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. 2006 Apr 5;10(3):402–418. doi: 10.1111/j.1750-3639.2000.tb00272.x

Antibody Association with a Novel Model for Primary Progressive Multiple Sclerosis: Induction of Relapsing‐Remitting and Progressive Forms of EAE in H2S Mouse Strains

Ikuo Tsunoda 1, Li‐Qing Kuang 1, Diethilde J Theil 1, Robert S Fujinami 1,✉
PMCID: PMC8098387  PMID: 10885659

Abstract

Multiple sclerosis (MS) can be divided into 4 clinical forms: relapsing‐remitting (RR), primary progressive (PP), secondary progressive (SP), and progressive relapsing (PR). Since PP‐MS is notably different from the other forms of MS, both clinically and pathologically, the question arises whether PP‐MS is immunologically similar to the other forms. The pathogenesis of the PP‐MS remains unclear, partly due to a lack of highly relevant animal models. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92–106, we have established animal models that mimic different forms of MS in 2 strains of H‐2s mice, SJL/J and A.SW. We induced experimental allergic encephalomyelitis (EAE) using MOG92‐106 in the presence or absence of supplemental Bordetella pertussis (BP). Although, SJL/J mice developed RR‐EAE whether BP was given or not, A.SW mice developed PP‐EAE without BP and SP‐EAE with BP. Histologically, SJL/J mice developed mild demyelinating disease with T cell infiltration, while A.SW mice developed large areas of plaque‐like demyelination with immunoglobulin deposition and neutrophil infiltration, but with minimal T cell infiltration. In A.SW mice without BP, high titer serum anti‐MOG antibody was detected and the anti‐MOG IgG2a/IgG1 ratio correlated with survival times of mice. We hypothesized that, in A.SW mice, a Th2 response favors production of myelinotoxic antibodies, leading to progressive forms with early death. Our new models indicate that a single encephalitogen could induce either RR‐, PP‐, or SP‐ forms of demyelinating disease in hosts with immunologically different humoral immune responses.

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References

  • 1. Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383: 787–793. [DOI] [PubMed] [Google Scholar]
  • 2. Acarín N, Río J, Fernández AL, Tintoré M, Durán I, Galán I, Montalban X (1996) Different antiganglioside antibody pattern between relapsing‐remitting and progressive multiple sclerosis. Acta Neurol Scand 93: 99–103. [DOI] [PubMed] [Google Scholar]
  • 3. Amor S, Groome N, Linington C, Morris MM, Dornmair K, Gardinier MV, Matthieu J‐M, Baker D (1994) Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. J Immunol 153: 4349–4356. [PubMed] [Google Scholar]
  • 4. Bauer J, Bradl M, Hickey WF, Forss‐Petter S, Breitschopf H, Linington C, Wekerle H, Lassmann H (1998) T‐cell apoptosis in inflammatory brain lesions: Destruction of T cells does not depend on antigen recognition. Am J Pathol 153: 715–724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Booss J, Esiri MM, Tourtellotte WW, Mason DY (1983) Immunohistological analysis of T lymphocyte subsets in the central nervous system in chronic progressive multiple sclerosis. J Neurol Sci 62: 219–232. [DOI] [PubMed] [Google Scholar]
  • 6. Bornstein MB, Miller A, Slagle S, Weitzman M, Drexler E, Keilson M, Spada V, Weiss W, Appel S, Rolak L, et al (1991)A placebo‐controlled, double‐blind, randomized, two‐center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. Neurology 41: 533–539. [DOI] [PubMed] [Google Scholar]
  • 7. Bramanti P, Sessa E, Rifici C, D'Aleo G, Floridia D, Di Bella P, Lublin F (1998) Enhanced spasticity in primary progressive MS patients treated with interferon beta‐1b. Neurology 51: 1720–1723. [DOI] [PubMed] [Google Scholar]
  • 8. Brown AM, McFarlin DE (1981) Relapsing experimental allergic encephalomyelitis in the SJL/J mouse. Lab Invest 45: 278–284. [PubMed] [Google Scholar]
  • 9. Coffman RL, Seymour BW, Lebman DA, Hiraki DD, Christiansen JA, Shrader B, Cherwinski HM, Savelkoul HFJ, Finkelman FD, Bond MW, Mosmann TR (1988) The role of helper T cell products in mouse B cell differentiation and isotype regulation. Immunol Rev 102: 5–28. [DOI] [PubMed] [Google Scholar]
  • 10. Cottrell DA, Kremenchutzky M, Rice GPA, Koopman WJ, Hader W, Baskerville J, Ebers GC (1999) The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis. Brain 122: 625–639. [DOI] [PubMed] [Google Scholar]
  • 11. Endoh M, Tabira T, Kunishita T, Sakai K, Yamamura T, Taketomi T (1986) DM‐20, a proteolipid apoprotein, is an encephalitogen of acute and relapsing autoimmune encephalomyelitis in mice. J Immunol 137: 3832–3835. [PubMed] [Google Scholar]
  • 12. European Study Group on Interferon β‐1b in Secondary Progressive MS (1998) Placebo‐controlled multicentre randomised trial of interferon β‐1b in treatment of secondary progressive multiple sclerosis. Lancet 352: 1491–1497. [PubMed] [Google Scholar]
  • 13. Fukazawa T, Hamada T, Kikuchi S, Sasaki H, Tashiro K, Maguchi S (1996) Antineutrophil cytoplasmic antibodies and the optic‐spinal form of multiple sclerosis in Japan. J Neurol Neurosurg Psychiatry 61: 203–204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Fukuda T, Yoshida T, Okada S, Hatano M, Miki T, Ishibashi K, Okabe S, Koseki H, Hirosawa S, Taniguchi M, Miyasaka N, Tokuhisa T (1997) Disruption of the Bcl6 gene results in an impaired germinal center formation. J Exp Med 186: 439–448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Gardinier MV, Amiguet P, Linington C, Matthieu J‐M (1992) Myelin/oligodendrocyte glycoprotein is a unique member of the immunoglobulin superfamily. J Neurosci Res 33: 177–187. [DOI] [PubMed] [Google Scholar]
  • 16. Genain CP, Abel K, Belmar N, Villinger F, Rosenberg DP, Linington C, Raine CS, Hauser SL (1996) Late complications of immune deviation therapy in a nonhuman primate. Science 274: 2054–2057. [DOI] [PubMed] [Google Scholar]
  • 17. Genain CP, Cannella B, Hauser SL, Raine CS (1999) Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 5: 170–175. [DOI] [PubMed] [Google Scholar]
  • 18. Gold R, Hartung H‐P, Lassmann H (1997) T‐cell apoptosis in autoimmune diseases: termination of inflammation in the nervous system and other sites with specialized immune‐defense mechanisms. Trends Neurosci 20: 399–404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Greer JM, Sobel RA, Sette A, Southwood S, Lees MB, Kuchroo VK (1996) Immunogenic and encephalitogenic epitope clusters of myelin proteolipid protein. J Immunol 156: 371–379. [PubMed] [Google Scholar]
  • 20. Guarnieri B, Lolli F, Amaducci L (1985) Polymorphonuclear neutral protease activity in multiple sclerosis and other diseases. Ann Neurol 18: 620–622. [DOI] [PubMed] [Google Scholar]
  • 21. Hjelmström P, Juedes AE, Fjell J, Ruddle NH (1998) B cell‐deficient mice develop experimental allergic encephalomyelitis with demyelination after myelin oligodendrocyte glycoprotein sensitization. J Immunol 161: 4480–4483. [PubMed] [Google Scholar]
  • 22. Johansson U, Sander B, Hultman P (1997) Effects of the murine genotype on T cell activation and cytokine production in murine mercury‐induced autoimmunity. J Autoimmun 10: 347–355. [DOI] [PubMed] [Google Scholar]
  • 23. Johnson MD, Lavin P, Whetsell WO Jr (1990) Fulminant monophasic multiple sclerosis, Marburg's type. J Neurol Neurosurg Psychiatry 53: 918–921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Kerlero de Rosbo N, Mendel I, Ben‐Nun A (1995) Chronic relapsing experimental autoimmune encephalomyelitis with a delayed onset and an atypical clinical course, induced in PL/J mice by myelin oligodendrocyte glycoprotein (MOG)‐derived peptide: preliminary analysis of MOG T cell epitopes. Eur J Immunol 25: 985–993. [DOI] [PubMed] [Google Scholar]
  • 25. Kojima K, Berger T, Lassmann H, Hinze‐Selch D, Zhang Y, Gehrmann J, Reske K, Wekerle H, Linington C (1994) Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100β molecule, a calcium binding protein of astroglia. J Exp Med 180: 817–829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Korczyn AD, Nisipeanu P (1996) Safety profile of copolymer 1: analysis of cumulative experience in the United States and Israel. J Neurol 243 [Suppl 1]: S23–S26. [DOI] [PubMed] [Google Scholar]
  • 27. Larsen JP, Kvaale G, Riise T, Nyland H, Aarli JA (1985) Multiple sclerosis—more than one disease Acta Neurol Scand 72: 145–150. [DOI] [PubMed] [Google Scholar]
  • 28. Lassmann H, Brunner C, Bradl M, Linington C (1988) Experimental allergic encephalomyelitis: the balance between encephalitogenic T lymphocytes and demyelinating antibodies determines size and structure of demyelinated lesions. Acta Neuropathol (Berl) 75: 566–576. [DOI] [PubMed] [Google Scholar]
  • 29. Levine S (1974) Hyperacute, neutrophilic, and localized forms of experimental allergic encephalomyelitis: A review. Acta Neuropathol (Berl) 28: 179–189. [DOI] [PubMed] [Google Scholar]
  • 30. Levine S, Sowinski R (1972) The role of mononuclear cell deficiency in the production of neutrophilic allergic encephalomyelitis: Parabiosis experiments. Proc Soc Exp Biol Med 141: 664–668. [DOI] [PubMed] [Google Scholar]
  • 31. Linington C, Berger T, Perry L, Weerth S, Hinze‐Selch D, Zhang Y, Lu H‐C, Lassmann H, Wekerle H (1993) T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system. Eur J Immunol 23: 1364–1372. [DOI] [PubMed] [Google Scholar]
  • 32. Linington C, Morgan BP, Scolding NJ, Wilkins P, Piddlesden S, Compston DAS (1989) The role of complement in the pathogenesis of experimental allergic encephalomyelitis. Brain 112: 895–911. [DOI] [PubMed] [Google Scholar]
  • 33. Linnington C, Webb M, Woodhams PL (1984) A novel myelin‐associated glycoprotein defined by a mouse monoclonal antibody. J Neuroimmunol 6: 387–396. [DOI] [PubMed] [Google Scholar]
  • 34. Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: Results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46: 907–911. [DOI] [PubMed] [Google Scholar]
  • 35. Mason DY, Cordell J, Brown M, Pallesen G, Ralfkiaer E, Rothbard J, Crumpton M, Gatter KC (1989) Detection of T cells in paraffin wax embedded tissue using antibodies against a peptide sequence from the CD3 antigen. J Clin Pathol 42: 1194–1200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Matsumoto Y, Kohyama K, Aikawa Y, Shin T, Kawazoe Y, Suzuki Y, Tanuma N (1998) Role of natural killer cells and TCRγδ T cells in acute autoimmune encephalomyelitis. Eur J Immunol 28: 1681–1688. [DOI] [PubMed] [Google Scholar]
  • 37. Matthews B (1998) Symptoms and signs of multiple sclerosis In: McAlpine's Multiple Sclerosis. Compston A, Ebers G, Lassmann H, McDonald I, Matthews B, Wekerle H (eds.), pp. 145–190, Churchill Livingstone, London . [Google Scholar]
  • 38. Määttä JA, Sjöholm UR, Nygårdas PT, Salmi AA, Hinkkanen AE (1998) Neutrophils secreting tumor necrosis factor alpha infiltrate the central nervous system of BALB/c mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 90: 162–175. [DOI] [PubMed] [Google Scholar]
  • 39. McColl SR, Staykova MA, Wozniak A, Fordham S, Bruce J, Willenborg DO (1998) Treatment with anti‐granulocyte antibodies inhibits the effector phase of experimental autoimmune encephalomyelitis. J Immunol 161: 6421–6426. [PubMed] [Google Scholar]
  • 40. McDonald WI (1994) Rachelle Fishman‐Matthew Moore Lecture. The pathological and clinical dynamics of multiple sclerosis. J Neuropathol Exp Neurol 53: 338–343. [DOI] [PubMed] [Google Scholar]
  • 41. Minderhoud JM, van der Hoeven JH, Prange AJ (1988) Course and prognosis of chronic progressive multiple sclerosis. Results of an epidemiological study. Acta Neurol Scand 78: 10–15. [DOI] [PubMed] [Google Scholar]
  • 42. Nakashima I, Fujihara K, Endo M, Seki H, Okita N, Takase S, Itoyama Y (1998) Clinical and laboratory features of myelitis patients with anti‐neutrophil cytoplasmic antibodies. J Neurol Sci 157: 60–66. [DOI] [PubMed] [Google Scholar]
  • 43. O'Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8: 275–283. [DOI] [PubMed] [Google Scholar]
  • 44. O'Neill JK, Baker D, Morris MM, Gschmeissner SE, Jenkins HG, Butt AM, Kirvell SL, Amor S (1998) Optic neuritis in chronic relapsing experimental allergic encephalomyelitis in Biozzi ABH mice: Demyelination and fast axonal transport changes in disease. J Neuroimmunol 82: 210–218. [DOI] [PubMed] [Google Scholar]
  • 45. O'Riordan JI, Gallagher HL, Thompson AJ, Howard RS, Kingsley DPE, Thompson EJ, McDonald WI, Miller DH (1996) Clinical, CSF, and MRI findings in Devic's neuromyelitis optica. J Neurol Neurosurg Psychiatry 60: 382–387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Olerup O, Hillert J, Fredrikson S, Olsson T, Kam‐Hansen S, Möller E, Carlsson B, Wallin J (1989) Primarily chronic progressive and relapsing/remitting multiple sclerosis: Two immunogenetically distinct disease entities. Proc Natl Acad Sci USA 86: 7113–7117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Pham‐Dinh D, Mattei M‐G, Nussbaum J‐L, Roussel G, Pontarotti P, Roeckel N, Mather IH, Artzt K, Lindahl KF, Dautigny A (1993) Myelin/oligodendrocyte glycoprotein is a member of a subset of the immunoglobulin superfamily encoded within the major histocompatibility complex. Proc Natl Acad Sci USA 90: 7990–7994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Piddlesden SJ, Storch MK, Hibbs M, Freeman AM, Lassmann H, Morgan BP (1994) Soluble recombinant complement receptor 1 inhibits inflammation and demyelination in antibody‐mediated demyelinating experimental allergic encephalomyelitis. J Immunol 152: 5477–5484. [PubMed] [Google Scholar]
  • 49. Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI (1994) A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain 117: 759–765. [DOI] [PubMed] [Google Scholar]
  • 50. Ryan MS, Griffin F, Mahon B, Mills KHG (1997) The role of the S‐1 and B‐oligomer components of pertussis toxin in its adjuvant properties for Th1 and Th2 cells. Biochem Soc Trans 25: 126S. [DOI] [PubMed] [Google Scholar]
  • 51. Simpson JF, Tourtellotte WW, Kokmen E, Parker JA, Itabashi HH, Mich AA (1969) Fluorescent protein tracing in multiple sclerosis brain tissue. Arch Neurol 20: 373–377. [DOI] [PubMed] [Google Scholar]
  • 52. Stefferl A, Brehm U, Storch M, Lambracht‐Washington D, Bourquin C, Wonigeit K, Lassmann H, Linington C (1999) Myelin oligodendrocyte glycoprotein induces experimental autoimmune encephalomyelitis in the “resistant” Brown Norway rat: Disease susceptibility is determined by MHC and MHC‐linked effects on the B cell response. J Immunol 163:40–49. [PubMed] [Google Scholar]
  • 53. Stone SH, Lerner EM II (1965) Chronic disseminated allergic encephalomyelitis in guinea pigs. Ann N Y Acad Sci 122: 227–241. [DOI] [PubMed] [Google Scholar]
  • 54. Storch MK, Stefferl A, Brehm U, Weissert R, Wallström E, Kerschensteiner M, Olsson T, Linington C, Lassmann H (1998) Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol 8: 681–694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Suen WE, Bergman CM, Hjelmström P, Ruddle NH (1997) A critical role for lymphotoxin in experimental allergic encephalomyelitis. J Exp Med 186: 1233–1240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Sun J, Link H, Olsson T, Xiao B‐G, Andersson G, Ekre H‐P, Linington C, Diener P (1991) T and B cell responses to myelin‐oligodendrocyte glycoprotein in multiple sclerosis. J Immunol 146: 1490–1495. [PubMed] [Google Scholar]
  • 57. Tanuma N, Matsumoto Y (1997) Recent advances in the immunopathology of experimental autoimmune encephalomyelitis: With special reference to cytokine production in the central nervous system. Neuropathology 17: 152–159. [Google Scholar]
  • 58. Thilenius ARB, Sabelko‐Downes KA, Russell JH (1999) The role of the antigen‐presenting cell in Fas‐mediated direct and bystander killing: Potential in vivo function of Fas in experimental allergic encephalomyelitis. J Immunol 162: 643–650. [PubMed] [Google Scholar]
  • 59. Thompson AJ, Polman CH, Miller DH, McDonald WI, Brochet B, Filippi M, Montalban X, De Sá J (1997) Primary progressive multiple sclerosis. Brain 120: 1085–1096. [DOI] [PubMed] [Google Scholar]
  • 60. Tsunoda I, Fujinami RS (1996) Two models for multiple sclerosis: Experimental allergic encephalomyelitis and Theiler's murine encephalomyelitis virus. J Neuropathol Exp Neurol 55: 673–686. [DOI] [PubMed] [Google Scholar]
  • 61. Tsunoda I, Kuang L‐Q, Tolley ND, Whitton JL, Fujinami RS (1998) Enhancement of experimental allergic encephalomyelitis (EAE) by DNA immunization with myelin proteolipid protein (PLP) plasmid DNA. J Neuropathol Exp Neurol 57: 758–767. [DOI] [PubMed] [Google Scholar]
  • 62. Tsunoda I, Kurtz CIB, Fujinami RS (1997) Apoptosis in acute and chronic central nervous system disease induced by Theiler's murine encephalomyelitis virus. Virology 228: 388–393. [DOI] [PubMed] [Google Scholar]
  • 63. Tsunoda I, McCright IJ, Kuang L‐Q, Zurbriggen A, Fujinami RS (1997) Hydrocephalus in mice infected with a Theiler's murine encephalomyelitis virus variant. J Neuropathol Exp Neurol 56: 1302–1313. [DOI] [PubMed] [Google Scholar]
  • 64. Tsunoda I, Tolley ND, Theil DJ, Whitton JL, Kobayashi H, Fujinami RS (1999) Exacerbation of viral and autoimmune animal models for multiple sclerosis by bacterial DNA. Brain Pathol 9: 481–493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Vicari AP, Zlotnik A (1996) Mouse NK1.1+ T cells: A new family of T cells. Immunol Today 17: 71–76. [DOI] [PubMed] [Google Scholar]
  • 66. Weissert R, Wallström E, Storch MK, Stefferl A, Lorentzen J, Lassmann H, Linington C, Olsson T (1998) MHC haplotype‐dependent regulation of MOG‐induced EAE in rats. J Clin Invest 102: 1265–1273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67. Whitaker JN, Mitchell GW (1997) Clinical features of multiple sclerosis In: Multiple Sclerosis: Clinical and Pathogenetic Basis. Raine CS, McFarland HF, Tourtellotte WW (eds.), pp. 3–19, Chapman & Hall, London . [Google Scholar]
  • 68. Willenborg DO, Fordham S, Bernard CCA, Cowden WB, Ramshaw IA (1996) IFN‐γ plays a critical down‐regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein‐induced autoimmune encephalomyelitis. J Immunol 157: 3223–3227. [PubMed] [Google Scholar]
  • 69. Willenborg DO, Fordham SA, Staykova MA, Ramshaw IA, Cowden WB (1999) IFN‐γ is critical to the control of murine autoimmune encephalomyelitis and regulates both in the periphery and in the target tissue: A possible role for nitric oxide. J Immunol 163: 5278–5286. [PubMed] [Google Scholar]
  • 70. Wilson SB, Kent SC, Patton KT, Orban T, Jackson RA, Exley M, Porcelli S, Schatz DA, Atkinson MA, Balk SP, Strominger JL, Hafler DA (1998) Extreme Th1 bias of invariant Vα24JαQ T cells in type 1 diabetes. Nature 391: 177–181. [DOI] [PubMed] [Google Scholar]
  • 71. Xiao B‐G, Linington C, Link H (1991) Antibodies to myelinoligodendrocyte glycoprotein in cerebrospinal fluid from patients with multiple sclerosis and controls. J Neuroimmunol 31: 91–96. [DOI] [PubMed] [Google Scholar]
  • 72. Yokoyama M, Zhang J, Whitton JL (1995) DNA immunization confers protection against lethal lymphocytic choriomeningitis virus infection. J Virol 69: 2684–2688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73. Yoshimoto T, Bendelac A, Hu‐Li J, Paul WE (1995) Defective IgE production by SJL mice is linked to the absence of CD4+, NK1.1+ T cells that promptly produce interleukin 4. Proc Natl Acad Sci USA 92: 11931–11934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74. Zhang B‐N, Yamamura T, Kondo T, Fujiwara M, Tabira T (1997) Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells. J Exp Med 186:1677–1687. [DOI] [PMC free article] [PubMed] [Google Scholar]

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