammensee, H G, Wagner, H and Schild, H.The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J Biol Chem 2002, 277: 20847–20853
Bethke, K, Staib, F, Distler, M, Schmitt, U, Jonuleit, H, Enk, A H, Galle, P R and Heike, M.Different efficiency of heat shock proteins to activate human monocytes and dendritic cells: Superiority of HSP60. J Immunol 2002, 169: 6141–6148
Flohé, S B, Bruggemann, J, Lendemans, S, Nikulina, M, Meierhoff, G, Flohé, S and Kolb, H.Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype. J Immunol 2003, 170: 2340–2348
Bulut, Y, Faure, E, Thomas, L, Karahashi, H, Michelsen, K S, Equils, O, Morrison, S G, Morrison, R P and Arditi, M.Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J Immunol 2002, 168: 1435–1440
Moudgil, K D, Chang, T T, Eradat, H, Chen, A M, Gupta, R S, Brahn, E and Sercarz, E E.Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis. J Exp Med 1997, 185: 1307–1316
Hirono, S, Dibrov, E, Hurtado, C, Kostenuk, A, Ducas, R and Pierce, G N.Chlamydia pneumoniae stimulates proliferation of vascular smooth muscle cells through induction of endogenous heat shock protein 60. Circ Res 2003, 93: 710–716
Beimnet, K, Soderstrom, K, Jindal, S, Gronberg, A, Frommel, D and Kiessling, R R.Induction of heat shock protein 60 expression in human monocytic cell lines infected with Mycobacterium leprae. Infect Immun 1996, 64: 4356–4358
Wainberg, Z, Oliveira, M, Lerner, S, Tao, Y and Brenner, B G.Modulation of stress protein (hsp27 and hsp70) expression in CD4+ lymphocytic cells following acute infection with human immunodeficiency virus type-1. Virology. 1997, 233: 364–373
Saito, K, Katsuragi, H, Mikami, M, Kato, C, Miyamaru, M and Nagaso, K.Increase of heat-shock protein and induction of γ/δ T cells in peritoneal exudate of mice after injection of live Fusobacterium nucleatum. Immunology 1997, 90: 229–235
Basu, S, Binder, R J, Suto, R, Anderson, K M and Srivastava, P K.Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activates the NF-κB pathway. Int Immunol 2000, 12: 1539–1546
Boog, C J P, Graeff-Meeder, E R, Lucassen, M A, Zee, R, Voorhorst Ogink, M M, Kooten, P J S, Geuze, H J and Eden, W.Two monoclonal antibodies generated against human hsp60 show reactivity with synovial membranes of patients with juvenile arthritis. J Exp Med 1992, 175: 1805–1810
Teshima, S, Rokutan, K, Takahashi, M, Nikawa, T and Kishi, K.Induction of heat shock proteins and their possible roles in macrophages during activation by macrophage colony-stimulating factor. Biochem J 1996, 315: 497–504
Ferris, D K, HarelBellan, A, Morimoto, R I, Welch, W J and Farrar, W L.Mitogen and lymphokine stimulation of heat shock proteins in T lymphocytes. Proc Natl Acad Sci USA 1988, 85: 3850–3854
Zugel, U and Kaufmann, S H.Immune response against heat shock proteins in infectious diseases. Immunobiology 1999, 201: 22–35
Chen, Y, Kuchroo, V K, Inobe, J, Hafler, D A and Weiner, H L.Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994, 265: 1237–1240
Moudgil, K D, Kim, E, Yun, O J, Chi, H H, Brahn, E and Sercarz, E E.Environmental modulation of autoimmune arthritis involves the spontaneous microbial induction of T cell responses to regulatory determinants within heat shock protein 65. J Immunol 2001, 166: 4237–4243
Prakken, B J, Wendling, U, Zee, R, Rutten, V P M, Kuis, W and Eden, W.Induction of IL-10 and inhibition of experimental arthritis are specific features of microbial heat shock proteins that are absent for other evolutionarily conserved immunodominant proteins. J Immunol 2001, 167: 4147–4153
Blachere, N E, Li, Z L, Chandawarkar, R Y, Suto, R, Jaikaria, N S, Basu, S, Udono, H and Srivastava, P K.Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med 1997, 186: 1315–1322
Chandawarkar, R Y, Wagh, M S and Srivastava, P K.The dual nature of specific immunological activity of tumour-derived gp96 preparations. J Exp Med 1999, 189: 1437–1442
Galazka, G, Walczak, A, Berkowicz, T and Selmaj, K.Effect of Hsp70-peptide complexes generated in vivo on modulation EAE. Adv Exp Med Biol 2001, 495: 227–230
Lohse, A W, Mor, F, Karin, N and Cohen, I R.Control of experimental autoimmune encephalomyelitis by T cells responding to activated T cells. Science 1989, 244: 820–822
Mimran, A, Mor, F, Carmi, P, Quintana, F J, Rotter, V and Cohen, I R.DNA vaccination with CD25 protects rats from adjuvant arthritis and induces an antiergotypic response. J Clin Invest 2004, 113: 924–932
Mor, F, Reizis, B, Cohen, I R and Steinman, L.IL-2 and TNF receptors as targets of regulatory T-T interactions: isolation and characterization of cytokine receptor-reactive T cell lines in the Lewis rat. J Immunol. 1996, 157: 4855–4861
Eden, W, Thole, J E R, Zee, R, Noordzij, A, Embden, J D A, Hensen, E J and Cohen, I R.Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature 1988, 331: 171–173
Vabulas, R M, Ahmad-Nejad, P, da Costa, C, Miethke, T, Kirschning, C J, Hacker, H and Wagner, H.Endocytosed HSP60s use Toll-like receptor 2 (TLR2) and TLR4 to activate the Toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem 2001, 276: 31332–31339
Becker, T, Hartl, F U and Wieland, F.CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol 2002, 158: 1277–1285
Basu, S, Binder, R J, Ramalingam, T and Srivastava, P K.CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70 and calreticulin. Immunity 2001, 14: 303–313
Caramalho, I, Lopes-Carvalho, T, Ostler, D, Zelenay, S, Haury, M and Demengeot, J.Regulatory T cells selectively express Toll-like receptors and are activated by lipopolysaccharide. J Exp Med 2003, 197: 403–411
Zanin-Zhorov, A, Nussbaum, G, Franitza, S, Cohen, I R and Lider, O.T cells respond to heat shock protein 60 via TLR2: activation of adhesion and inhibition of chemokine receptors. FASEB J 2003, 17: 1567–1569
Cohen I R, Quintana F J, Nussbaum G, Cohen M, Zanin A and Lider O. HSP60 and the regulation of inflammation: physiological and pathological. In Eden, W. (Ed.) Heat Shock Proteins and Inflammation. Birkhauser Verlag A G, Basel 2004, pp 1–13
Werner, S and Grose, R.Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003, 83: 835–870
Cohen, I R and Schwartz, M.Autoimmune maintenance and neuroprotection of the central nervous system. J Neuroimmunol 1999, 100: 111–114
Quintana F J and Cohen I R. Type I diabetes mellitus, infection and Toll-like receptors. In Shoenfeld, Y. and Rose, N. (Eds.) Infection and Autoimmunity. Elsevier, Amsterdam 2004
Cohen, I R.Tending Adam's Garden: Evolving the Cognitive Immune Self. Academic Press, London: 2000