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Tolerization against atherosclerosis using heat shock protein 60

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Cell Stress and Chaperones Aims and scope

Abstract

Atherosclerosis is a chronic inflammatory disease of the artery wall, and both innate and adaptive immunity play important roles in the pathogenesis of this disease. In several experimental and human experiments of early atherosclerotic lesions, it has been shown that the first pathogenic event in atherogenesis is intimal infiltration of T cells at predilection sites. These T cells react to heat shock protein 60 (HSP60), which is a ubiquitous self-antigen expressed on the surface of endothelial cells (ECs) together with adhesion molecules in response to classical risk factors for atherosclerosis. When HSP60 is expressed on the EC surface, it can act as a “danger-signal” for both cellular and humoral immune reactions. Acquired by infection or vaccination, beneficial protective immunity to microbial HSP60 and bona fide autoimmunity to biochemically altered autologous HSP60 is present in all humans. Thus, the development of atherosclerosis during aging is paid by the price for lifelong protective preexisting anti-HSP60 immunity by harmful (auto)immune cross-reactive attack on arterial ECs maltreated by atherosclerosis risk factors. This is supported by experiments, which shows that bacterial HSP60 immunization can lead and accelerate experimental atherosclerosis. This review article presents accumulating proof that supports the idea that tolerization with antigenic HSP60 protein or its peptides may arrest or even prevent atherosclerosis by increased production of regulatory T cells and/or anti-inflammatory cytokines. Recent data indicates that HSP60, or more likely some of its derivative peptides, has immunoregulatory functions. Therefore, these peptides may have important potential for being used as diagnostic agents or therapeutic targets.

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References

  • Afek A, George J, Gilburd B, Rauova L, Goldberg I, Kopolovic J, Harats D, Shoenfeld Y (2000) Immunization of low-density lipoprotein receptor deficient (LDL-RD) mice with heat shock protein 65 (HSP-65) promotes early atherosclerosis. J Autoimmun 14:115–121

    Article  CAS  PubMed  Google Scholar 

  • Aldridge S (2012) Toll-like receptor blocker slows beta cell death in type 1 diabetes. Nat Biotechnol 30:124

    Article  CAS  PubMed  Google Scholar 

  • Almanzar G, Ollinger R, Leuenberger J, Onestingel E, Rantner B, Zehm S, Cardini B, van der Zee R, Grundtman C, Wick G (2012) Autoreactive HSP60 epitope-specific T-cells in early human atherosclerotic lesions. J Autoimmun 39:441–450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amberger A, Maczek C, Jurgens G, Michaelis D, Schett G, Trieb K, Eberl T, Jindal S, Xu Q, Wick G (1997) Co-expression of ICAM-1, VCAM-1, ELAM-1 and Hsp60 in human arterial and venous endothelial cells in response to cytikones and oxidized low-density lipoproteins. Cell Stress Chaperones 2:94–103

  • Ashburner M (1970) Patterns of puffing activity in the salivary gland chromosomes of Drosophila. V. Responses to environmental treatments. Chromosoma 31:356–376

    Article  CAS  PubMed  Google Scholar 

  • Benagiano M, D'Elios MM, Amedei A, Azzurri A, van der Zee R, Ciervo A, Rombola G, Romagnani S, Cassone A, Del Prete G (2005) Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques. J Immunol 174:6509–6517

    Article  CAS  PubMed  Google Scholar 

  • Billetta R, Ghahramani N, Morrow O, Prakken B, de Jong H, Meschter C, Lanza P, Albani S (2012) Epitope-specific immune tolerization ameliorates experimental autoimmune encephalomyelitis. Clin Immunol 145:94–101

    Article  CAS  PubMed  Google Scholar 

  • Birk OS, Douek DC, Elias D, Takacs K, Dewchand H, Gur SL, Walker MD, van der Zee R, Cohen IR, Altmann DM (1996) A role of HSP60 in autoimmune diabetes: analysis in a transgenic model. Proc Natl Acad Sci U S A 93:1032–1037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bobryshev YV (2010) Dendritic cells and their role in atherogenesis. Lab Invest 90:970–984

    Article  PubMed  Google Scholar 

  • Bobryshev YV, Lord RS (1996) Structural heterogeneity and contacting interactions of vascular dendritic cells in early atherosclerotic lesions of the human aorta. J Submicrosc Cytol Pathol 28:49–60

    CAS  PubMed  Google Scholar 

  • Bobryshev YV, Lord RS (1998) Mapping of vascular dendritic cells in atherosclerotic arteries suggests their involvement in local immune-inflammatory reactions. Cardiovasc Res 37:799–810

    Article  CAS  PubMed  Google Scholar 

  • Borges TJ, Porto BN, Teixeira CA, Rodrigues M, Machado FD, Ornaghi AP, de Souza AP, Maito F, Pavanelli WR, Silva JS, Bonorino C (2010) Prolonged survival of allografts induced by mycobacterial Hsp70 is dependent on CD4+CD25+ regulatory T cells. PLoS One 5:e14264

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brett SJ, Lamb JR, Cox JH, Rothbard JB, Mehlert A, Ivanyi J (1989) Differential pattern of T cell recognition of the 65-kDa mycobacterial antigen following immunization with the whole protein or peptides. Eur J Immunol 19:1303–1310

    Article  CAS  PubMed  Google Scholar 

  • Burian K, Kis Z, Virok D, Endresz V, Prohaszka Z, Duba J, Berencsi K, Boda K, Horvath L, Romics L, Fust G, Gonczol E (2001) Independent and joint effects of antibodies to human heat-shock protein 60 and Chlamydia pneumoniae infection in the development of coronary atherosclerosis. Circulation 103:1503–1508

  • Choi JI, Chung SW, Kang HS, Rhim BY, Park YM, Kim US, Kim SJ (2004) Epitope mapping of Porphyromonas gingivalis heat-shock protein and human heat-shock protein in human atherosclerosis. J Dent Res 83:936–940

    Article  CAS  PubMed  Google Scholar 

  • Cybulsky MI, Jongstra-Bilen J (2010) Resident intimal dendritic cells and the initiation of atherosclerosis. Curr Opin Lipidol 21:397–403

    Article  CAS  PubMed  Google Scholar 

  • Elias D, Cohen IR (1996) The HSP60 peptide p277 arrests the autoimmune diabetes induced by the toxin streptozotocin. Diabetes 45:1168–1172

    Article  CAS  PubMed  Google Scholar 

  • Elias D, Reshef T, Birk OS, van der Zee R, Walker MD, Cohen IR (1991) Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. Proc Natl Acad Sci U S A 88:3088–3091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ford PJ, Gemmell E, Hamlet SM, Hasan A, Walker PJ, West MJ, Cullinan MP, Seymour GJ (2005) Cross-reactivity of GroEL antibodies with human heat shock protein 60 and quantification of pathogens in atherosclerosis. Oral Microbiol Immunol 20:296–302

    Article  CAS  PubMed  Google Scholar 

  • Foteinos G, Afzal AR, Mandal K, Jahangiri M, Xu Q (2005) Anti-heat shock protein 60 autoantibodies induce atherosclerosis in apolipoprotein E-deficient mice via endothelial damage. Circulation 112:1206–1213

    Article  CAS  PubMed  Google Scholar 

  • George J, Shoenfeld Y, Afek A, Gilburd B, Keren P, Shaish A, Kopolovic J, Wick G, Harats D (1999) Enhanced fatty streak formation in C57BL/6J mice by immunization with heat shock protein-65. Arterioscler Thromb Vasc Biol 19:505–510

    Article  CAS  PubMed  Google Scholar 

  • George J, Greenberg S, Barshack I, Goldberg I, Keren G, Roth A (2003) Immunity to heat shock protein 65—an additional determinant in intimal thickening. Atherosclerosis 168:33–38

    Article  CAS  PubMed  Google Scholar 

  • Grundtman C, Wick G (2011) The autoimmune concept of atherosclerosis. Curr Opin Lipidol 22:327–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grundtman C, Kreutmayer SB, Almanzar G, Wick MC, Wick G (2011) Heat shock protein 60 and immune inflammatory responses in atherosclerosis. Arterioscler Thromb Vasc Biol 31:960–968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grundtman C, Jakic B, Buszko M, Onestingel E, Almanzar G, Demetz E, Dietrich H, Cappellano G, Wick G (2015) Mycobacterial heat shock protein 65 (mbHSP65)-induced atherosclerosis: preventive oral tolerization and definition of atheroprotective and atherogenic mbHSP65 peptides. Atherosclerosis 242:303–310

    Article  CAS  PubMed  Google Scholar 

  • Harats D, Yacov N, Gilburd B, Shoenfeld Y, George J (2002) Oral tolerance with heat shock protein 65 attenuates Mycobacterium tuberculosis-induced and high-fat-diet-driven atherosclerotic lesions. J Am Coll Cardiol 40:1333–1338

    Article  CAS  PubMed  Google Scholar 

  • Hoppichler F, Koch T, Dzien A, Gschwandtner G, Lechleitner M (2000) Prognostic value of antibody titre to heat-shock protein 65 on cardiovascular events. Cardiology 94:220–223

    Article  CAS  PubMed  Google Scholar 

  • Huber SA, Sakkinen P, David C, Newell MK, Tracy RP (2001) T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. Circulation 103:2610–2616

    Article  CAS  PubMed  Google Scholar 

  • Huurman VA, Decochez K, Mathieu C, Cohen IR, Roep BO (2007) Therapy with the hsp60 peptide DiaPep277 in C-peptide positive type 1 diabetes patients. Diabetes Metab Res Rev 23:269–275

    Article  CAS  PubMed  Google Scholar 

  • Huurman VA, van der Meide PE, Duinkerken G, Willemen S, Cohen IR, Elias D, Roep BO (2008) Immunological efficacy of heat shock protein 60 peptide DiaPep277 therapy in clinical type I diabetes. Clin Exp Immunol 152:488–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin L, Zhu A, Wang Y, Chen Q, Xiong Q, Li J, Sun Y, Li T, Cao R, Wu J, Liu J (2008) A Th1-recognized peptide P277, when tandemly repeated, enhances a Th2 immune response toward effective vaccines against autoimmune diabetes in nonobese diabetic mice. J Immunol 180:58–63

    Article  CAS  PubMed  Google Scholar 

  • Jing H, Yong L, Haiyan L, Yanjun M, Yun X, Yu Z, Taiming L, Rongyue C, Liang J, Jie W, Li Z, Jingjing L (2011) Oral administration of Lactococcus lactis delivered heat shock protein 65 attenuates atherosclerosis in low-density lipoprotein receptor-deficient mice. Vaccine 29:4102–4109

    Article  PubMed  CAS  Google Scholar 

  • Kanwar RK, Kanwar JR, Wang D, Ormrod DJ, Krissansen GW (2001) Temporal expression of heat shock proteins 60 and 70 at lesion-prone sites during atherogenesis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 21:1991–1997

    Article  CAS  PubMed  Google Scholar 

  • Khallou-Laschet J, Tupin E, Caligiuri G, Poirier B, Thieblemont N, Gaston AT, Vandaele M, Bleton J, Tchapla A, Kaveri SV, Rudling M, Nicoletti A (2006) Atheroprotective effect of adjuvants in apolipoprotein E knockout mice. Atherosclerosis 184:330–341

    Article  CAS  PubMed  Google Scholar 

  • Kleindienst R, Xu Q, Willeit J, Waldenberger FR, Weimann S, Wick G (1993) Immunology of atherosclerosis. Demonstration of heat shock protein 60 expression and T lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions. Am J Pathol 142:1927–1937

    CAS  PubMed  PubMed Central  Google Scholar 

  • Klingenberg R, Ketelhuth DF, Strodthoff D, Gregori S, Hansson GK (2012) Subcutaneous immunization with heat shock protein-65 reduces atherosclerosis in Apoe(-)/(-) mice. Immunobiology 217:540–547

    Article  CAS  PubMed  Google Scholar 

  • Knoflach M, Kiechl S, Kind M, Said M, Sief R, Gisinger M, van der Zee R, Gaston H, Jarosch E, Willeit J, Wick G (2003) Cardiovascular risk factors and atherosclerosis in young males: ARMY study (atherosclerosis risk-factors in male youngsters). Circulation 108:1064–1069

    Article  PubMed  Google Scholar 

  • Knoflach M, Kiechl S, Mayrl B, Kind M, Gaston JS, van der Zee R, Faggionato A, Mayr A, Willeit J, Wick G (2007) T-cell reactivity against HSP60 relates to early but not advanced atherosclerosis. Atherosclerosis 195:333–338

    Article  CAS  PubMed  Google Scholar 

  • Knoflach M, Kiechl S, Penz D, Zangerle A, Schmidauer C, Rossmann A, Shingh M, Spallek R, Griesmacher A, Bernhard D, Robatscher P, Buchberger W, Draxl W, Willeit J, Wick G (2009) Cardiovascular risk factors and atherosclerosis in young women: atherosclerosis risk factors in female youngsters (ARFY study). Stroke 40:1063–1069

    Article  CAS  PubMed  Google Scholar 

  • Koffeman EC, Genovese M, Amox D, Keogh E, Santana E, Matteson EL, Kavanaugh A, Molitor JA, Schiff MH, Posever JO, Bathon JM, Kivitz AJ, Samodal R, Belardi F, Dennehey C, van den Broek T, van Wijk F, Zhang X, Zieseniss P, Le T, Prakken BA, Cutter GC, Albani S (2009) Epitope-specific immunotherapy of rheumatoid arthritis: clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial. Arthritis Rheum 60:3207–3216

    Article  CAS  PubMed  Google Scholar 

  • Lamb DJ, El-Sankary W, Ferns GA (2003) Molecular mimicry in atherosclerosis: a role for heat shock proteins in immunisation. Atherosclerosis 167:177–185

    Article  CAS  PubMed  Google Scholar 

  • Lazar L, Ofan R, Weintrob N, Avron A, Tamir M, Elias D, Phillip M, Josefsberg Z (2007) Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: a randomised, double-blind phase II study. Diabetes Metab Res Rev 23:286–291

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Takemoto N, Kurata H, Kamogawa Y, Miyatake S, O'Garra A, Arai N (2000) GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells. J Exp Med 192:105–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li H, Ding Y, Yi G, Zeng Q, Yang W (2012) Establishment of nasal tolerance to heat shock protein-60 alleviates atherosclerosis by inducing TGF-beta-dependent regulatory T cells. J Huazhong Univ Sci Technolog Med Sci 32:24–30

    Article  PubMed  CAS  Google Scholar 

  • Lindquist S, Craig EA (1988) The heat-shock proteins. Annu Rev Genet 22:631–677

    Article  CAS  PubMed  Google Scholar 

  • Liu P, Yu YR, Spencer JA, Johnson AE, Vallanat CT, Fong AM, Patterson C, Patel DD (2008) CX3CR1 deficiency impairs dendritic cell accumulation in arterial intima and reduces atherosclerotic burden. Arterioscler Thromb Vasc Biol 28:243–250

    Article  CAS  PubMed  Google Scholar 

  • Liu A, Ming JY, Fiskesund R, Ninio E, Karabina SA, Bergmark C, Frostegard AG, Frostegard J (2015) Induction of dendritic cell-mediated T-cell activation by modified but not native low-density lipoprotein in humans and inhibition by annexin a5: involvement of heat shock proteins. Arterioscler Thromb Vasc Biol 35:197–205

    Article  CAS  PubMed  Google Scholar 

  • Lu X, Chen D, Endresz V, Xia M, Faludi I, Burian K, Szabo A, Csanadi A, Miczak A, Gonczol E, Kakkar V (2010) Immunization with a combination of ApoB and HSP60 epitopes significantly reduces early atherosclerotic lesion in Apobtm2SgyLdlrtm1Her/J mice. Atherosclerosis 212:472–480

    Article  CAS  PubMed  Google Scholar 

  • Lu X, Xia M, Endresz V, Faludi I, Szabo A, Gonczol E, Mundkur L, Chen D, Kakkar V (2012) Impact of multiple antigenic epitopes from ApoB100, hHSP60 and Chlamydophila pneumoniae on atherosclerotic lesion development in Apob(tm2Sgy)Ldlr(tm1Her)J mice. Atherosclerosis 225:56–68

    Article  CAS  PubMed  Google Scholar 

  • Maron R, Sukhova G, Faria AM, Hoffmann E, Mach F, Libby P, Weiner HL (2002) Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation 106:1708–1715

    Article  CAS  PubMed  Google Scholar 

  • Mayr M, Metzler B, Kiechl S, Willeit J, Schett G, Xu Q, Wick G (1999) Endothelial cytotoxicity mediated by serum antibodies to heat shock proteins of Escherichia coli and Chlamydia pneumoniae: immune reactions to heat shock proteins as a possible link between infection and atherosclerosis. Circulation 99:1560–1566

    Article  CAS  PubMed  Google Scholar 

  • Mayr M, Kiechl S, Willeit J, Wick G, Xu Q (2000) Infections, immunity, and atherosclerosis: associations of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus with immune reactions to heat-shock protein 60 and carotid or femoral atherosclerosis. Circulation 102:833–839

    Article  CAS  PubMed  Google Scholar 

  • McKenzie SL, Henikoff S, Meselson M (1975) Localization of RNA from heat-induced polysomes at puff sites in Drosophila melanogaster. Proc Natl Acad Sci U S A 72:1117–1121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Metzler B, Mayr M, Dietrich H, Singh M, Wiebe E, Xu Q, Wick G (1999) Inhibition of arteriosclerosis by T-cell depletion in normocholesterolemic rabbits immunized with heat shock protein 65. Arterioscler Thromb Vasc Biol 19:1905–1911

    Article  CAS  PubMed  Google Scholar 

  • Millonig G, Niederegger H, Rabl W, Hochleitner BW, Hoefer D, Romani N, Wick G (2001a) Network of vascular-associated dendritic cells in intima of healthy young individuals. Arterioscler Thromb Vasc Biol 21:503–508

    Article  CAS  PubMed  Google Scholar 

  • Millonig G, Niederegger H, Wick G (2001b) Analysis of the cellular composition of the arterial intima with modified en face techniques. Lab Invest 81:639–641

    Article  CAS  PubMed  Google Scholar 

  • Millonig G, Malcom GT, Wick G (2002) Early inflammatory-immunological lesions in juvenile atherosclerosis from the pathobiological determinants of atherosclerosis in youth (PDAY)-study. Atherosclerosis 160:441–448

    Article  CAS  PubMed  Google Scholar 

  • Moran L, Mirault ME, Arrigo AP, Goldschmidt-Clermont M, Tissieres A (1978) Heat shock of Drosophila melanogaster induces the synthesis of new messenger RNAs and proteins. Philos Trans R Soc Lond B Biol Sci 283:391–406

    Article  CAS  PubMed  Google Scholar 

  • Mori Y, Kitamura H, Song QH, Kobayashi T, Umemura S, Cyong JC (2000) A new murine model for atherosclerosis with inflammation in the periodontal tissue induced by immunization with heat shock protein 60. Hypertens Res 23:475–481

    Article  CAS  PubMed  Google Scholar 

  • Mundkur L, Mukhopadhyay R, Samson S, Varma M, Kale D, Chen D, Shivaprasad S, Sivanandan H, Soman V, Lu X, Kakkar VV (2013a) Mucosal tolerance to a combination of ApoB and HSP60 peptides controls plaque progression and stabilizes vulnerable plaque in Apob(tm2Sgy)Ldlr(tm1Her)/J mice. PLoS One 8:e58364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mundkur LA, Varma M, Shivanandan H, Krishna D, Kumar K, Lu X, Kakkar VV (2013b) Activation of inflammatory cells and cytokines by peptide epitopes in vitro: a simple in-vitro screening assay for prioritizing them for in-vivo studies. Inflamm Res 62:471–481

    Article  CAS  PubMed  Google Scholar 

  • Murshid A, Gong J, Calderwood SK (2012) The role of heat shock proteins in antigen cross presentation. Front Immunol 3:63

    Article  PubMed  PubMed Central  Google Scholar 

  • Ohue R, Hashimoto K, Nakamoto M, Furukawa Y, Masuda T, Kitabatake N, Tani F (2011) Bacterial heat shock protein 60, GroEL, can induce the conversion of naive T cells into a CD4 CD25(+) Foxp3-expressing phenotype. J Innate Immun 3:605–613

    Article  CAS  PubMed  Google Scholar 

  • Perschinka H, Mayr M, Millonig G, Mayerl C, van der Zee R, Morrison SG, Morrison RP, Xu Q, Wick G (2003) Cross-reactive B-cell epitopes of microbial and human heat shock protein 60/65 in atherosclerosis. Arterioscler Thromb Vasc Biol 23:1060–1065

    Article  CAS  PubMed  Google Scholar 

  • Pockley AG, Wu R, Lemne C, Kiessling R, de Faire U, Frostegard J (2000) Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertension 36:303–307

    Article  CAS  PubMed  Google Scholar 

  • Prakken BJ, Samodal R, Le TD, Giannoni F, Yung GP, Scavulli J, Amox D, Roord S, de Kleer I, Bonnin D, Lanza P, Berry C, Massa M, Billetta R, Albani S (2004) Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis. Proc Natl Acad Sci U S A 101:4228–4233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quintana FJ, Carmi P, Mor F, Cohen IR (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 50:3712–3720

    Article  CAS  PubMed  Google Scholar 

  • Raz I, Elias D, Avron A, Tamir M, Metzger M, Cohen IR (2001) 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 358:1749–1753

    Article  CAS  PubMed  Google Scholar 

  • Raz I, Avron A, Tamir M, Metzger M, Symer L, Eldor R, Cohen IR, Elias D (2007) Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved beta-cell function: extension of a randomized, double-blind, phase II trial. Diabetes Metab Res Rev 23:292–298

    Article  CAS  PubMed  Google Scholar 

  • Ritossa FM (1962) A new puffing pattern induced by a temperature shock and DNP in Drosophila. Experientia 18:571–573

    Article  CAS  Google Scholar 

  • Ritossa FM (1964) Experimental activation of specific loci in polytene chromosomes of Drosophila. Exp Cell Res 35:601–607

    Article  CAS  PubMed  Google Scholar 

  • Rossmann A, Henderson B, Heidecker B, Seiler R, Fraedrich G, Singh M, Parson W, Keller M, Grubeck-Loebenstein B, Wick G (2008) T-cells from advanced atherosclerotic lesions recognize hHSP60 and have a restricted T-cell receptor repertoire. Exp Gerontol 43:229–237

    Article  CAS  PubMed  Google Scholar 

  • Schett G, Xu Q, Amberger A, Van der Zee R, Recheis H, Willeit J, Wick G (1995) Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity. J Clin Invest 96:2569–2577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seitz CS, Kleindienst R, Xu Q, Wick G (1996) Coexpression of heat-shock protein 60 and intercellular-adhesion molecule-1 is related to increased adhesion of monocytes and T cells to aortic endothelium of rats in response to endotoxin. Lab Invest 74:241–252

    CAS  PubMed  Google Scholar 

  • Shoenfeld Y, Harats D, George J (2000) Heat shock protein 60/65, beta 2-glycoprotein I and oxidized LDL as players in murine atherosclerosis. J Autoimmun 15:199–202

    Article  CAS  PubMed  Google Scholar 

  • Spradling A, Penman S, Pardue ML (1975) Analysis of drosophila mRNA by in situ hybridization: sequences transcribed in normal and heat shocked cultured cells. Cell 4:395–404

    Article  CAS  PubMed  Google Scholar 

  • Sun J, Hartvigsen K, Chou MY, Zhang Y, Sukhova GK, Zhang J, Lopez-Ilasaca M, Diehl CJ, Yakov N, Harats D, George J, Witztum JL, Libby P, Ploegh H, Shi GP (2010) Deficiency of antigen-presenting cell invariant chain reduces atherosclerosis in mice. Circulation 122:808–820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tamura Y, Torigoe T, Kukita K, Saito K, Okuya K, Kutomi G, Hirata K, Sato N (2012) Heat-shock proteins as endogenous ligands building a bridge between innate and adaptive immunity. Immunotherapy 4:841–852

    Article  CAS  PubMed  Google Scholar 

  • Tanaka S, Kimura Y, Mitani A, Yamamoto G, Nishimura H, Spallek R, Singh M, Noguchi T, Yoshikai Y (1999) Activation of T cells recognizing an epitope of heat-shock protein 70 can protect against rat adjuvant arthritis. J Immunol 163:5560–5565

    CAS  PubMed  Google Scholar 

  • Tanaka K, Namba T, Arai Y, Fujimoto M, Adachi H, Sobue G, Takeuchi K, Nakai A, Mizushima T (2007) Genetic evidence for a protective role for heat shock factor 1 and heat shock protein 70 against colitis. J Biol Chem 282:23240–23252

    Article  CAS  PubMed  Google Scholar 

  • Thompson SJ, Butcher PD, Patel VK, Rook GA, Stanford J, van der Zee R, Elson CJ (1991) Modulation of pristane-induced arthritis by mycobacterial antigens. Autoimmunity 11:35–43

    Article  CAS  PubMed  Google Scholar 

  • Tissieres A, Mitchell HK, Tracy UM (1974) Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs. J Mol Biol 84:389–398

    Article  CAS  PubMed  Google Scholar 

  • van Herwijnen MJ, Wieten L, van der Zee R, van Kooten PJ, Wagenaar-Hilbers JP, Hoek A, den Braber I, Anderton SM, Singh M, Meiring HD, van Els CA, van Eden W, Broere F (2012) Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis. Proc Natl Acad Sci U S A 109:14134–14139

    Article  PubMed  PubMed Central  Google Scholar 

  • van Puijvelde GH, Hauer AD, de Vos P, van den Heuvel R, van Herwijnen MJ, van der Zee R, van Eden W, van Berkel TJ, Kuiper J (2006) Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation 114:1968–1976

    Article  PubMed  CAS  Google Scholar 

  • van Puijvelde GH, van Es T, van Wanrooij EJ, Habets KL, de Vos P, van der Zee R, van Eden W, van Berkel TJ, Kuiper J (2007) Induction of oral tolerance to HSP60 or an HSP60-peptide activates T cell regulation and reduces atherosclerosis. Arterioscler Thromb Vasc Biol 27:2677–2683

    Article  PubMed  CAS  Google Scholar 

  • Wallin RP, Lundqvist A, More SH, von Bonin A, Kiessling R, Ljunggren HG (2002) Heat-shock proteins as activators of the innate immune system. Trends Immunol 23:130–135

    Article  CAS  PubMed  Google Scholar 

  • Waltner-Romen M, Falkensammer G, Rabl W, Wick G (1998) A previously unrecognized site of local accumulation of mononuclear cells. The vascular-associated lymphoid tissue. J Histochem Cytochem 46:1347–1350

    Article  CAS  PubMed  Google Scholar 

  • Wendling U, Paul L, van der Zee R, Prakken B, Singh M, 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 164:2711–2717

    Article  CAS  PubMed  Google Scholar 

  • Westwood JT, Clos J, Wu C (1991) Stress-induced oligomerization and chromosomal relocalization of heat-shock factor. Nature 353:822–827

    Article  CAS  PubMed  Google Scholar 

  • Wick G, Kleindienst R, Dietrich H, Xu Q (1992) Is atherosclerosis an autoimmune disease? Trends Food Sci Tech 3:114–119

    Article  CAS  Google Scholar 

  • Wick G, Schett G, Amberger A, Kleindienst R, Xu Q (1995) Is atherosclerosis an immunologically mediated disease? Immunol Today 16:27–33

    Article  CAS  PubMed  Google Scholar 

  • Wick G, Knoflach M, Xu Q (2004) Autoimmune and inflammatory mechanisms in atherosclerosis. Annu Rev Immunol 22:361–403

    Article  CAS  PubMed  Google Scholar 

  • Wick G, Jakic B, Buszko M, Wick MC, Grundtman C (2014) The role of heat shock proteins in atherosclerosis. Nat Rev Cardiol 11:516–529

    Article  CAS  PubMed  Google Scholar 

  • Wieten L, Berlo SE, Ten Brink CB, van Kooten PJ, Singh M, van der Zee R, Glant TT, Broere F, van Eden W (2009) IL-10 is critically involved in mycobacterial HSP70 induced suppression of proteoglycan-induced arthritis. PLoS One 4:e4186

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wigren M, Bengtsson D, Duner P, Olofsson K, Bjorkbacka H, Bengtsson E, Fredrikson GN, Nilsson J (2009) Atheroprotective effects of alum are associated with capture of oxidized LDL antigens and activation of regulatory T cells. Circ Res 104:e62–e70

    Article  CAS  PubMed  Google Scholar 

  • Willeit J, Kiechl S (1993) Prevalence and risk factors of asymptomatic extracranial carotid artery atherosclerosis. A population-based study. Arterioscler Thromb 13:661–668

    Article  CAS  PubMed  Google Scholar 

  • 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 36:2571–2576

    Article  CAS  PubMed  Google Scholar 

  • Xiong Q, Li J, Jin L, Liu J, Li T (2009) Nasal immunization with heat shock protein 65 attenuates atherosclerosis and reduces serum lipids in cholesterol-fed wild-type rabbits probably through different mechanisms. Immunol Lett 125:40–45

    Article  CAS  PubMed  Google Scholar 

  • Xu Q, Wick G (1996) The role of heat shock proteins in protection and pathophysiology of the arterial wall. Mol Med Today 2:372–379

    Article  CAS  PubMed  Google Scholar 

  • Xu QB, Oberhuber G, Gruschwit ZM, Wick G (1990) Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks, and atherosclerotic plaques in young and aged human specimens. Clin Immunol Immunopathol 56:344–359

    Article  CAS  PubMed  Google Scholar 

  • Xu Q, Dietrich H, Steiner HJ, Gown AM, Schoel B, Mikuz G, Kaufmann SH, Wick G (1992) Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. Arterioscler Thromb 12:789–799

    Article  CAS  PubMed  Google Scholar 

  • Xu Q, Kleindienst R, Waitz W, Dietrich H, Wick G (1993a) Increased expression of heat shock protein 65 coincides with a population of infiltrating T lymphocytes in atherosclerotic lesions of rabbits specifically responding to heat shock protein 65. J Clin Invest 91:2693–2702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Q, Willeit J, Marosi M, Kleindienst R, Oberhollenzer F, Kiechl S, Stulnig T, Luef G, Wick G (1993b) Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis. Lancet 341:255–259

    Article  CAS  PubMed  Google Scholar 

  • Xu Q, Kleindienst R, Schett G, Waitz W, Jindal S, Gupta RS, Dietrich H, Wick G (1996) Regression of arteriosclerotic lesions induced by immunization with heat shock protein 65-containing material in normocholesterolemic, but not hypercholesterolemic, rabbits. Atherosclerosis 123:145–155

    Article  CAS  PubMed  Google Scholar 

  • Xu Q, Kiechl S, Mayr M, Metzler B, Egger G, Oberhollenzer F, Willeit J, Wick G (1999) Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis: clinical significance determined in a follow-up study. Circulation 100:1169–1174

    Article  CAS  PubMed  Google Scholar 

  • Xu Q, Schett G, Perschinka H, Mayr M, Egger G, Oberhollenzer F, Willeit J, Kiechl S, Wick G (2000) Serum soluble heat shock protein 60 is elevated in subjects with atherosclerosis in a general population. Circulation 102:14–20

    Article  CAS  PubMed  Google Scholar 

  • Young RA, Elliott TJ (1989) Stress proteins, infection, and immune surveillance. Cell 59:5–8

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, He M, Cheng L, Chen Y, Zhou L, Zeng H, Pockley AG, Hu FB, Wu T (2008) Elevated heat shock protein 60 levels are associated with higher risk of coronary heart disease in Chinese. Circulation 118:2687–2693

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Xiong Q, Hu X, Sun Y, Tan X, Zhang H, Lu Y, Liu J (2012) A novel atherogenic epitope from Mycobacterium tuberculosis heat shock protein 65 enhances atherosclerosis in rabbit and LDL receptor-deficient mice. Heart Vessels 27:411–418

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Rheumatology Unit, Karolinska Institutet, Center for Molecular Medicine (CMM) L8:04, Karolinska University Hospital Solna, S-17176, Stockholm, Sweden

    Cecilia Wick

  2. Laboratory of Autoimmunity, Division for Experimental Pathophysiology and Immunology, Biocenter, Innsbruck Medical University, Innsbruck, A-6020, Austria

    Cecilia Wick

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Wick, C. Tolerization against atherosclerosis using heat shock protein 60. Cell Stress and Chaperones 21, 201–211 (2016). https://doi.org/10.1007/s12192-015-0659-z

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  • DOI: https://doi.org/10.1007/s12192-015-0659-z

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