title: Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis.
abstract: Relapsing experimental autoimmune encephalomyelitis (R-EAE) is a CD4+ T cell-mediated demyelinating disease model for multiple sclerosis. Myelin destruction during the initial relapsing phase of R-EAE in SJL mice initiated by immunization with the proteolipid protein (PLP) epitope PLP139-151 is associated with activation of T cells specific for the endogenous, non-cross-reactive PLP178-191 epitope (intramolecular epitope spreading), while relapses in R-EAE induced with the myelin basic protein (MBP) epitope MBP84-104 are associated with PLP139-151-specific responses (intermolecular epitope spreading). Here, we demonstrate that T cells specific for endogenous myelin epitopes play the major pathologic role in mediating clinical relapses. T cells specific for relapse-associated epitopes can serially transfer disease to naive recipients and are demonstrable in the CNS of mice with chronic R-EAE. More importantly, induction of myelin-specific tolerance to relapse-associated epitopes, by i.v. injection of ethylene carbodiimide-fixed peptide-pulsed APCs, either before disease initiation or during remission from acute disease effectively blocks the expression of the initial disease relapse. Further, blockade of B7-1-mediated costimulation with anti-B7-1 F(ab) during disease remission from acute PLP139-151-induced disease prevents clinical relapses by inhibiting activation of PLP178-191-specific T cells. The protective effects of anti-B7-1 F(ab) treatment are long-lasting and highly effective even when administered following the initial relapsing episode wherein spreading to a MBP epitope (MBP84-104) is inhibited. Collectively, these data indicate that epitope spreading is B7-1 dependent, plays a major pathologic role in disease progression, and follows a hierarchical order associated with the relative encephalitogenic dominance of the myelin epitopes (PLP139-151 > PLP178-191 > MBP84-104).
authors.affiliation: Department of Microbiology, Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Vanderlugt
authors.forename: K L
authors.initials: KL
authors.lastname: Neville
authors.forename: K M
authors.initials: KM
authors.lastname: Nikcevich
authors.forename: T N
authors.initials: TN
authors.lastname: Eagar
authors.forename: J A
authors.initials: JA
authors.lastname: Bluestone
authors.forename: S D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001324:Autoantigens / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology*; D018122:B7-1 Antigen / Q000276:immunology / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D016056:Immunodominant Epitopes / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology / Q000502:physiology; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage / Q000276:immunology / Q000502:physiology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000502:physiology; D012008:Recurrence; D013601:T-Lymphocytes / Q000637:transplantation; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D018122:B7-1 Antigen; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C094241:myelin basic protein 84-104; C435023:myelin proteolipid protein (139-151)