Heat Shock Proteins in Multiple Sclerosis

  • Celia F. BrosnanEmail author
  • Luca Battistini
  • Krzysztof Selmaj
Part of the Neuroscience Intelligence Unit book series


In this review, we have addressed the possible contribution of heat shock proteins (HSP) to the pathogenesis of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS). A particular focus of the review is on the families of HSP27, HSP60 and HSP70 because there is good evidence for both RNA and protein that expression levels of these HSP are altered in lesioned areas of the CNS. Using a variety of different approaches, the data support a role for these HSP in the generation of the immune response, particularly in the more chronic phases of the disease process. In addition, we review evidence supporting a protective role for these HSP in the injured CNS. This dual role of HSP makes an analysis of their effects in degenerative CNS diseases difficult to determine with certainty. Nevertheless, ongoing data are persuasive that this remains an important area of research that is likely to continue to contribute to our understanding of disease pathogenesis in MS.


Multiple Sclerosis Heat Shock Protein Experimental Autoimmune Encephalomyelitis Myelin Basic Protein Small Heat Shock Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Weiner HL. Multiple sclerosis is an inflammatory T-cell-mediated autoimmune disease. Arch Neurol 2004; 61(10):1613–1615.CrossRefPubMedGoogle Scholar
  2. 2.
    Steinman L, Martin R, Bernard C et al. Multiple sclerosis: Deeper understanding of its pathogenesis reveals new targets for therapy. Annu Rev Neurosci 2002; 25:491–505.CrossRefPubMedGoogle Scholar
  3. 3.
    Lassmann H, Ransohoff RM. The CD4-thl model for multiple sclerosis: A critical [Correction Of Crucial] Reappraisal. Trends Immunol 2004; 25(3):132–137.CrossRefPubMedGoogle Scholar
  4. 4.
    Segal BM. Experimental autoimmune encephalomyelitis: Cytokines, effector t cells, and Antigen-presenting cells in a prototypical Thl-mediated autoimmune disease. Curr Allergy Asthma Rep 2003; 3(1):86–93.CrossRefPubMedGoogle Scholar
  5. 5.
    Wekerle H, Kojima K, Lannes-Vieira J et al. Animal models. Ann Neurol 1994; 36(Suppl):S47–53.CrossRefPubMedGoogle Scholar
  6. 6.
    Miller SD, Eagar TN. Functional role of epitope spreading in the chronic pathogenesis of autoimmune and Virus-induced demyelinating diseases. Adv Exp Med Biol 2001; 490:99–107.PubMedGoogle Scholar
  7. 7.
    Cross AH, Tuohy VK, Raine CS. Development of reactivity to new myelin antigens during chronic relapsing autoimmune demyelination. Cell Immunol 1993; 146(2):261–269.CrossRefPubMedGoogle Scholar
  8. 8.
    Kaufmann SH, Schoel B, Van Embden JD et al. Heat-shock protein 60: Implications for pathogenesis of and protection against bacterial infections. Immunol Rev 1991; 121:67–90.CrossRefPubMedGoogle Scholar
  9. 9.
    Bar-Or A, Oliveira EM, Anderson DE et al. Molecular pathogenesis of multiple sclerosis. J Neuroimmunol 1999; 100(1–2):252–259.CrossRefPubMedGoogle Scholar
  10. 10.
    Oliveira EM, Bar-Or A, Waliszewska AI et al. CTLA-4 dysregulation in the activation of myelin basic protein reactive t cells may distinguish patients with multiple sclerosis from healthy controls. J Autoimmun 2003; 20(1):71–81.CrossRefPubMedGoogle Scholar
  11. 11.
    Moseley P. Stress proteins and the immune response. Immunopharmacology 2000; 48(3):299–302.CrossRefPubMedGoogle Scholar
  12. 12.
    Cohen IR. Autoimmunity to chaperonins in the pathogenesis of arthritis and diabetes. Annu Rev Immunol 1991; 9:567–589.CrossRefPubMedGoogle Scholar
  13. 13.
    Chandawarkar RY, Wagh MS, Kovalchin JT et al. Immune modulation with high-dose heat-shock protein Gp96: Therapy of murine autoimmune diabetes and encephalomyelitis. Int Immunol 2004; 16(4):615–624.CrossRefPubMedGoogle Scholar
  14. 14.
    Kappe G, Franck E, Verschuure P et al. The human genome encodes 10 alpha-crystallin-related small heat shock proteins: Hspbl-10. Cell Stress Chaperones. Spring 2003; 8(1):53–61.CrossRefPubMedGoogle Scholar
  15. 15.
    Der Perng M, Quinlan RA. Neuronal diseases: Small heat shock proteins calm your nerves. Curr Biol 2004; 14(15):R625–626.CrossRefGoogle Scholar
  16. 16.
    Ciocca DR, Oesterreich S, Chamness GC et al. Biological and clinical implications of heat shock protein 27,000 (Hsp27): A review. J Natl Cancer Inst 1993; 85(19):1558–1570.CrossRefPubMedGoogle Scholar
  17. 17.
    Van Noort JM, Van Sechel AC, Bajramovic JJ et al. The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis. Nature 1995; 375(6534):798–801.CrossRefPubMedGoogle Scholar
  18. 18.
    Chou YK, Burrows GG, Latocha D et al. CD4 T-cell epitopes of human alpha B-crystallin. J Neurosci Res 2004; 75(4):516–523.CrossRefPubMedGoogle Scholar
  19. 19.
    Holmoy T, Vartdal F. Cerebrospinal fluid t cells from multiple sclerosis patients recognize autologous epstein-barr virus-transformed b cells. J Neurovirol 2004; 10(1):52–56.CrossRefPubMedGoogle Scholar
  20. 20.
    Tajouri L, Mellick AS, Ashton KJ et al. Quantitative and qualitative changes in gene expression patterns characterize the activity of plaques in multiple sclerosis. Brain Res Mol Brain Res 2003; 119(2):170–183.CrossRefPubMedGoogle Scholar
  21. 21.
    Van Veen T, Van Winsen L, Crusius JB et al. [Alpha]B-crystallin genotype has impact on the multiple sclerosis phenotype. Neurology 2003; 61(9):1245–1249.PubMedGoogle Scholar
  22. 22.
    Vojdani A, Vojdani E, Cooper E. Antibodies to myelin basic protein, myelin oligodendrocytes peptides, alpha-beta-crystallin, lymphocyte activation and cytokine production in patients with multiple sclerosis. J Intern Med 2003; 254(4):363–374.CrossRefPubMedGoogle Scholar
  23. 23.
    Celet B, Akman-Demir G, Serdaroglu P et al. Anti-alpha B-crystallin immunoreactivity in inflammatory nervous system diseases. J Neurol 2000; 247(12):935–939.CrossRefPubMedGoogle Scholar
  24. 24.
    Bajramovic JJ, Plomp AC, Goes A et al. Presentation of alpha B-crystallin to t cells in active multiple sclerosis lesions: An early event following inflammatory demyelination. J Immunol 2000; 164(8):4359–4366.PubMedGoogle Scholar
  25. 25.
    Bajramovic JJ, Lassmann H, Van Noort JM. Expression of alpha B-crystallin in glia cells during lesional development in multiple sclerosis. J Neuroimmunol 1997; 78(1–2):143–151.CrossRefPubMedGoogle Scholar
  26. 26.
    Van Noort JM, Van Sechel AC, Van Stipdonk MJ et al. The small heat shock protein alpha B-crystallin as key autoantigen in multiple sclerosis. Prog Brain Res 1998; 117:435–452.CrossRefPubMedGoogle Scholar
  27. 27.
    Aquino DA, Capello E, Weisstein J et al. Multiple sclerosis: Altered expression of 70-and 27-kDa heat shock proteins in lesions and myelin. J Neuropathol Exp Neurol 1997; 56(6):664–672.PubMedGoogle Scholar
  28. 28.
    Richter-Landsberg C, Bauer NG. Tau-inclusion body formation in oligodendroglia: The role of stress proteins and proteasome inhibition. Int J Dev Neurosci 2004; 22(7):443–451.CrossRefPubMedGoogle Scholar
  29. 29.
    Chabas D, Baranzini SE, Mitchell D et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001; 294(5547):1731–1735.CrossRefPubMedGoogle Scholar
  30. 30.
    Thoua NM, Van Noort JM, Baker D et al. Encephalitogenic and immunogenic potential of the stress protein alphaB-crystallin in biozzi ABH (H-2A(G7)) Mice. J Neuroimmunol 2000; 104(1):47–57.CrossRefPubMedGoogle Scholar
  31. 31.
    Seamons A, Perchellet A, Goverman J. Immune tolerance to myelin proteins. Immunol Res 2003; 28(3):201–221.CrossRefPubMedGoogle Scholar
  32. 32.
    Starckx S, Van Den Steen PE, Verbeek R et al. A novel rationale for inhibition of gelatinase B in multiple sclerosis: MMP-9 destroys alpha B-crystallin and generates A promiscuous T cell epitope. J Neuroimmunol 2003; 141(1–2):47–57.CrossRefPubMedGoogle Scholar
  33. 33.
    Opdenakker G, Nelissen I, Van Damme J. Functional roles and therapeutic targeting of gelatinase B and chemokines in multiple sclerosis. Lancet Neurol 2003; 2(12):747–756.CrossRefPubMedGoogle Scholar
  34. 34.
    Bever Jr CT, Rosenberg GA. Matrix metalloproteinases in multiple sclerosis: Targets of therapy or markers of injury? Neurology 1999; 53(7):1380–1381.PubMedGoogle Scholar
  35. 35.
    Bukau B, Horwich AL. The Hsp70 and Hsp60 chaperone machines. Cell 1998; 92(3):351–366.CrossRefPubMedGoogle Scholar
  36. 36.
    Martin J. Molecular chaperones and mitochondrial protein folding. J Bioenerg Biomembr 1997; 29(1):35–43.CrossRefPubMedGoogle Scholar
  37. 37.
    Gao YL, Brosnan CF, Raine CS. Experimental autoimmune encephalomyelitis. Qualitative and semiquantitative differences in heat shock protein 60 expression in the central nervous system. J Immunol 1995; 154(7):3548–3556.PubMedGoogle Scholar
  38. 38.
    Mor F, Cohen IR. Analysis of the autoimmune infiltrate in experimental encephalomyelitis. Isr J Med Sci 1992; 28(2):139–140.PubMedGoogle Scholar
  39. 39.
    Quintana FJ, Carmi P, Mor F et al. 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(7):3533–3541.PubMedGoogle Scholar
  40. 40.
    Brosnan CF, Battistini L, Gao YL et al. Heat shock proteins and multiple sclerosis: A review. J Neuropathol Exp Neurol 1996; 55(4):389–402.CrossRefPubMedGoogle Scholar
  41. 41.
    Gao YL, Raine CS, Brosnan CF. Humoral response to Hsp 65 in multiple sclerosis and other neurologic conditions. Neurology 1994; 44(5):941–946.PubMedGoogle Scholar
  42. 42.
    Prabhakar S, Kurien E, Gupta RS et al. Heat shock protein immunoreactivity in CSF: Correlation with oligoclonal banding and demyelinating disease. Neurology 1994; 44(9):1644–1648.PubMedGoogle Scholar
  43. 43.
    Raine CS. The dale E. mcfarlin memorial lecture: The immunology of the multiple sclerosis lesion. Ann Neurol 1994; 36(Suppl):S61–72.CrossRefPubMedGoogle Scholar
  44. 44.
    Koga T, Wand-Wurttenberger A, Debruyn J et al. T cells against a bacterial heat shock protein recognize stressed macrophages. Science 1989; 245(4922):1112–1115.CrossRefPubMedGoogle Scholar
  45. 45.
    Cohen IR, Quintana FJ, Mimran A. Tregs in T cell vaccination: Exploring the regulation of regulation. J Clin Invest 2004; 114(9):1227–1232.PubMedGoogle Scholar
  46. 46.
    Iwahashi M, Yamamura M, Aita T et al. Expression of toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum 2004; 50(5):1457–1467.CrossRefPubMedGoogle Scholar
  47. 47.
    Habich C, Baumgart K, Kolb H et al. The receptor for heat shock protein 60 on macrophages is saturable, specific, and distinct from receptors for other heat shock proteins. J Immunol 2002; 168(2):569–576.PubMedGoogle Scholar
  48. 48.
    Ohashi K, Burkart V, Flohe S et al. Cutting edge: Heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol 2000; 164(2):558–561.PubMedGoogle Scholar
  49. 49.
    Vabulas RM, Ahmad-Nejad P, Ghose S et al. HSP70 as endogenous stimulus of the toll/interleukin-1 receptor signal pathway. J Biol Chem 2002; 277(17):15107–15112.CrossRefPubMedGoogle Scholar
  50. 50.
    Vabulas RM, Wagner H, Schild H. Heat shock proteins as ligands of toll-like receptors. Curr Top Microbiol Immunol 2002; 270:169–184.PubMedGoogle Scholar
  51. 51.
    Matzinger P. An innate sense of danger. Ann NY Acad Sci 2002; 961:341–342.CrossRefPubMedGoogle Scholar
  52. 52.
    Salvetti M, Ristori G, Buttinelli C et al. The immune response to mycobacterial 70-kda heat shock proteins frequently involves autoreactive T cells and is quantitatively disregulated in multiple sclerosis. J Neuroimmunol 1996; 65(2):143–153.CrossRefPubMedGoogle Scholar
  53. 53.
    Salvetti M, Buttinelli C, Ristori G et al. Heat shock proteins as targets for gamma-delta T cells in multiple sclerosis. Ann Neurol 1992; 32(3):410–411.CrossRefPubMedGoogle Scholar
  54. 54.
    Birnbaum G. Stress proteins: Their role in the normal central nervous system and in disease states, especially multiple sclerosis. Springer Semin Immunopathol 1995; 17(1):107–118.CrossRefPubMedGoogle Scholar
  55. 55.
    Birnbaum G, Kotilinek L. Heat shock or stress proteins and their role as autoantigens in multiple sclerosis. Ann NY Acad Sci 1997; 835:157–167.CrossRefPubMedGoogle Scholar
  56. 56.
    Stinissen P, Vandevyver C, Medaer R et al. 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 1995; 154(9):4883–4894.PubMedGoogle Scholar
  57. 57.
    Battistini L, Selmaj K, Kowal C et al. Multiple sclerosis: Limited diversity of the V delta 2-J delta 3 T-cell receptor in chronic active lesions. Ann Neurol 1995; 37(2):198–203.CrossRefPubMedGoogle Scholar
  58. 58.
    Gullo CA, Teoh G. Heat shock proteins: To present or not, that is the question. Immunol Lett 2004; 94(1–2):1–10.CrossRefPubMedGoogle Scholar
  59. 59.
    Robert J. Evolution of heat shock protein and immunity. Dev Comp Immunol 2003; 27(6–7):449–464.CrossRefPubMedGoogle Scholar
  60. 60.
    Fremont DH, Hendrickson WA, Marrack P et al. Structures of an MHC class II molecule with covalendy bound single peptides. Science 1996; 272(5264):1001–1004.CrossRefPubMedGoogle Scholar
  61. 61.
    Cwiklinska H, Mycko MP, Luvsannorov O et al. Heat shock protein 70 associations with myelin basic protein and proteolipid protein in multiple sclerosis brains. Int Immunol 2003; 15(2):241–249.CrossRefPubMedGoogle Scholar
  62. 62.
    Mycko MP, Cwiklinska H, Szymanski J et al. Inducible heat shock protein 70 promotes myelin autoantigen presentation by the HLA class II. J Immunol 2004; 172(1):202–213.PubMedGoogle Scholar
  63. 63.
    Aquino DA, Klipfel AA, Brosnan CF et al. 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 1993; 61(4):1340–1348.CrossRefPubMedGoogle Scholar
  64. 64.
    Jaattela M. Overexpression of major heat shock protein hsp70 inhibits tumor necrosis factor-induced activation of phospholipase A2. J Immunol 1993; 151(8):4286–4294.PubMedGoogle Scholar
  65. 65.
    Feinstein DL, Galea E, Aquino DA et al. Heat shock protein 70 suppresses astroglial-inducible nitric-oxide synthase expression by decreasing NFkappaB activation. J Biol Chem 1996; 271(30):17724–17732.CrossRefPubMedGoogle Scholar
  66. 66.
    Paidas CN, Mooney ML, Theodorakis NG et al. Accelerated recovery after endotoxic challenge in heat shock-pretreated mice. Am J Physiol Regul Integr Comp Physiol 2002; 282(5):R1374–1381.PubMedGoogle Scholar
  67. 67.
    Van Molle W, Wielockx B, Mahieu T et al. HSP70 protects against TNF-induced lethal inflammatory shock. Immunity 2002; 16(5):685–695.CrossRefPubMedGoogle Scholar
  68. 68.
    Jacquier-Sarlin MR, Fuller K, Dinh-Xuan AT et al. Protective effects of Hsp70 in inflammation. Experientia 1994; 50(11–12):1031–1038.CrossRefPubMedGoogle Scholar
  69. 69.
    Klettner A. The induction of heat shock proteins as a potential strategy to treat neurodegenerative disorders. Drug News Perspect 2004; 17(5):299–306.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Celia F. Brosnan
    • 1
    Email author
  • Luca Battistini
    • 2
  • Krzysztof Selmaj
    • 3
  1. 1.Department of PathologyAlbert Einstein College of MedicineBronxUSA
  2. 2.Neuroimmmunology Unit European Center for Brain ResearchSanta Lucia FoundationRomeItaly
  3. 3.Department of NeurologyMedical University of LodzLodzPoland

Personalised recommendations