title: Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis.
abstract: Chronic progression of two T cell-mediated central nervous system (CNS) demyelinating models of multiple sclerosis, relapsing EAE (R-EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is dependent on the activation of T cells to endogenous myelin epitopes (epitope spreading). Using transfer of carboxyfluorescein succinyl ester (CFSE)-labeled T-cell receptor (TCR)-transgenic T cells and mixed bone marrow chimeras, we show that activation of naive proteolipid protein (PLP)139-151-specific T cells in SJL mice undergoing PLP178-191-induced R-EAE or TMEV-IDD occurs directly in the CNS and not in the cervical lymph nodes or other peripheral lymphoid organs. Examination of the antigen-presentation capacity of antigen-presenting cell (APC) populations purified from the CNS of mice with PLP178-191-induced R-EAE shows that only F4/80-CD11c+CD45hi dendritic cells (DCs) efficiently present endogenous antigen to activate naive PLP139-151-specific T cells in vitro. In contrast, DCs as well as F4/80+CD45hi macrophages and F4/80+CD45lo microglia activate a PLP139-151-specific helper T cell line. The data suggest that naive T cells enter the inflamed CNS and are activated by local APCs, possibly DCs, to initiate epitope spreading.
authors.affiliation: Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Eileen J
authors.initials: EJ
authors.lastname: McMahon
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Bailey
authors.forename: Carol Vanderlugt
authors.initials: CV
authors.lastname: Castenada
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Waldner
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D018188:Cardiovirus Infections / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology; D003711:Demyelinating Diseases / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D017945:Theilovirus
chemical_list: D000939:Epitopes