Previous studies from our laboratory have demonstrated a predominant response to myelin oligodendrocyte glycoprotein (MOG) in patients with multiple sclerosis (MS) and showed that this molecule is able to induce in Lewis rats a chronic relapsing MS-like disease with extensive demyelination. To further study the possibility that MOG is a primary target antigen in MS, we have begun to investigate the encephalitogenicity and antibody response of different sequences of the extracellular domains of MOG in Lewis rats. We report that none of the synthetic peptides encompassing the MOG amino acid sequences 1-21, 67-87, 104-117 and 202-218 were encephalitogenic. In contrast, a single injection of MOG35-55 was able to induce severe neurological signs associated with inflammation and demyelination. All rats injected with MOG peptides 1-21, 35-55, 67-87 and 202-218 developed a high level of antibodies to their respective immunizing peptides as detected by ELISA and immunoblotting. Although all MOG peptide antisera reacted with immunoblots of native MOG separated under reducing conditions, only anti-MOG35-55 and anti-MOG202-218 antibodies reacted to native MOG, when tested under nonreducing conditions. These results indicate that the MOG35-55 peptide, which is found in the extracellular Ig V-like domain of MOG, is not only an encephalitogenic epitope but could also be an important determinant for initiating antibody-mediated demyelination. As indicated by the absence of reactivity to the other MOG peptides tested, as well as other central nervous system myelin proteins including myelin basic protein and proteolipid protein, the antibody response produced by MOG peptides is highly restricted.