The role of the humoral phase of the immune response in development of T cell-mediated experimental allergic encephalomyelitis (EAE) had not been clearly defined previously even though studies of the myelin basic protein (MBP) molecule had demonstrated the presence not only of T cell but also B cell epitopes capable of inducing cell-mediated immunity and antibody formation. Particularly relevant to this report are the immunological expressions of the region which induces EAE in the Lewis rat. The development of primary demyelination in Lewis rats is preceded by a cell-mediated immune response as well as antibody formation, both of which are highly specific to the encephalitogenic 14-residue peptide that defines the 69-84 region of the parent MBP. Our results are consistent with the dogma that EAE is a T cell-mediated disease, but they also clearly demonstrate an important role for specific antibodies in the development of these T cells responsible for demyelination. The antibody response, which may be heteroclitic, is necessary for T cells to develop into an effector T cell subset. Without this B cell response the subsequent T cell response does not lead to demyelination. In this report we shall discuss these findings and further show that the T cell and B cell epitopes, which are located within the 14-residue sequence, are physically separated and dependent upon the form of synthetic peptides known to induce T cell-mediated and/or humoral immunity.(ABSTRACT TRUNCATED AT 250 WORDS)