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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 p 104–117 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 oftheTcell repertoire responding to the p 104–117 determinant. Tcell lines responding to the cryptic p104–117 show limited TCR-Vβ utilization compared to the diverse repertoire responding to the dominant p 139–151 determinant. The repertoire deletions are accompanied by low level production of pathogenic Th1 cytokines (IFNγ; IL-2) and increased production of regulatory Th2 (IL-4) cytokine in activated p104–117 primed T cells. Thus, the delayed encephalito-genicity of p104–117 may be due to TCR-Vβ 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.