EPITOPE SPECIFICITY AND V-GENE EXPRESSION OF CEREBROSPINAL-FLUID T-CELLS SPECIFIC FOR INTACT VERSUS CRYPTIC EPITOPES OF MYELIN BASIC-PROTEIN

Recent evidence supports the possible involvement of myelin basic prot ein (BP) as one of the target autoantigens in multiple sclerosis (MS), including elevated frequencies of MS blood and cerebrospinal fluid (C SF) T cells, and the presence in MS plaque tissue of Vbeta gene sequen ces and CDR3 motifs characteristic of BP-reactive T cells. Because of its proximity to the target organ, the CSF has long been thought to ha rbor T cells involved in the pathogenic process. In order to evaluate their frequency and response characteristics, BP-reactive T cells were isolated by limiting dilution from the CSF of patients with MS and ot her neurological diseases (OND) for quantitation and determination of epitope specificity and Valpha and Vbeta gene expression. In addition to isolates responsive to intact BP epitopes that were present at a si gnificantly higher frequency in MS versus OND CSF, we here describe a second clonotype responsive to 'cryptic' BP epitopes that is present a t approximately equal frequencies in MS and OND patients. In spite of their difference in recognition of intact versus 'cryptic' BP determin ants, both clonotypes predominantly recognized epitopes in the N termi nal half of human BP, using a similar V gene repertoire that included biased use of Valpha2 and to a lesser degree Vbeta7 and Vbeta18. These V gene biases were not related to the epitope specificity of the T ce lls, indicating that V gene selection is not epitope-driven. These dat a suggest that there is differential recognition of intact versus 'cry ptic' BP determinants in MS versus OND patients that may be related to the processing and presentation of BP to the immune system.