Indirect evidence suggests that an autoimmune response to myelin basic protein (MBP) may be involved in the pathogenesis of multiple sclerosis (MS). In MS, several reports have suggested that restricted T-cell populations respond to MPB, as in inbred rodents with the MS disease model experimental allergic encephalomyelitis. In experimental allergic encephalomyelitis, the T-cell repertoire to MBP varies between strains, and in MS it is likely that the response to MBP is also best defined under conditions where genetic differences between subjects are controlled. In this report, the fine specificity of the T-cell response to MBP was assessed in three families, each with multiple individuals affected with MS. We found that (1) comparable frequencies of MBP-reactive T-cell lines were obtained from peripheral blood of MS patients and their healthy siblings. Human leukocyte antigen (HLA) identical sibling pairs discordant for MS had similar frequencies of MBP-reactive T-cell lines. (2) A broad spectrum of MBP epitopes was recognized by T-cell lines from all individuals studied. Within a family, the fine specificity of MBP recognition showed little or no overlap between individuals, even between HLA identical siblings. (3) Recognition of MBP epitopes occurred in the context of different HLA class II alleles. At least four DR alleles each served as restricting elements for recognition of P82-101 or the carboxy terminal region of MBP, two regions thought to be important in the human T-cell response to the molecule. No relationship between the use of a particular DR allele and a response to a particular region of MBP could be established.(ABSTRACT TRUNCATED AT 250 WORDS)