title: Determinant-regulated onset of experimental autoimmune encephalomyelitis: distinct epitopes of myelin proteolipid protein mediate either acute or delayed disease in SJL/J mice.
abstract: In the present study we address the question of whether distinct self-determinants can target alternative autoimmune disease patterns in experimental autoimmune encephalomyelitis (EAE), an animal model widely used for studying multiple sclerosis. We have found that the clinical course of EAE can be determined by the target peptide selected for induction of disease. In SJL/J mice, actively induced and passively transferred EAE mediated by the immunodominant PLP determinants p139-151 and p178-191 consistently produced a rapid onset of severe clinical signs. In contrast, a delayed onset of both active and passive EAE is associated with the nondominant cryptic PLP determinant p104-117. The delayed disease induced with p104-117 is not associated with any unusual peptide feature, with bystander immunoregulation, with inept class II MHC binding, or with failure to induce T cell expression of CD44, VLA-4, or IL-2 receptor upon activation. However, delayed disease is associated with innate qualities of the T cell repertoire responding to the p104-117 determinant. T cell lines responding to the cryptic p104-117 show limited TCR-V beta utilization compared to the diverse repertoire responding to the dominant p139-151 determinant. The repertoire deletions are accompanied by low level production of pathogenic Th1 cytokines (IFN gamma; IL-2) and increased production of regulatory Th2 (IL-4) cytokine in activated p104-117 primed T cells. Thus, the delayed encephalitogenicity of p104-117 may be due to TCR-V beta deletions and activation defects in the responding T cell repertoire. The development of "slow disease" mediated by autoreactivity against hidden self-determinants may have important implications in the pathogenesis of both relapsing and chronic autoimmune demyelinating disease.
authors.affiliation: Department of Immunology, Cleveland Clinic Foundation, OH 44195, USA.
authors.forename: V K
authors.initials: VK
authors.lastname: Tuohy
authors.forename: D M
authors.initials: DM
authors.lastname: Thomas
authors.forename: T
authors.initials: T
authors.lastname: Haqqi
authors.forename: M
authors.initials: M
authors.lastname: Yu
authors.forename: J M
authors.initials: JM
authors.lastname: Johnson
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000276:immunology*; D005260:Female; D016056:Immunodominant Epitopes / Q000276:immunology*; D039041:Integrin alpha4beta1; D016023:Integrins / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D018991:Myelin Proteolipid Protein / Q000276:immunology* / Q000502:physiology*; D010455:Peptides / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000145:classification / Q000276:immunology; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D016056:Immunodominant Epitopes; D039041:Integrin alpha4beta1; D016023:Integrins; D018991:Myelin Proteolipid Protein; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016201:Receptors, Lymphocyte Homing