Recent studies using murine animal model systems indicate that clinical progression of autoimmune disease may be due to the sequential accumulation of neoautoreactivity characterized by extensive plasticity of self recognition. In the present study, we addressed the question of whether a similar paradigm of self recognition is implicated in the development of multiple sclerosis (MS), a demyelinating disease with a presumed autoimmune etiology. Our approach was to determine serial changes over a 12-18-mo period in response to an epitope-mapping series of 265 12-mer peptides of myelin proteolipid protein (PLP) by patients with isolated monosymptomatic demyelinating syndromes (IMDS), a group of distinct clinical disorders with variable rates of progression to MS. Our data showed that an extensive array of proteolipid protein peptides could elicit autoreactivity. Moreover, differential autoreactive patterns were evident within IMDS patient subpopulations. Monocentric monophasic IMDS patients with no evidence of prior subclinical disease typically showed fully sustained autoreactivity characterized by extensive plasticity, epitope focusing, shifting, and spreading of responses to new self determinants. In contrast, multicentric monophasic IMDS patients with putative evidence of prior asymptomatic lesion formation typically showed partially sustained autoreactivity characterized by abrupt abrogation of responses to an extensive array of self determinants. No sustained autoreactivity was observed in normal control subjects or in patients with other neurologic diseases. Our results indicate that self recognition associated with the development of MS is a developmental process characterized by autoreactive diversity, plasticity, and instability.