Abstract
Autoimmune diseases are typically characterized by a persistent inflammatory self-recognition process that ultimately leads to chronic progressive disability. Over the past several years we have addressed the fundamental question of why autoimmune diseases are chronic. Our working hypothesis in these studies has been that autoimmunity involves a continuous acquisition of new self-recognition events, thereby providing an inflammatory steady-state that leads to chronicity. This acquired T cell neoautoreactivity is commonly referred to as epitope spreading. By studying multiple sclerosis (MS) and its related animal model, experimental autoimmune encephalomyelitis (EAE), we have found that chronic progression of autoimmune disease is invariably linked to the development of an epitope-spreading process that manifests as a cascade of inflammatory T cell neoautoreactivities to a sequential series of predictable new target self-antigens. However, our most recent observations indicate that the emergence of epitope spreading is accompanied by a concurrent regression of the established primary autoreactivity associated with disease onset. Thus, our studies indicate that progression of autoimmune disease involves a shifting of T cell autoreactivity from primary initiating self-determinants to defined cascades of secondary determinants that sustain the inflammatory self-recognition process during progression to chronicity. Our data support the view that the natural development of self-recognition during autoimmune disease may best be understood when considered in the temporal context of an “epitope du jour” and “moving target” perspective.
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References
Allen M., Sandberg-Wollheim M, Sjogren K., Erlich H. A., Petterson U. and Gyllensten U. (1994): Association of susceptibility to multiple sclerosis in Sweden with HL A class II DRB1 and DQB1 alleles. Hum. Immunol., 39, 41–48.
Beck R. W., Cleary P. A., Trobe J. D., Kaufman D. I., Kupersmith M. J., Paty D. W. and Brown C. H. (1993): The effect of corticosteroid for acute optic neuritis on the subsequent development of multiple sclerosis. N. Engl. J. Med., 329, 1764–1769.
Bhardwaj V., Kumar V., Grewal I. S., Dao T., Lehmann P. V., Geysen H. M. and Sercarz E. E. (1994): T cell determinant structure of myelin basic protein in B10. PL, SJL/J, and their F1s. J. Immunol., 152, 3711–3719.
Correale J., Gilmore W., Lopez J., Li S. Q., McMillan M. and Weiner L. P. (1996): Defective post-thymic tolerance mechanisms during the chronic progressive stage of multiple sclerosis. Nat. Med., 2, 1354–1360.
Cross A. H., Tuohy V. K. and Raine C. S. (1993): Development of reactivity to new myelin antigens during chronic relapsing autoimmune demyelination. Cell. Immunol., 146, 261–269.
De Silva D. R., Urdahl K. B. and Jenkins M. K. (1991): Clonal anergy is induced in vitro by T cell receptor occupancy in the absence of proliferation. J. Immunol., 147, 3261–3267.
Filippi M., Horsfield M. A., Morrissey S. P., MacManus D. G., Rudge P., McDonald W. I. and Miller D. H. (1994): Quantitative brain MRI lesion load predicts the course of clinically isolated syndromes suggestive of multiple sclerosis. Neurology, 44, 635–641.
Francis D. A., Thompson A. J., Brookes P., Davey N., Lechler R. I., McDonald W. I. and Batchelor J. R. (1991): Multiple sclerosis and HLA: Is the susceptibility gene really HLA-DR or-DQ? Hum. Immunol., 32, 119–124.
Gallimore A., Glithero A., Godkin A., Tissot A. C., Pluckthun A., Elliott T, Hengartner H. and Zinkernagel R. (1998): Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J. Exp. Med., 187, 1383–1393.
Lehmann P. V., Forsthuber T., Miller A. and Sercarz E. E. (1992): Spreading of T cell autoimmunity to cryptic determinants of an autoantigen. Nature, 358, 155–157.
Martin R., McFarland H. F. and McFarlin D. E. (1992): Immunological aspects of demyelinating diseases. Annu. Rev. Immunol., 10, 153–187.
McCarron R. M., Fallis R. J. and McFarlin D. E. (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 B. L., Vanderlugt C. L., Dal Canto M. C. and Miller S. D. (1995): Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis. J. Exp. Med., 182, 75–86.
Mor F. and Coher I. R. (1993): Shifts in the epitopes of myelin basic protein recognized by Lewis rat T cells before, during, and after the induction of experimental autoimmune encephalomyelitis. J. Clin. Invest., 92, 2199–2206.
Morrissey S. P., Miller D. H., Kendall B. E., Kingsley D. P., Kelly M. A., Francis D. A., MacManus D. G. and Mc Donald W. I. (1993): The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. Brain, 116, 135–146.
Offner H., Hashim G. A. and Vandenbark A. A. (1991): T cell receptor peptide therapy triggers autoregulation of experimental encephalomyelitis. Science, 251, 430–432.
Pelfrey C. M., Tranquill L. R., Boehme S. A., McFarland H. F. and Lenardo M. J. (1995): Two mechanisms of antigen-specific apoptosis of myelin basic protein (MBP)-specific T lymphocytes derived from multiple sclerosis patients and normal individuals. J. Immunol, 154, 6191–6202.
Perry L. L., Barzaga-Gilbert E. and Trotter J. L. (1991): T cell sensitization to proteolipid protein in myelin basic protein-induced relapsing experimental allergic encephalomyelitis. J. Neuroimmunol., 33, 7–15.
Raine C. S. (1984): Biology of disease. Analysis of autoimmune demyelination: its impact upon multiple sclerosis. Lab. Invest., 50, 608–635.
Schwartz R. H. (1990): A cell culture model for T lymphocyte clonal anergy. Science, 248, 1349–1356.
Sobel R. A., Tuohy V. K. and Lees M. B. (1991): Parental MHC molecule haplotype expression in (SJL/JxSWR) F1 mice with acute experimental allergic encephalomyelitis induced with two different synthetic peptides of myelin proteolipid protein. J. Immunol., 146, 543–549.
Steinman L. (1996): Multiple sclerosis: A coordinated immunological attack against myelin in the central nervous system. Cell, 85, 299–302.
Tanaka H., Ota K., Ikusaka M., Ejima M. and Maruyama S. (1995): Expression of Fas-antigen on T cells in multiple sclerosis (Japanese). Rinsho Shinkeigaku, 35, 299–301.
Tuohy V. K., Fritz R. B. and Ben-Nun A. (1994): Self-determinants in autoimmune demyelinating disease: Changes in T-cell response specificity. Curr. Opin. Immunol., 6, 887–891.
Tuohy V. K. and Thomas D. M. (1995): Sequence 104–117 of myelin proteolipid protein is a cryptic encephalitogenic T cell determinant for SJL/J mice. J. Neuroimmunol., 56, 161–170.
Tuohy V. K., Yu M., Weinstock-Guttman B. and Kinkel R. P. (1997): Diversity and plasticity of self-recognition during the development of multiple sclerosis. J. Clin. Invest., 99, 1682–1690.
Tuohy V. K., Yu M., Yin L., Kawczak J. A. and Kinkel R. P. (1999a): Regression and spreading of self-recognition during the development of autoimmune demyelinating disease. J. Autoimmun., 13, 11–20.
Tuohy V. K., Yu M., Yin L., Kawczak J. A. and Kinkel R. P. (1999b): Spontaneous regression of primary autoreactivity during chronic progression of experimental autoimmune encephalomyelitis and multiple sclerosis. J. Exp. Med., 189, 1033–1042.
Vandenbark A. A., Hashim G. and Offner H. (1989): Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis. Nature, 341, 541–544.
Vanderlugt C. J. and Miller S. D. (1996): Epitope spreading. Curr. Opin. Immunol., 8, 831–836.
Van Parijs L. V., Perez V. L., Biuckians A., Maki R. G., London C. A. and Abbas A. K. (1997): Role of interleukin 12 and costimulators in T cell anergy in vivo. J. Exp. Med., 186, 1119–1128.
Yu M., Johnson J. M. and Tuohy V. K. (1996a): 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., 183, 1777–1788.
Yu M., Johnson J. M. and Tuohy V. K. (1996b): Generation of autonomously pathogenic neoautoreactive Th1 cells during the development of the determinant spreading cascade in murine autoimmune encephalomyelitis. J. Neurosci. Res., 45, 463–470.
Yu M., Kinkel R. P., Weinstock-Guttman B., Cook D. J. and Tuohy V. K. (1998): HLA-DP: A class II restriction molecule involved in epitope spreading during the development of multiple sclerosis. Hum. Immunol., 59, 15–24.
Zhang J., Vandevyver C., Stinissen P. and Raus J. (1995): In vivo clonotypic regulation of human myelin basic protein-reactive T cells by T cell vaccination. J. Immunol., 155, 5868–5877.
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Tuohy, V.K., Kinkel, R.P. (2001). Epitope Spreading: A Mechanism for Progression of Autoimmune Disease. In: Górski, A., Krotkiewski, H., Zimecki, M. (eds) Autoimmunity. Springer, Dordrecht. https://doi.org/10.1007/978-94-010-0981-2_4
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DOI: https://doi.org/10.1007/978-94-010-0981-2_4
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