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. 2002 Feb 11;8(6):831–836. doi: 10.1016/S0952-7915(96)80012-4

Epitope spreading

Carol J Vanderlugt 1, Stephen D Miller 1,∗
PMCID: PMC7135770  PMID: 8994863

Abstract

Epitope (determinant) spreading is the development of immune responses to endogenous epitopes secondary to the release of self antigens during a chronic autoimmune or inflammatory response. The past year has seen considerable advances in our understanding of the contribution of epitope spreading to the chronic pathogenesis of experimental T-cell-mediated and antibody-mediated autoimmune diseases. Most significantly, conclusive functional evidence for a major role for epitope spreading in the chronic pathogenesis of murine relapsing-remitting experimental autoimmune encephalomyelitis, a CD4+ T-cell-mediated model of multiple sclerosis, was forthcoming.

Abbreviations: APC antigen-presenting cell, BCR B cell receptor, CNS central nervous system, DTH delayed-type hypersensitivity, EAE experimental autoimmune encephalomyelitis, GAD glutamic acid decarboxylase, MBP myelin basic protein, NOD nonobese diabetic, PLP proteolipid protein, R-EAE relapsing-remitting EAE, SLE systemic lupus erythematosus, TCR T cell receptor, TNF tumor necrosis factor

References

  • 1.Oldstone MB. Molecular mimicry and autoimmune disease. Cell. 1987;50:819–820. doi: 10.1016/0092-8674(87)90507-1. [DOI] [PubMed] [Google Scholar]
  • 2.Gianani R, Sarvetnick N. Viruses, cytokines, antigens, and autoimmunity. Proc Natl Acad Sci USA. 1996;93:2257–2259. doi: 10.1073/pnas.93.6.2257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Miller SD, Karpus WJ. The immunopathogenesis and regulation of T-cell mediated demyelinating diseases. Immunol Today. 1994;15:356–361. doi: 10.1016/0167-5699(94)90173-2. [DOI] [PubMed] [Google Scholar]
  • 4.Miller SD, McRae BL, Vanderlugt CL, Nikcevich KM, Pope JG, Pope L, Karpus WJ. Evolution of the T cell repertoire during the course of experimental autoimmune encephalomyelitis. Immunol Rev. 1995;144:225–244. doi: 10.1111/j.1600-065x.1995.tb00071.x. of special interest. [DOI] [PubMed] [Google Scholar]; The authors review evidence for epitope spreading to endogenous myelin epitopes in peptide-induced R-EAE models in the SJL/J mouse and following infection with Theilers' murine encephalomyelitis virus.
  • 5.Perry LL, Barzaga ME. Kinetics and specificity of T and B cell responses in relapsing experimental allergic encephalomyelitis. J Immunol. 1987;138:1434–1441. [PubMed] [Google Scholar]
  • 6.McCarron RM, Fallis RJ, McFarlin DE. Alterations in T cell antigen specificity and class II restriction during the course of chronic relapsing experimental allergic encephalomyelitis. J Neuroimmunol. 1990;29:73–79. doi: 10.1016/0165-5728(90)90149-h. [DOI] [PubMed] [Google Scholar]
  • 7.Perry LL, Barzaga-Gilbert E, Trotter JL. T cell sensitization to proteolipid protein in myelin basic protein-induced experimental allergic encephalomyelitis. J Neuroimmunol. 1991;33:7–16. doi: 10.1016/0165-5728(91)90029-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Cross AH, Tuohy VK, Raine CS. Development of reactivity to new myelin antigens during chronic relapsing autoimmune demyelination. Cell Immunol. 1993;146:261–269. doi: 10.1006/cimm.1993.1025. [DOI] [PubMed] [Google Scholar]
  • 9.Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992;358:155–157. doi: 10.1038/358155a0. [DOI] [PubMed] [Google Scholar]
  • 10.McRae BL, Vanderlugt CL, Dal Canto MC, Miller SD. Functional evidence for epitope spreading in the relapsing pathology of EAE in the SJL/J mouse. J Exp Med. 1995;182:75–85. doi: 10.1084/jem.182.1.75. of outstanding interest. [DOI] [PMC free article] [PubMed] [Google Scholar]; The authors show the involvement of intermolecular epitope spreading to PLP139-151 in MBP84-104-induced R-EAE and intramolecular epitope spreading to PLP178-191 in PLP139-151 induced R-EAE. The extent of activation of relapse-associated epitopes was shown to correlate with the degree of tissue damage during acute disease. Splenic T cells specific for the relapse-associated epitopes could transfer disease to naive mice and tolerance to the intact PLP protein during disease remission (which inhibited responses to both the initiating and relapse-associated epitope) prevented disease relapses.
  • 11.Zhao ML, Fritz RB. The immune response to a subdominant epitope in myelin basic protein exon-2 results in immunity to intra- and intermolecular dominant epitopes. J Neuroimmunol. 1995;61:179–184. doi: 10.1016/0165-5728(95)00090-o. of special interest. [DOI] [PubMed] [Google Scholar]; The authors show that R-EAE induced by transfer of a T cell line specific for the product exon-2 of the MBP gene leads to R-EAE in the SJL/J mouse and the subsequent development of splenic proliferative responses to MBPAc1·11, MBP43-88, MBP89-101, and PLP139-151, PLP139-151·specific lines derived from the recipient mice transferred R-EAE to naive recipients.
  • 12.Jansson L, Diener P, Engstrom A, Olsson T, Holmdahl R. Spreading of the immune response to different myelin basic protein peptides in chronic experimental autoimmune encephalomyelitis in B10.RIII mice. Eur J Immunol. 1995;25:2195–2200. doi: 10.1002/eji.1830250812. of special interest. [DOI] [PubMed] [Google Scholar]; The authors show that induction of R-EAE in B10.RIII mice immunized with MBP89-101 eventually results in the development of interferon-producing T cells to peptides outside of this region.
  • 13.Yu M, Johnson JM, Tuohy VK. A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease. J Exp Med. 1996;183:1777–1788. doi: 10.1084/jem.183.4.1777. of outstanding interest. [DOI] [PMC free article] [PubMed] [Google Scholar]; The authors determine the sequential pattern of epitope spreading in PLP139-151-induced R-EAE in the (SWR×SJL)F1 mouse and show that tolerance to the relapse-associated MBP87-99 epitope blocks disease progression.
  • 14.Tan L-J, Kennedy MK, Dal Canto MC, Miller SD. Successful treatment of paralytic relapses in adoptive experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance. J Immunol. 1991;147:1797–1802. [PubMed] [Google Scholar]
  • 15.Miller SD, Vanderlugt CL, Lenschow DJ, Pope JG, Karandikar NJ, Dal Canto MC, Bluestone JA. Blockade of CD28/B7-1 interaction prevents epitope spreading and clinical relapses of murine EAE. Immunity. 1995;3:739–745. doi: 10.1016/1074-7613(95)90063-2. of outstanding interest. [DOI] [PubMed] [Google Scholar]; The authors show that treatment of SJL/J mice during remission from active PLP139-151-induced R-EAE with anti-B7-1 Fab fragments blocks the activation of T cell specific for the relapse-associated PLP178-191 epitope and inhibits expression of clinical relapses.
  • 16.Samson MF, Smilek DE. Reversal of acute experimental autoimmune encephalomyelitis and prevention of relapses by treatment with a myelin basic protein peptide analogue modified to form long-lived peptide-MHC complexes. J Immunol. 1995;155:2737–2746. [PubMed] [Google Scholar]
  • 17.Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GSP, Robinson P, Atkinson MA, Sercarz EE, Tobin AJ, Lehmann PV. Spontaneous loss of T cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature. 1993;366:69–72. doi: 10.1038/366069a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Tisch R, Yang XD, Singer SM, Liblau RS, Fugger L, McDevitt HO. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature. 1993;366:72–75. doi: 10.1038/366072a0. [DOI] [PubMed] [Google Scholar]
  • 19.Tian J, Atkinson MA, Clare-Salzler M, Herschenfeld A, Forsthuber T, Lehmann PV, Kaufman DL. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J Exp Med. 1996;183:1561–1567. doi: 10.1084/jem.183.4.1561. of outstanding interest. [DOI] [PMC free article] [PubMed] [Google Scholar]; The authors show that intranasal tolerance to the proposed disease inducting epitope on GAD65 results in activation of Th2 cells which reduce the incidence of diabetes in NOD mice and blocks the activation of autoreactive T cell responses to other pancreatic β-cell antigens.
  • 20.James JA, Gross T, Scofield RH, Harley JB. Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B'-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity. J Exp Med. 1995;181:453–461. doi: 10.1084/jem.181.2.453. of outstanding interest. [DOI] [PMC free article] [PubMed] [Google Scholar]; The authors show in an experimental model of SLE that rabbits primed to Sm B/B' peptides develop an SLE-like syndrome along with autoantibody responses to spliceosomal proteins other than Sm B/B'.
  • 21.Topfer F, Gordon T, McCluskey J. Intra- and intermolecular spreading of autoimmunity involving the nuclear self-antigens La (SS-B) and Ro (SS-A) Proc Natl Acad Sci USA. 1995;92:875–879. doi: 10.1073/pnas.92.3.875. of outstanding interest. [DOI] [PMC free article] [PubMed] [Google Scholar]; The authors show that, upon immunization of mice with a fragment of the La protein, autoantibody responses to other non-cross-reactive components of the La/Ro ribonucleoprotein complex are generated.
  • 22.Fujinami RS, Oldstone MB. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science. 1985;230:1043–1045. doi: 10.1126/science.2414848. [DOI] [PubMed] [Google Scholar]
  • 23.Scherer MT, Ignatowicz L, Winslow GM, Kappler JW, Marrack P. Superantigens: bacterial and viral proteins that manipulate the immune system. Annu Rev Cell Biol. 1993;9:101–128. doi: 10.1146/annurev.cb.09.110193.000533. [DOI] [PubMed] [Google Scholar]
  • 24.Liebert UG, Linington C, Ter Meulen V. Induction of autoimmune reactions to myelin basic protein in measles virus encephalitis in Lewis rats. J Neuroimmunol. 1988;17:103–118. doi: 10.1016/0165-5728(88)90018-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Liebert UG, Hashim GA, Ter Meulen V. Chracterization of measles virus-induced cellular autoimmune reactions against myelin basic protein in Lewis rats. J Neuroimmunol. 1990;29:139–147. doi: 10.1016/0165-5728(90)90156-H. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Ter Meulen V. Autoimmune reactions against myelin basic protein induced by corona and measles viruses. Ann NY Acad Sci. 1988;540:202–209. doi: 10.1111/j.1749-6632.1988.tb27062.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Mokhtarian F, Shi Y, Zhu PF, Grob D. Immune responses, and autoimmune outcome, during virus infection of the central nervous system. Cell Immunol. 1994;157:195–210. doi: 10.1006/cimm.1994.1216. [DOI] [PubMed] [Google Scholar]
  • 28.Mokhtarian F, Grob D, Griffin DE. Role of the immune response in Sindbis virus-induced paralysis of SJL/J mice. J Immunol. 1989;143:633–637. [PubMed] [Google Scholar]
  • 29.Miller SD, Gerety SJ. Immunologic aspects of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. Semin Virol. 1990;1:263–272. [Google Scholar]
  • 30.Vaughan JH, Valbracht JR, Nguyen MD, Handley HH, Smith RS, Patrick K, Rhodes GH. Epstein-Barr virus-induced autoimmune responses. I. Immunoglobulin M autoantibodies to proteins mimicking and not mimicking Epstein-Barr virus nuclear antigen-1. J Clin Invest. 1995;95:1306–1315. doi: 10.1172/JCI117781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Vaughan JH, Nguyen MD, Valbracht JR, Patrick K, Rhodes GH. Epstein-Barr virus-induced autoimmune responses. II. Immunoglobulin G autoantibodies to mimicking and nonmimicking epitopes. Presence in autoimmune disease. J Clin Invest. 1995;95:1316–1327. doi: 10.1172/JCI117782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Sercarz EE, Lehmann PV, Ametani A, Benichou G, Miller A, Moudgil K. Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol. 1993;11:729–766. doi: 10.1146/annurev.iy.11.040193.003501. [DOI] [PubMed] [Google Scholar]
  • 33.Lehmann PV, Sercarz EE, Forsthuber T, Dayan CM, Gammon G. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol Today. 1993;14:203–208. doi: 10.1016/0167-5699(93)90163-F. [DOI] [PubMed] [Google Scholar]
  • 34.Elson CJ, Barker RN, Thompson SJ, Williams NA. Immunologically ignorant autoreactive T cells, epitope spreading and repertoire limitation. Immunol Today. 1995;16:71–76. doi: 10.1016/0167-5699(95)80091-3. [DOI] [PubMed] [Google Scholar]
  • 35.Mamula MJ, Janeway CA., Jr Do B cells drive the diversification of immune responses? Immunol Today. 1993;14:151–154. doi: 10.1016/0167-5699(93)90274-O. [DOI] [PubMed] [Google Scholar]

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