Molecular Medicine

, Volume 18, Issue 6, pp 1018–1028 | Cite as

Heat Shock Protein 70: Roles in Multiple Sclerosis

  • María José Mansilla
  • Xavier Montalban
  • Carmen Espejo
Review Article


Heat shock proteins (HSP) have long been considered intracellular chaperones that possess housekeeping and cytoprotective functions. Consequently, HSP overexpression was proposed as a potential therapy for neurodegenerative diseases characterized by the accumulation or aggregation of abnormal proteins. Recently, the discovery that cells release HSP with the capacity to trigger proinflammatory as well as immunoregulatory responses has focused attention on investigating the role of HSP in chronic inflammatory autoimmune diseases such as multiple sclerosis (MS). To date, the most relevant HSP is the inducible Hsp70, which exhibits both cytoprotectant and immunoregulatory functions. Several studies have presented contradictory evidence concerning the involvement of Hsp70 in MS or experimental autoimmune encephalomyelitis (EAE), the MS animal model. In this review, we dissect the functions of Hsp70 and discuss the controversial data concerning the role of Hsp70 in MS and EAE.



We thank Joseph A Graells for his help with editing the language in the manuscript. This study was supported by Red Española de Esclerosis Multiple (REEM) (RD07/0060) from the Fondo de Investigación Sanitaria (FIS), Ministry of Science and Innovation, Spain; and the Ajuts per donar Suport als Grups de Recerca de Catalunya (2009 SGR 0793) from the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya, Spain. CE is partially supported by the Miguel Servet program (CP07/00146) from the FIS, Ministry of Science and Innovation, Spain.


  1. 1.
    Flynn GC, Chappell TG, Rothman JE. (1989) Peptide binding and release by proteins implicated as catalysts of protein assembly. Science. 245:385–90.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Beckmann RP, Mizzen LE, Welch WJ. (1990) Interaction of Hsp 70 with newly synthesized proteins: implications for protein folding and assembly. Science. 248:850–4.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Hartl FU, Hayer-Hartl M. (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science. 295:1852–8.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Murakami H, Pain D, Blobel G. (1988) 70-kD heat shock-related protein is one of at least two distinct cytosolic factors stimulating protein import into mitochondria. J. Cell Biol. 107:2051–7.CrossRefGoogle Scholar
  5. 5.
    Shi Y, Thomas JO. (1992) The transport of proteins into the nucleus requires the 70-kilodalton heat shock protein or its cytosolic cognate. Mol. Cell. Biol. 12:2186–92.Google Scholar
  6. 6.
    Ritossa FA. (1962) New puffing pattern induced by temperature shock and DNP in Drosophila. Experentia. 18:571–3.CrossRefGoogle Scholar
  7. 7.
    Li GC, Werb Z. (1982) Correlation between synthesis of heat shock proteins and development of thermotolerance in Chinese hamster fibroblasts. Proc. Natl. Acad. Sci. U. S. A. 79:3218–22.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Riabowol KT, Mizzen LA, Welch WJ. (1988) Heat shock is lethal to fibroblasts microinjected with antibodies against hsp70. Science. 242:433–6.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Lindquist S, Craig EA. (1988) The heat-shock proteins. Annu. Rev. Genet. 22:631–77.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Welch WJ. (1993) Heat shock proteins functioning as molecular chaperones: their roles in normal and stressed cells. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 339:327–33.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Jaattela M. (1999) Heat shock proteins as cellular lifeguards. Ann. Med. 31:261–71.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Hunt C, Morimoto RI. (1985) Conserved features of eukaryotic hsp70 genes revealed by comparison with the nucleotide sequence of human hsp70. Proc. Natl. Acad. Sci. U. S. A. 82:6455–9.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Tavaria M, Gabriele T, Kola I, Anderson RL. (1996) A hitchhiker’s guide to the human Hsp70 family. Cell Stress Chaperones. 1:23–8.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Daugaard M, Rohde M, Jaattela M. (2007) The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions. FEBS Lett. 581:3702–10.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Sospedra M, Martin R. (2005) Immunology of multiple sclerosis. Annu. Rev. Immunol. 23:683–747.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. (2000) Multiple sclerosis. N. Engl. J. Med. 343:938–52.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Rajaiah R, Moudgil KD. (2009) Heat-shock proteins can promote as well as regulate autoimmunity. Autoimmun. Rev. 8:388–93.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    van Eden W, van der Zee R, Prakken B. (2005) Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat. Rev. Immunol. 5:318–30.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Tytell M, Hooper PL. (2001) Heat shock proteins: new keys to the development of cytoprotective therapies. Expert Opin. Ther. Targets. 5:267–87.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Turturici G, Sconzo G, Geraci F. (2011) Hsp70 and its molecular role in nervous system diseases. Biochem. Res. Int. 2011:618127.Google Scholar
  21. 21.
    National MS Society. About MS: who gets MS [Internet]? [cited 2012 Aug 27]. Available from:
  22. 22.
    Compston A, Coles A. (2002) Multiple sclerosis. Lancet. 359:1221–31.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Whitacre CC. (2001) Sex differences in autoimmune disease. Nat. Immunol. 2:777–80.Google Scholar
  24. 24.
    Sundstrom P, et al. (2004) An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. Neurology. 62:2277–82.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. (2006) Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 296:2832–8.CrossRefGoogle Scholar
  26. 26.
    Smolders J, Damoiseaux J, Menheere P, Hupperts R. (2008) Vitamin D as an immune modulator in multiple sclerosis, a review. J. Neuroimmunol. 194:7–17.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Handel AE, et al. (2011) Smoking and multiple sclerosis: an updated meta-analysis. PLoS One. 6:e16149.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Dyment DA, Ebers GC, Sadovnick AD. (2004) Genetics of multiple sclerosis. Lancet Neurol. 3:104–10.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Hafler DA, et al. (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357:851–62.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Frohman EM, Racke MK, Raine CS. (2006) Multiple sclerosis—the plaque and its pathogenesis. N. Engl. J. Med. 354:942–55.CrossRefGoogle Scholar
  31. 31.
    Zamvil SS, Steinman L. (1990) The T lymphocyte in experimental allergic encephalomyelitis. Annu. Rev. Immunol. 8:579–621.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Pettinelli CB, McFarlin DE. (1981) Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: requirement for Lyt 1+ 2− T lymphocytes. J. Immunol. 127:1420–3.PubMedGoogle Scholar
  33. 33.
    Mokhtarian F, McFarlin DE, Raine CS. (1984) Adoptive transfer of myelin basic protein-sensitized T cells produces chronic relapsing demyelinating disease in mice. Nature. 309:356–8.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    van der Veen RC, Trotter JL, Clark HB, Kapp JA. (1989) The adoptive transfer of chronic relapsing experimental allergic encephalomyelitis with lymph node cells sensitized to myelin proteolipid protein. J. Neuroimmunol. 21:183–91.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Wucherpfennig KW, Strominger JL. (1995) Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell. 80:695–705.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. (2004) Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 199:971–9.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Dore-Duffy P, Washington R, Dragovic L. (1993) Expression of endothelial cell activation antigens in microvessels from patients with multiple sclerosis. Adv. Exp. Med. Biol. 331:243–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Comabella M, Khoury SJ. (2012) Immunopathogenesis of multiple sclerosis. Clin. Immunol. 142:2–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Morimoto RI. (1998) Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes. Dev. 12:3788–96.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Mayer MP, Bukau B. (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell. Mol. Life Sci. 62:670–84.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Voellmy R, Boellmann F. (2007) Chaperone regulation of the heat shock protein response. Adv. Exp. Med. Biol. 594:89–99.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Freedman MS, Buu NN, Ruijs TC, Williams K, Antel JP. (1992) Differential expression of heat shock proteins by human glial cells. J. Neuroimmunol. 41:231–8.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Satoh J, Yamamura T, Kunishita T, Tabira T. (1992) Heterogeneous induction of 72-kDa heat shock protein (HSP72) in cultured mouse oligodendrocytes and astrocytes. Brain Res. 573:37–43.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Satoh J, Kim SU. (1994) HSP72 induction by heat stress in human neurons and glial cells in culture. Brain Res. 653:243–50.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Foster JA, Brown IR. (1997) Differential induction of heat shock mRNA in oligodendrocytes, microglia, and astrocytes following hyperthermia. Brain Res. Mo Brain Res. l. 45:207–18.CrossRefGoogle Scholar
  46. 46.
    Mosser DD, Morimoto RI. (2004) Molecular chaperones and the stress of oncogenesis. Oncogene. 23:2907–18.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Benn SC, Woolf CJ. (2004) Adult neuron survival strategies—slamming on the brakes. Nat. Rev. Neurosci. 5:686–700.Google Scholar
  48. 48.
    Beere HM. (2004) “The stress of dying”: the role of heat shock proteins in the regulation of apoptosis. J. Cell Sci. 117:2641–51.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Lanneau D, de Thonel A, Maurel S, Didelot C, Garrido C. (2007) Apoptosis versus cell differentiation: role of heat shock proteins HSP90, HSP70 and HSP27. Prion. 1:53–60.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Evans CG, Wisen S, Gestwicki JE. (2006) Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1–42) aggregation in vitro. J. Biol. Chem. 281:33182–91.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Magrane J, Smith RC, Walsh K, Querfurth HW. (2004) Heat shock protein 70 participates in the neuroprotective response to intracellularly expressed beta-amyloid in neurons. J. Neurosci. 24:1700–6.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Dou F, et al. (2003) Chaperones increase association of tau protein with microtubules. Proc. Natl. Acad. Sci. U. S. A. 100:721–6.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Muchowski PJ, et al. (2000) Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl. Acad. Sci. U. S. A. 97:7841–6.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM. (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science. 295:865–8.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Heneka MT, et al. (2001) The heat shock response reduces myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in mice. J. Neurochem. 77:568–79.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Zhang JF, Huang R, Xu J, Jin SJ, Yang YJ. (2007) Protective effects of heat shock preconditioning on the experimental autoimmune encephalomyelitis rats [in Chinese]. Zhongguo Dang Dai Er Ke Za Zhi. 9:563–6.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Brown IR. (1991) Expression of heat shock genes (hsp70) in the mammalian nervous system. Results Probl. Cell Differ. 17:217–29.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Tytell M, Greenberg SG, Lasek RJ. (1986) Heat shock-like protein is transferred from glia to axon. Brain Res. 363:161–4.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Hightower LE, Guidon PT Jr. (1989) Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins. J. Cell Physiol. 138:257–66.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Sheller RA, Smyers ME, Grossfeld RM, Ballinger ML, Bittner GD. (1998) Heat-shock proteins in axoplasm: high constitutive levels and transfer of inducible isoforms from glia. J. Comp. Neurol. 396:1–11.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Guzhova I, et al. (2001) In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance. Brain Res. 914:66–73.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Gao YL, Brosnan CF, Raine CS. (1995) Experimental autoimmune encephalomyelitis. Qualitative and semiquantitative differences in heat shock protein 60 expression in the central nervous system. J. Immunol. 154:3548–56.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Aquino DA, Klipfel AA, Brosnan CF, Norton WT. (1993) The 70-kDa heat shock cognate protein (HSC70) is a major constituent of the central nervous system and is up-regulated only at the mRNA level in acute experimental autoimmune encephalomyelitis. J. Neurochem. 61:1340–8.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Aquino DA, et al. (1997) Multiple sclerosis: altered expression of 70- and 27-kDa heat shock proteins in lesions and myelin. J. Neuropathol. Exp. Neurol. 56:664–72.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Chabas D, et al. (2001) The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science. 294:1731–5.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Rajdev S, et al. (2000) Mice overexpressing rat heat shock protein 70 are protected against cerebral infarction. Ann. Neurol. 47:782–91.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Hoehn B, et al. (2001) Overexpression of HSP72 after induction of experimental stroke protects neurons from ischemic damage. J. Cereb. Blood Flow Metab. 21:1303–9.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Stadelmann C, et al. (2005) Tissue preconditioning may explain concentric lesions in Balo’s type of multiple sclerosis. Brain. 128:979–87.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Brosnan CF, Battistini L, Gao YL, Raine CS, Aquino DA. (1996) Heat shock proteins and multiple sclerosis: a review. J. Neuropathol. Exp. Neurol. 55:389–402.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Bajramovic JJ, et al. (2000) Differential expression of stress proteins in human adult astrocytes in response to cytokines. J. Neuroimmunol. 106:14–22.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    D’Souza SD, Antel JP, Freedman MS. (1994) Cytokine induction of heat shock protein expression in human oligodendrocytes: an interleukin-1-mediated mechanism. J. Neuroimmunol. 50:17–24.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Fleshner M, Johnson JD. (2005) Endogenous extra-cellular heat shock protein 72: releasing signal(s) and function. Int. J. Hyperthermia. 21:457–71.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Binder RJ, Vatner R, Srivastava P. (2004) The heat-shock protein receptors: some answers and more questions. Tissue Antigens. 64:442–51.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Calderwood SK, Mambula SS, Gray PJ Jr. (2007) Extracellular heat shock proteins in cell signaling and immunity. Ann. N. Y. Acad. Sci. 1113:28–39.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Van Eden W, Wick G, Albani S, Cohen I. (2007) Stress, heat shock proteins, and autoimmunity: how immune responses to heat shock proteins are to be used for the control of chronic inflammatory diseases. Ann. N. Y. Acad. Sci. 1113:217–37.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int. Immunol. 12:1539–46.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Hunter-Lavin C, et al. (2004) Hsp70 release from peripheral blood mononuclear cells. Biochem. Biophys. Res. Commun. 324:511–7.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Clayton A, Turkes A, Navabi H, Mason MD, Tabi Z. (2005) Induction of heat shock proteins in B-cell exosomes. J. Cell Sci. 118:3631–8.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Lancaster GI, et al. (2004) Exercise induces the release of heat shock protein 72 from the human brain in vivo. Cell Stress Chaperones. 9:276–80.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Bausero MA, Gastpar R, Multhoff G, Asea A. (2005) Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72. J. Immunol. 175:2900–12.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Asea A, et al. (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 277:15028–34.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Multhoff G, et al. (1999) Heat shock protein 70 (Hsp70) stimulates proliferation and cytolytic activity of natural killer cells. Exp. Hematol. 27:1627–36.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Gross C, et al. (2003) Heat shock protein 70-reactivity is associated with increased cell surface density of CD94/CD56 on primary natural killer cells. Cell Stress Chaperones. 8:348–60.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Gastpar R, et al. (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res. 65:5238–47.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Asea A, et al. (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat. Med. 6:435–42.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Moroi Y, et al. (2000) Induction of cellular immunity by immunization with novel hybrid peptides complexed to heat shock protein 70. Proc. Natl. Acad. Sci. U. S. A. 97:3485–90.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Lehner T, et al. (2000) Heat shock proteins generate beta-chemokines which function as innate adjuvants enhancing adaptive immunity. Eur. J. Immunol. 30:594–603.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Panjwani NN, Popova L, Srivastava PK. (2002) Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J. Immunol. 168:2997–3003.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Singh-Jasuja H, et al. (2000) The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor. Eur. J. Immunol. 30:2211–5.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Kuppner MC, et al. (2001) The role of heat shock protein (hsp70) in dendritic cell maturation: hsp70 induces the maturation of immature dendritic cells but reduces DC differentiation from monocyte precursors. Eur. J. Immunol. 31:1602–9.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Becker T, Hartl FU, Wieland F. (2002) CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J. Cell Biol. 158:1277–85.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Suto R, Srivastava PK. (1995) A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science. 269:1585–8.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Doody AD, et al. (2004) Glycoprotein 96 can chaperone both MHC class I- and class II-restricted epitopes for in vivo presentation, but selectively primes CD8+ T cell effector function. J. Immunol. 172:6087–92.CrossRefGoogle Scholar
  94. 94.
    Li Y, Subjeck J, Yang G, Repasky E, Wang XY. (2006) Generation of anti-tumor immunity using mammalian heat shock protein 70 DNA vaccines for cancer immunotherapy. Vaccine. 24:5360–70.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Gong J, et al. (2010) A heat shock protein 70-based vaccine with enhanced immunogenicity for clinical use. J. Immunol. 184:488–96.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Bausinger H, et al. (2002) Endotoxin-free heat-shock protein 70 fails to induce APC activation. Eur. J. Immunol. 32:3708–13.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    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. 278:174–9.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Cwiklinska H, et al. (2003) Heat shock protein 70 associations with myelin basic protein and proteolipid protein in multiple sclerosis brains. Int. Immunol. 15:241–9.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Mycko MP, et al. (2004) Inducible heat shock protein 70 promotes myelin autoantigen presentation by the HLA class II. J. Immunol. 172:202–13.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Lund BT, et al. (2006) Association of MBP peptides with Hsp70 in normal appearing human white matter. J. Neurol. Sci. 249:122–34.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Galazka G, et al. (2006) Brain-derived heat shock protein 70-peptide complexes induce NK cell-dependent tolerance to experimental autoimmune encephalomyelitis. J. Immunol. 176:1588–99.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Galazka G, et al. (2007) EAE tolerance induction with Hsp70-peptide complexes depends on H60 and NKG2D activity. J. Immunol. 179:4503–12.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Mycko MP, et al. (2008) A heat shock protein gene (Hsp70.1) is critically involved in the generation of the immune response to myelin antigen. Eur. J. Immunol. 38:1999–2013.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Battistini L, et al. (1995) Gamma delta T cell receptor analysis supports a role for HSP 70 selection of lymphocytes in multiple sclerosis lesions. Mol. Med. 1:554–62.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Freedman MS, Ruijs TC, Selin LK, Antel JP. (1991) Peripheral blood gamma-delta T cells lyse fresh human brain-derived oligodendrocytes. Ann. Neurol. 30:794–800.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Lockhart E, Green AM, Flynn JL. (2006) IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J. Immunol. 177:4662–9.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Sutton CE, et al. (2009) Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 31:331–41.CrossRefGoogle Scholar
  108. 108.
    Rachitskaya AV, et al. (2008) Cutting edge: NKT cells constitutively express IL-23 receptor and RORgammat and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion. J. Immunol. 180:5167–71.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Cwiklinska H, Mycko MP, Szymanska B, Matysiak M, Selmaj KW. (2010) Aberrant stressinduced Hsp70 expression in immune cells in multiple sclerosis. J. Neurosci. Res. 88:3102–10.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Routsias JG, Tzioufas AG. (2006) The role of chaperone proteins in autoimmunity. Ann. N. Y. Acad. Sci. 1088:52–64.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Lamb JR, et al. (1989) Stress proteins may provide a link between the immune response to infection and autoimmunity. Int. Immunol. 1:191–6.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Munk ME, et al. (1989) T lymphocytes from healthy individuals with specificity to self-epitopes shared by the mycobacterial and human 65-kilodalton heat shock protein. J. Immunol. 143:2844–9.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Abulafia-Lapid R, et al. (1999) T cell proliferative responses of type 1 diabetes patients and healthy individuals to human hsp60 and its peptides. J. Autoimmun. 12:121–9.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Perschinka H, et al. (2003) Cross-reactive B-cell epitopes of microbial and human heat shock protein 60/65 in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 23:1060–5.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Res PC, et al. (1988) Synovial fluid T cell reactivity against 65 kD heat shock protein of mycobacteria in early chronic arthritis. Lancet. 2:478–80.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Salvetti M, et al. (1992) T-lymphocyte reactivity to the recombinant mycobacterial 65- and 70-kDa heat shock proteins in multiple sclerosis. J. Autoimmun. 5:691–702.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Salvetti M, et al. (1996) The immune response to mycobacterial 70-kDa heat shock proteins frequently involves autoreactive T cells and is quantitatively disregulated in multiple sclerosis. J. Neuroimmunol. 65:143–53.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Stinissen P, et al. (1995) Increased frequency of gamma delta T cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. Reactivity, cytotoxicity, and T cell receptor V gene rearrangements. J. Immunol. 154:4883–94.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Chiba S, et al. (2006) Autoantibodies against HSP70 family proteins were detected in the cerebrospinal fluid from patients with multiple sclerosis. J. Neurol. Sci. 241:39–43.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Jorgensen C, Gedon E, Jaquet C, Sany J. (1998) Gastric administration of recombinant 65 kDa heat shock protein delays the severity of type II collagen induced arthritis in mice. J. Rheumatol. 25:763–7.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Wendling U, et al. (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.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Chandawarkar RY, Wagh MS, Kovalchin JT, Srivastava P. (2004) Immune modulation with high-dose heat-shock protein gp96: therapy of murine autoimmune diabetes and encephalomyelitis. Int. Immunol. 16:615–24.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Birnbaum G, et al. (1998) Heat shock proteins and experimental autoimmune encephalomyelitis. II: environmental infection and extra-neuraxial inflammation alter the course of chronic relapsing encephalomyelitis. J. Neuroimmunol. 90:149–61.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Raz I, et al. (2001) Beta-cell function in newonset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet. 358:1749–53.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Wieten L, et al. (2009) IL-10 is critically involved in mycobacterial HSP70 induced suppression of proteoglycan-induced arthritis. PLoS One. 4:e4186.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Pockley AG, Shepherd J, Corton JM. (1998) Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. Immunol. Invest. 27:367–77.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Pockley AG, Bulmer J, Hanks BM, Wright BH. (1999) Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals. Cell Stress Chaperones. 4:29–35.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Pockley AG, Muthana M, Calderwood SK. (2008) The dual immunoregulatory roles of stress proteins. Trends Biochem. Sci. 33:71–9.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Wright BH, Corton JM, El-Nahas AM, Wood RF, Pockley AG. (2000) Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease. Heart Vessels. 15:18–22.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Pockley AG, et al. (2000) Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertension. 36:303–7.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Pockley AG, Georgiades A, Thulin T, de Faire U, Frostegard J. (2003) Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension. Hypertension. 42:235–8.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Birnbaum G, Kotilinek L. (1997) Heat shock or stress proteins and their role as autoantigens in multiple sclerosis. Ann. N. Y. Acad. Sci. 835:157–67.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Bustamante MF, et al. (2011) Implication of the Toll-like receptor 4 pathway in the response to interferon-beta in multiple sclerosis. Ann. Neurol. 70:634–45.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Yokota S, Chiba S, Furuyama H, Fujii N. (2010) Cerebrospinal fluids containing anti-HSP70 autoantibodies from multiple sclerosis patients augment HSP70-induced proinflammatory cytokine production in monocytic cells. J. Neuroimmunol. 218:129–33.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Milner CM, Campbell RD. (1990) Structure and expression of the three MHC-linked HSP70 genes. Immunogenetics. 32:242–51.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Favatier F, Bornman L, Hightower LE, Gunther E, Polla BS. (1997) Variation in hsp gene expression and Hsp polymorphism: do they contribute to differential disease susceptibility and stress tolerance? Cell Stress Chaperones. 2:141–55.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Wu B, Hunt C, Morimoto R. (1985) Structure and expression of the human gene encoding major heat shock protein HSP70. Mol. Cell. Biol. 5:330–41.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Ramachandran S, Bell RB. (1995) Heat shock protein 70 gene polymorphisms and multiple sclerosis. Tissue Antigens. 46:140–1.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Cascino I, et al. (1994) HSP70-1 promoter region polymorphism tested in three autoimmune diseases. Immunogenetics. 39:291–3.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Niino M, et al. (2001) Heat shock protein 70 gene polymorphism in Japanese patients with multiple sclerosis. Tissue Antigens. 58:93–6.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Satoh J, et al. (2005) Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis. Neurobiol. Dis. 18:537–50.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Mandel M, Gurevich M, Pauzner R, Kaminski N, Achiron A. (2004) Autoimmunity gene expression portrait: specific signature that intersects or differentiates between multiple sclerosis and systemic lupus erythematosus. Clin. Exp. Immunol. 138:164–70.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Bomprezzi R, et al. (2003) Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease. Hum. Mol. Genet. 12:2191–9.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Cudkowicz ME, et al. (2008) Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis. Muscle Nerve. 38:837–44.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Traynor BJ, et al. (2006) Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology. 67:20–7.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Benn SC, Brown RH Jr. (2004) Putting the heat on ALS. Nat. Med. 10:345–7.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Kieran D, et al. (2004) Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat. Med. 10:402–5.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Dello Russo C, et al. (2006) The heat-shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis. J. Neurochem. 99:1351–62.CrossRefGoogle Scholar
  149. 149.
    Jurivich DA, Sistonen L, Kroes RA, Morimoto RI. (1992) Effect of sodium salicylate on the human heat shock response. Science. 255:1243–5.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Ohtsuka K, Kawashima D, Gu Y, Saito K. (2005) Inducers and co-inducers of molecular chaperones. Int. J. Hyperthermia. 21:703–11.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Eriksen JL, et al. (2003) NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J. Clin. Invest. 112:440–9.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Fu YF, et al. (2006) (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, prevents experimental autoimmune encephalomyelitis via inhibiting T cell activation. J. Neuroimmunol. 175:142–51.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Wang Y, Mei Y, Feng D, Xu L. (2008) Triptolide modulates T-cell inflammatory responses and ameliorates experimental autoimmune encephalomyelitis. J. Neurosci. Res. 86:2441–9.PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Kizelsztein P, Komarnytsky S, Raskin I. (2009) Oral administration of triptolide ameliorates the clinical signs of experimental autoimmune encephalomyelitis (EAE) by induction of HSP70 and stabilization of NF-kappaB/IkappaBalpha transcriptional complex. J. Neuroimmunol. 217:28–37.PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Liu Q, et al. (2004) Triptolide (PG-490) induces apoptosis of dendritic cells through sequential p38 MAP kinase phosphorylation and caspase 3 activation. Biochem. Biophys. Res. Commun. 319:980–6.PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Westerheide SD, Kawahara TL, Orton K, Morimoto RI. (2006) Triptolide, an inhibitor of the human heat shock response that enhances stress-induced cell death. J. Biol. Chem. 281:9616–22.PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Liu Q. (2011) Triptolide and its expanding multiple pharmacological functions. Int. Immunopharmacol. 11:377–83.PubMedCrossRefPubMedCentralGoogle Scholar

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Authors and Affiliations

  • María José Mansilla
    • 1
  • Xavier Montalban
    • 1
  • Carmen Espejo
    • 1
  1. 1.Unitat de Neuroimmunologia Clínica, Centre d’Esclerosi Múltiple de Catalunya (CEM-Cat), Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’HebronUniversitat Autònoma de BarcelonaBarcelonaSpain

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