HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Katz-Levy, Y. Articles by Miller, S. D. Search for Related Content PubMed PubMed Citation Articles by Katz-Levy, Y. Articles by Miller, S. D.

Temporal Development of Autoreactive Th1 Responses and Endogenous Presentation of Self Myelin Epitopes by Central Nervous System-Resident APCs in Theiler’s Virus-Infected Mice¹

Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611

Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a chronic-progressive, immune-mediated CNS demyelinating disease and a relevant model of multiple sclerosis. Myelin destruction is initiated by TMEV-specific CD4⁺ T cells targeting persistently infected CNS-resident APCs leading to activation of myelin epitope-specific CD4⁺ T cells via epitope spreading. We examined the temporal development of virus- and myelin-specific T cell responses and acquisition of virus and myelin epitopes by CNS-resident APCs during the chronic disease course. CD4⁺ T cell responses to virus epitopes arise within 1 wk after infection and persist over a >300-day period. In contrast, myelin-specific T cell responses are first apparent 50–60 days postinfection, appear in an ordered progression associated with their relative encephalitogenic dominance, and also persist. Consistent with disease initiation by virus-specific CD4⁺ T cells, CNS mononuclear cells from TMEV-infected SJL mice endogenously process and present virus epitopes throughout the disease course, while myelin epitopes are presented only after initiation of myelin damage (>50–60 days postinfection). Activated F4/80⁺ APCs expressing high levels of MHC class II and B7 costimulatory molecules and ingested myelin debris chronically accumulate in the CNS. These results suggest a process of autoimmune induction in which virus-specific T cell-mediated bystander myelin destruction leads to the recruitment and activation of infiltrating and CNS-resident APCs that process and present endogenous myelin epitopes to autoreactive T cells in a hierarchical order.

This article has been cited by other articles:

				W Rashid, G R Davies, D T Chard, C M Griffin, D R Altmann, A J Thompson, and D H Miller Relationship of triple dose contrast enhanced lesions with clinical measures and brain atrophy in early relapsing-remitting multiple sclerosis: a two-year longitudinal study Multiple Sclerosis, March 1, 2007; 13(2): 178 - 185. [Abstract] [PDF]

				S. Schif-Zuck, G. Wildbaum, and N. Karin Coadministration of Plasmid DNA Constructs Encoding an Encephalitogenic Determinant and IL-10 Elicits Regulatory T Cell-Mediated Protective Immunity in the Central Nervous System J. Immunol., December 1, 2006; 177(11): 8241 - 8247. [Abstract] [Full Text] [PDF]

				A. M. Ercolini and S. D. Miller Mechanisms of Immunopathology in Murine Models of Central Nervous System Demyelinating Disease J. Immunol., March 15, 2006; 176(6): 3293 - 3298. [Abstract] [Full Text] [PDF]

				K. C. O'Connor, H. Appel, L. Bregoli, M. E. Call, I. Catz, J. A. Chan, N. H. Moore, K. G. Warren, S. J. Wong, D. A. Hafler, et al. Antibodies from Inflamed Central Nervous System Tissue Recognize Myelin Oligodendrocyte Glycoprotein J. Immunol., August 1, 2005; 175(3): 1974 - 1982. [Abstract] [Full Text] [PDF]

				J. L. Croxford, J. K. Olson, H. A. Anger, and S. D. Miller Initiation and Exacerbation of Autoimmune Demyelination of the Central Nervous System via Virus-Induced Molecular Mimicry: Implications for the Pathogenesis of Multiple Sclerosis J. Virol., July 1, 2005; 79(13): 8581 - 8590. [Abstract] [Full Text] [PDF]

				M. Bradl, J. Bauer, A. Flugel, H. Wekerle, and H. Lassmann Complementary Contribution of CD4 and CD8 T Lymphocytes to T-Cell Infiltration of the Intact and the Degenerative Spinal Cord Am. J. Pathol., May 1, 2005; 166(5): 1441 - 1450. [Abstract] [Full Text] [PDF]

				S. Schif-Zuck, J. Westermann, N. Netzer, Y. Zohar, M. Meiron, G. Wildbaum, and N. Karin Targeted Overexpression of IL-18 Binding Protein at the Central Nervous System Overrides Flexibility in Functional Polarization of Antigen-Specific Th2 Cells J. Immunol., April 1, 2005; 174(7): 4307 - 4315. [Abstract] [Full Text] [PDF]

				M. Trottier, B. P. Schlitt, A. Y. Kung, and H. L. Lipton Transition from Acute to Persistent Theiler's Virus Infection Requires Active Viral Replication That Drives Proinflammatory Cytokine Expression and Chronic Demyelinating Disease J. Virol., November 15, 2004; 78(22): 12480 - 12488. [Abstract] [Full Text] [PDF]

				A. Jahng, I. Maricic, C. Aguilera, S. Cardell, R. C. Halder, and V. Kumar Prevention of Autoimmunity by Targeting a Distinct, Noninvariant CD1d-reactive T Cell Population Reactive to Sulfatide J. Exp. Med., April 5, 2004; 199(7): 947 - 957. [Abstract] [Full Text] [PDF]

				E. L. Oleszak, J. R. Chang, H. Friedman, C. D. Katsetos, and C. D. Platsoucas Theiler's Virus Infection: a Model for Multiple Sclerosis Clin. Microbiol. Rev., January 1, 2004; 17(1): 174 - 207. [Abstract] [Full Text] [PDF]

				J. Tian, A. P. Olcott, and D. L. Kaufman Antigen-Based Immunotherapy Drives the Precocious Development of Autoimmunity J. Immunol., December 1, 2002; 169(11): 6564 - 6569. [Abstract] [Full Text] [PDF]

				A. F. de Vos, M. van Meurs, H. P. Brok, L. A. Boven, R. Q. Hintzen, P. van der Valk, R. Ravid, S. Rensing, L. Boon, B. A. 't Hart, et al. Transfer of Central Nervous System Autoantigens and Presentation in Secondary Lymphoid Organs J. Immunol., November 15, 2002; 169(10): 5415 - 5423. [Abstract] [Full Text] [PDF]

				C. Martinat, I. Mena, and M. Brahic Theiler's Virus Infection of Primary Cultures of Bone Marrow-Derived Monocytes/Macrophages J. Virol., November 13, 2002; 76(24): 12823 - 12833. [Abstract] [Full Text] [PDF]

				I. Djilali-Saiah, P. Lapierre, S. Vittozi, and F. Alvarez DNA Vaccination Breaks Tolerance for a Neo-Self Antigen in Liver: A Transgenic Murine Model of Autoimmune Hepatitis J. Immunol., November 1, 2002; 169(9): 4889 - 4896. [Abstract] [Full Text] [PDF]

				J. K. Olson, T. N. Eagar, and S. D. Miller Functional Activation of Myelin-Specific T Cells by Virus-Induced Molecular Mimicry J. Immunol., September 1, 2002; 169(5): 2719 - 2726. [Abstract] [Full Text] [PDF]

				I. A. Scarisbrick, S. I. Blaber, C. F. Lucchinetti, C. P. Genain, M. Blaber, and M. Rodriguez Activity of a newly identified serine protease in CNS demyelination Brain, June 1, 2002; 125(6): 1283 - 1296. [Abstract] [Full Text] [PDF]

				P. A. Brex, O. Ciccarelli, J. I. O'Riordan, M. Sailer, A. J. Thompson, and D. H. Miller A Longitudinal Study of Abnormalities on MRI and Disability from Multiple Sclerosis N. Engl. J. Med., January 17, 2002; 346(3): 158 - 164. [Abstract] [Full Text] [PDF]

				J. K. Olson, A. M. Girvin, and S. D. Miller Direct Activation of Innate and Antigen-Presenting Functions of Microglia following Infection with Theiler's Virus J. Virol., October 15, 2001; 75(20): 9780 - 9789. [Abstract] [Full Text] [PDF]

				J. Tian, S. Gregori, L. Adorini, and D. L. Kaufman The Frequency of High Avidity T Cells Determines the Hierarchy of Determinant Spreading J. Immunol., June 15, 2001; 166(12): 7144 - 7150. [Abstract] [Full Text] [PDF]