DEFINITION OF ENCEPHALITOGENIC AND IMMUNODOMINANT EPITOPES OF GUINEA-PIG MYELIN BASIC-PROTEIN (GP-BP) IN LEWIS RATS TOLERIZED NEONATALLY WITH GP-BP OR GP-BP PEPTIDES

Two distinct epitopes of guinea pig basic protein (Gp-BP), residues 72 -89 and 87-99, possess encephalitogenic activity in Lewis rats. The pu rpose of this study was to determine to what degree the 87-99 epitope functions in rats that have been injected with whole Gp-BP, and whethe r additional epitopes in Gp-BP are encephalitogenic. To address these questions, we induced neonatal tolerance to the dominant synthetic (S) 72-89 peptide or to the combination of both S72-89 and S87-99 peptides , and evaluated resistance to experimental autoimmune encephalomyeliti s (EAE) induced by Gp-BP, as well as T cell responses to peptides that encompassed most of the Gp-BP molecule. The results demonstrated that virtually all of the encephalitogenic activity of Gp-BP resides withi n the two described encephalitogenic epitopes. Moreover, deletion of r esponses to the dominant epitopes prompted T cell responses to other n onencephalitogenic epitopes of Gp-BP, a pattern of response observed p reviously in rats that had recovered from EAE and in those protected f rom EAE by vaccination with TCR peptides. These data may have relevanc e to human autoimmune diseases such as multiple sclerosis in that natu rally or immunologically regulated responses to dominant epitopes that are likely to be encephalitogenic may be obscured by increased respon ses to relatively innocuous determinants of basic protein. Elevated re sponses to potentially pathogenic autoantigens will likely involve bot h types of determinants, thus, underscoring the importance of distingu ishing encephalitogenic from nonencephalitogenic determinants.