Full Access
Heat shock proteins and experimental autoimmune encephalomyelitis (EAE): I. Immunization with a peptide of the myelin protein 2′,3′ cyclic nucleotide 3′ phosphodiesterase that is cross-reactive with a heat shock protein alters the course of EAE
G. Birnbaum,
L. Kotilinek,
P. Schlievert,
H.B. Clark,
J. Trotter,
E. Horvath,
E. Gao,
M. Cox,
P.E. Braun,
Corresponding Author
G. Birnbaum
Departments of Neurology, Microbiology, and Laboratory Medicine and Pathology, University of Minnesota, Minneapolis
Department of Neurology, University of Minnesota, Box 295, UMHC, Minneapolis, MN 55455Search for more papers by this authorL. Kotilinek
Departments of Neurology, Microbiology, and Laboratory Medicine and Pathology, University of Minnesota, Minneapolis
Search for more papers by this authorP. Schlievert
Departments of Neurology, Microbiology, and Laboratory Medicine and Pathology, University of Minnesota, Minneapolis
Search for more papers by this authorH.B. Clark
Departments of Neurology, Microbiology, and Laboratory Medicine and Pathology, University of Minnesota, Minneapolis
Search for more papers by this authorJ. Trotter
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorE. Horvath
Biochemistry Department, McGill University, Montreal, Canada
Search for more papers by this authorE. Gao
Biochemistry Department, McGill University, Montreal, Canada
Search for more papers by this authorM. Cox
Biochemistry Department, McGill University, Montreal, Canada
Search for more papers by this authorP.E. Braun
Biochemistry Department, McGill University, Montreal, Canada
Search for more papers by this authorG. Birnbaum,
L. Kotilinek,
P. Schlievert,
H.B. Clark,
J. Trotter,
E. Horvath,
E. Gao,
M. Cox,
P.E. Braun,
Corresponding Author
G. Birnbaum
Departments of Neurology, Microbiology, and Laboratory Medicine and Pathology, University of Minnesota, Minneapolis
Department of Neurology, University of Minnesota, Box 295, UMHC, Minneapolis, MN 55455Search for more papers by this authorL. Kotilinek
Departments of Neurology, Microbiology, and Laboratory Medicine and Pathology, University of Minnesota, Minneapolis
Search for more papers by this authorP. Schlievert
Departments of Neurology, Microbiology, and Laboratory Medicine and Pathology, University of Minnesota, Minneapolis
Search for more papers by this authorH.B. Clark
Departments of Neurology, Microbiology, and Laboratory Medicine and Pathology, University of Minnesota, Minneapolis
Search for more papers by this authorJ. Trotter
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorE. Horvath
Biochemistry Department, McGill University, Montreal, Canada
Search for more papers by this authorE. Gao
Biochemistry Department, McGill University, Montreal, Canada
Search for more papers by this authorM. Cox
Biochemistry Department, McGill University, Montreal, Canada
Search for more papers by this authorP.E. Braun
Biochemistry Department, McGill University, Montreal, Canada
Search for more papers by this authorFirst published: 15 May 1996
Citations: 30
Abstract
We describe sequence similarity and immunologic cross-reactivity between a peptide of the mycobacterial hsp, HSP65, and the myelin protein 2′,3′ cyclic nucleotide 3′ phosphodiesterase (CNP). We demonstrate that immunization with the homologous cross-reactive CNP peptide (hsp-CNP peptide) has significant biological consequences. Rats immunized with hsp-CNP peptide in either complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA) produce large amounts of peptide-specific antibody. Isotypes of antibodies in animals immunized with peptide in CFA are IgG1 and IgG2a. Isotypes of antibodies in rats immunized with peptide in IFA are predominantly IgG1, with low titers of IgG2a. T cell proliferative responses to HSP65 are present in rats immunized with peptide in CFA. T cell responses to HSP65 initially are absent in rats immunized with peptide in IFA but develop over time. T cell proliferative responses to hsp-CNP peptide were not detected. None of the groups of rats developed clinical or histologic evidence of experimental autoimmune encephalomyelitis (EAE). To induce EAE, rats preimmunized with hsp-CNP peptide were challenged with guinea pig spinal cord (GPSC) emulsified in CFA. Rats preimmunized with peptide in CFA developed severe EAE. Rats preimmunized with hsp-CNP peptide in IFA were protected from EAE, with both a lower incidence and severity of disease. Injecting the murine monoclonal antibody recognizing the shared HSP65 and CNP epitope did not protect against EAE. Our data suggest that a Th2 pattern of immune response to a CNP peptide that itself is non-encephalitogenic protects against EAE. Immune responses to either hsp or myelin proteins cross-reactive with hsp may play an important role in the development of EAE. © 1996 Wiley-Liss, Inc.
References
- Agrewala JN, Raghava GP, Mishra GC (1993): Measurement and computation of murine interleukin-4 and interferon-gamma by exploiting the unique abilities of these lymphokines to induce the secretion of IgG1 and IgG2a. J. Immunoassay 14: 83–97.
- Anderson DC, Barry ME, Buchanan TM (1988): Exact definition of species-specific and cross-reactive epitopes of the 65-kilodalton protein of Mycobacterium leprae using synthetic peptides. J Immunol 141: 607–613.
- Ben-Nun A, Yossefi S, Lehmann D (1993): Protection against autoimmune disease by bacterial agents. II. PPD and pertussis toxin as proteins active in protecting mice against experimental autoimmune encephalomyelitis. Eur J Immunol 23: 689–696.
- Ben-Nun A, Mendel I, Sappler G, Kerlero de Rosbo N (1995): A 12-kDa protein of Mycobacterium tuberculosis protects mice against experimental autoimmune encephalomyelitis. Protection in the absence of shared T cell epitopes with encephalitogenic proteins. J Immunol 154: 2939–2948.
- Birnbaum G, Kotilinek L (1993): Antibodies to 70-kd heat shock protein are present in CSF and sera from patients with multiple sclerosis. 45th Annual Meeting of the American Academy of Neurology, New York.
- Birnbaum G, Schlievert P (1992): Antibodies to mycobacterial antigens in the spinal fluids and blood from patients with multiple sclerosis and other neurologic diseases. Neurology 42: 247.
- Birnbaum G, Kotilinek L, Albrecht L (1993): Spinal fluid lymphocytes from a subgroup of multiple sclerosis patients respond to mycobacterial antigens. Ann Neurol 34: 18–24.
- Blomster-Hautamaa DA, Novick RP, Schlievert PM (1986): Localization of biologic functions of toxic shock syndrome toxin-1 by use of monoclonal antibodies and cyanogen bromide-generated toxin fragments. J Immunol 137: 3572–3576.
- Braun PE, Bambrick LL, Edwards AM, Bernier L (1990): 2′,3′ -Cyclic nucleotide 3′-phosphodiesterase has characteristics of cytoskeletal proteins. A hypothesis for its function. Ann NY Acad Sci 605: 55–65.
- Braun PE, De Angelis D, Shtybel WW, Bernier L (1991): Isoprenoid modification permits 2′,3′-cyclic nucleotide 3′-phosphodiesterase to bind to membranes. J Neurosci Res 30: 540–544.
- Cem MM, Yazici H, Ozbakir F, Tuzun Y (1988): The HLA association of lepromatous leprosy and borderline lepromatous leprosy in Turkey A preliminary study. Int J Dermatol 27: 246–247.
- Chung IY, Norris JG, Benveniste EN (1991): Differential tumor necrosis factor alpha expression by astrocytes from experimental allergic encephalomyelitis-susceptible and -resistant rat strains. J Exp Med 173: 801–811.
- De Angelis D, Cox M, Gao E, Braun PE (1993): Cellular and molecular characteristics of CNP suggest regulatory mechanisms in myelinogenesis. In S Salvati (ed): “ A Multidisciplinary Approach to Myelin Diseases II.” New York: Plenum Press, pp 49–58.
- DeKruyff RH, Rizzo LV, Umetsu DT (1993): Induction of immunoglobulin synthesis by CD4+ T cell clones. Semin Immunol 5: 421–430.
- Demenais F, Feingold N (1986): HLAand leprosy. Pathol Biol (Paris) 34: 735–737.
- de Vries RR (1991): Genetic control of immunopathology induced by Mycobacterium leprae. Am J Trop Med Hyg 44(4 Pt 2): 4–11.
- Elias D, Cohen IR (1994): Peptide therapy for diabetes in NOD mice. Lancet 343: 704–706.
- Elias D, Markovits D, Reshef T, van der Zee R, Cohen IR (1990): Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein. Proc Natl Acad Sci USA 87: 1576–1580.
- 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 USA 88: 3088–3091.
- Gaston JS, Life PF, Bailey LC, Bacon PA (1989): In vitro response to a 65-kilodalton mycobacterial protein by synovial T cells from inflammatory arthritis patients. J Immunol 143: 2494–2500.
- Gaston JS, Life PF, Jenner PJ, Colston MJ, Bacon PA (1990): Recognition of a mycobacteria-specific epitope in the 65-kD heatshock protein by synovial fluid-derived T cell clones. J Exp Med 171: 831–841.
- Glynn P, Weedon D, Edwards J, Suckling AJ, Cuzner ML (1982): Humoral immunity in chronic relapsing experimental autoimmune encephalomyelitis. The major oligoclonal IgG bands are antibodies to mycobacteria. J Neurol Sci 57: 369–384.
- Gorodezky C, Flores J, Arevalo N, Castro LE, Silva A, Rodriguez O (1987): Tuberculoid leprosy in Mexicans is associated with HLA-DR3. Lepr Rev 58: 401–406.
- Goverman J, Woods A, Larson L, Weiner LP, Hood L, Zaller DM (1993): Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72: 551–560.
- Gravel M, De Angelis D, Braun PE (1994): Molecular cloning and characterization of rat brain 2′,3′-cyclicnucleotide 3′-phosphodiesterase isoform 2. J Neurosci Res 38: 243–247.
- Holman FM, Hinton DR, Johnson K, Merrill JE (1989): Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med 170: 607–612.
- Ilangumaran S, Narayan NPS, Rama G, Muthukkaruppan V (1994): Cellular and humoral immune responses to recombinant 65-kD antigen of Mycobacterium leprae in leprosy patients and healthy controls. Clin Exp Immunol 96: 79–85.
- Inman RD (1991): Infectious etiology of rheumatoid arthritis. Rheum Dis Clin North Am 17: 859–870.
- Khoury SJ, Hancock WW, Weiner HL (1992): Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. J Exp Med 176: 1355–1364.
- Kikuchi I, Ozawa T, Hirayama K, Sasazuki T (1986): An HLA-linked gene controls susceptibility to lepromatous leprosy through T cell regulation. Lepr Rev 2: 139–142.
- Kim SJ, Choi IH, Dahlberg S, Nisperos B, Kim JD, Hansen JA (1987): HLA and leprosy in Koreans. Tissue Antigens 29: 146–153.
- Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W (1993): Interleukin-10-deficient mice develop chronic entercolitis. Cell 75: 263–274.
- Kurihara T, Monoh K, Sakimura K, Takahashi Y (1990): Alternative splicing of mouse brain 2′,3′-cyclic-nucleotide 3′-phosphodiesterase mRNA. Biochem Biophys Res Commun 170: 1074–1081.
- Laemmli UK (1970): Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685.
- Lehmann D, Ben Nun A (1992): Bacterial agents protect against autoimmune disease. I. Mice pre-exposed to Bordetella pertussis or Mycobacterium tuberculosis are highly refractory to induction of experimental autoimmune encephalomyelitis. J Autoimmun 5: 675–690.
- Lehmann PV, Forsthuber T, Miller A, Sercarz EE (1992): Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 358: 155–157.
- Lehmann PV, Sercarz EE, Forsthuber T, Dayan CM, Gammon G (1993): Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol Today 14: 203–208.
- Lehner T, Lavery E, Smith R, van der Zee R, Mizushima Y, Shinnick T (1991): Association between the 65-kilodalton heat shock protein, Streptococcus sanguis, and the corresponding antibodies in Behcet's syndrome. Infect Immun 59: 1434–1441.
- Lin MS, Chen YW (1993): B cell differentiation. II. Isotype potential of a single B cell. Cell Immunol 150: 343–352.
- McCarron RM, Fallis RJ, McFarlin DE (1990): Alterations in T cell antigen specificity and class II restriction during the course of chronic relapsing experimental allergic encephalomyelitis. J Neuroimmunol 29: 73–79.
- McRae BL, Vanderlugt CL, Del Canto MC, Miller SD (1995): Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis. J Exp Med 182: 75–85.
- Mehta PD, Patrick BA, Wisniewski HM (1985): Specificity of oligoclonal IgG bands in sera from chronic relapsing experimental allergic encephalomyelitis guinea pigs. J Immunol 134: 2338–2342.
- Mitsuzawa E, Yasuda T, Tamura N, Ohtani S (1984): Pretreatment with antigen or adjuvant, and the preventability of allergic encephalomyelitis induced by basic protein with synthetic muramyl dipeptide in comparison with Freund's complete adjuvant. Jpn J Exp Med 54: 97–107.
- Modlin RL (1994): Thl-Th2 paradigm: Insights from leprosy. J Invest Dermatol 102: 828–832.
- G Möller (ed) (1991): “ Heat-Shock Proteins and the Immune System.” Immunological Reviews, Vol 121. Coppenhagen: Munksgaard International Publishers, pp 5–220.
- Mor F, Cohen IR (1992): T cells in the lesion of experimental autoimmune encephalomyelitis. Enrichment for reactivities to myelin basic protein and to heat shock proteins. J Clin Invest 90: 2447–2455.
- RI Morimoto, A Tissières, C Georgopoulos (eds) (1990): “ Stress Proteins in Biology and Medicine.” Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, pp 1–450.
- Munk ME, Schoel B, Modrow S, Karr RW, Young RA, Kaufmann SH (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: 2844–2849.
- Mutis T, Cornelisse YE, Datema G, van den Elsen PJ, Ottenhoff TH, de Vries RR (1994): Definition of a human suppressor T-cell epitope. Proc Natl Acad Sci USA 91: 9456–9460.
- Ottenhoff TH, de Vries RR (1987): HLA class II immune response and suppression genes in leprosy. Int J Lepr Other Mycobact Dis 55: 521–534.
- Ottenhoff TH, Converse PJ, Bjune G, de Vries RR (1987): HLA antigens and neural reversal reactions in Ethiopian borderline tuberculoid leprosy patients. Int J Lepr Other Mycobact Dis 55: 261–266.
- Panitch HS, Hirsch RL, Haley AS, Johnson KP (1987a): Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1: 893–895.
- Panitch HS, Hirsch RL, Schindler J, Johnson KP (1987b): Treatment of multiple sclerosis with gammainterferon: Exacerbations associated with activation of the immune system. Neurology 37: 1097–1102.
- Powell MB, Mitchell D, Lederman J, et al. (1990): Lymphotoxin and tumor necrosis factor-alpha production by myelin basic protein-specific T cell clones correlates with encephalitogenicity. Int Immunol 2: 539–544.
- Rani R, Zaheer SA, Mukherjee R (1992): Do human leukocyte antigens have a role to play in differential manifestation of multibacillary leprosy: A study on multibacillary leprosy patients from north India. Tissue Antigens 40: 124–127.
- Res PC, Schaar CG, Breedveld FC, et al. (1988): Synovial fluid T cell reactivity against 65 kD heat shock protein of mycobacteria in early chronic arthritis. Lancet 2: 478–480.
- Richert JR, Namikawa T, Kies MW, Alvord EJ (1982): Failure of serum from recovered rats to prevent enhanced adoptive transfer of experimental allergic encephalomyelitis. J Neurol Sci 53: 225–232.
- Rizzo LV, DeKruyff RH, Umetsu DT (1992): Generation of B cell memory and affinity maturation. Induction with Th1 and Th2 T cell clones. J Immunol 148: 3733–3739.
- Ruddle NH, Bergman CM, McGrath KM, et al. (1990): An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med 172: 1193–1200.
- Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I (1993): Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75: 253–261.
- Santambrogio L, Hochwald GM, Saxena B, et al. (1993): Studies on the mechanisms by which transforming growth factor-beta (TGF-beta) protects against allergic encephalomyelitis. Antagonism between TGF-beta and tumor necrosis factor. J Immunol 151: 1116–1127.
- Schijns VE, Claassen IJ, Vermeulen AA, Horzinek MC, Osterhaus AD (1992): Modulation of antiviral immune responses by exogenous cytokines: Effects of tumour necrosis factor-alpha, interleukin-1 alpha, interleukin-2 and interferon-gamma on the immunogenicity of an inactivated rabies vaccine. J Gen Virol 75: 55–63.
- Selmaj K, Raine CS, Cannella B, Brosnan CF (1991): Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J Clin Invest 87: 949–954.
- Sharief MK, Hentges R (1991): Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis. N Engl J Med 325: 467–472.
- Sibley WA, Bamford CR, Clark K (1985): Clinical viral infections and multiple sclerosis. Lancet 1: 1313–1315.
- Sieling PA, Modlin RL (1994): Cytokine patterns at the site of mycobacterial infection. Immunobiology 191: 378–387.
- Sprinkle TJ (1989): 2′,3′-Cyclic nucleotide 3′-phosphodiesterase, an oligodendrocyte-Schwann cell and myelin-associated enzyme of the nervous system. Crit Rev Neurobiol 4: 235–301.
- Stevens DB, Gould KE, Swanborg RH (1994): Transforming growth factor-beta 1 inhibits tumor necrosis factor-alpha/lymphotoxin production and adoptive transfer of disease by effector cells of autoimmune encephalomyelitis. J Neuroimmunol 51: 77–83.
- Thompson RJ (1992): 2′,3′-Cyclic nucleotide-3′-phosphohydrolase and signal transduction in central nervous system myelin. Biochem Soc Trans 20: 621–626.
- Thompson SJ, Elson CJ (1993): Susceptibility to pristane-induced arthritis is altered with changes in bowel flora. Immunol Lett 36: 227–231.
- Vandenbark AA, Burger DR, Vetto RM (1975): Cell-mediated immunity in experimental allergic encephalomyelitis: Cross reactivity between myelin basic protein and mycobacteria antigens. Proc Soc Exp Biol Med 148: 1233–1236.
- van den Broek MF, Hogervorst EJ, Van Bruggen MC, Van Eden W, van der Zee R, van den Berg WB (1989): Protection against streptococcal cell wall-induced arthritis by pretreatment with the 65-kD mycobacterial heat shock protein. J Exp Med 170: 449–466.
- van Eden W (1990): Heat-shock proteins in autoimmune arthritis: A critical contribution based on the adjuvant arthritis model. Apmis 98: 383–394.
- van Eden W, Holoshitz J, Nevo Z, Frenkel A, Klajman A, Cohen IR (1985): Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc Natl Acad Sci USA 82: 5117–5120.
- van Eden W, Hogervorst EJ, Hensen EJ, van der Zee R, van Embden JD, Cohen IR (1989): A carti1age-mimicking T-cell epitope on a 65K mycobacterial heat-shock protein: Adjuvant arthritis as a model for human rheumatoid arthritis. Curr Top Microbiol Immunol 145: 27–43.
- Wilder RL, Crofford LJ (1991): Do infectious agents cause rheumatoid arthritis? Clin Orthol Relat Res 265: 36–41.
- 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.
- Young D, Lathigra R, Hendrix R, Sweetser D, Young RA (1988): Stress proteins are immune targets in leprosy and tuberculosis. Proc Natl Acad Sci USA 85: 4267–4270.
Citing Literature
