Region 65-102 of the myelin basic protein (MBP) houses a number of antigenic determinants known to induce delayed-type hypersensitivity, experimental allergic encephalomyelitis (EAE), suppressor cell function, and antibodies. In this report we describe the biological activity of synthetic peptides S53, S55, and S49 with sequence homology to region 69-84 of the rat, guinea pig, and bovine MBP. Peptide S53-A, defined by residues 75-84 of the guinea pig (SQRSQDEN) and of the rat (SQRTQDEN) MBP induced clinical signs of disease in Lewis rats. These included weight loss, flaccid tail, "muscle wasting," and hind-leg weakness. Histological examination of brain, spinal cord, and sciatic nerve sections of diseased rats revealed the complete absence of focal and perivascular lymphocytic infiltrates characteristic of demyelinating EAE lesions. Elongation of peptide S53 by three or six residues to residue sequences naturally found at its N-terminal end gave rise to peptides S55S (PQKSQRSQDEN) and S49S (GSLPQKSQRSDQDEN), respectively. Lewis rats challenged with either S55S or S49S developed classical clinical and histological signs of EAE. Severe hindleg paralysis was accompanied by incontinence and sometimes death. Injected in the form of carrier-free peptide, S53 was a meager B cell immunogen. S53 conjugated with methylated-bovine serum albumin was also a potent immunogen and produced clinical signs of disease without CNS pathology. By comparison, carrier-free S55S and S49S were potent immunogens giving rise to antibodies that cross reacted completely and competitively with S55S but considerably less so with S53. The results show that the sequence of S53 defines an epitope responsible for the formation of anti353 antibodies. Elongation of the S53 sequence at its Nterminal end generated an additional epitope which induced cell-mediated immunity responsible for the concomitant development of pathological signs of EAE. It may be concluded that the induction of classical signs of EAE requires specific and defined sequences capable of expressing both B cell and T cell functions.