IDENTIFICATION OF A NOVEL T-CELL EPITOPE OF HUMAN PROTEOLIPID PROTEIN(RESIDUES 40-60) RECOGNIZED BY PROLIFERATIVE AND CYTOLYTIC CD4-CELLS FROM MULTIPLE-SCLEROSIS PATIENTS( T)

Research into the pathogenesis of multiple sclerosis (MS) has focused on myelin antigens as potential targets of autoimmune attack. Proteoli pid protein (PLP), which makes up more than 50% of central nervous sys tem myelin, is a hydrophobic membrane protein with many properties tha t historically have made it difficult to study. The use of synthetic p eptides based on the PLP sequence provides an alternative method for s tudying the immunological properties of PLP. Using peripheral blood ly mphocytes from MS patients, long-term TCL established in the presence of PLP reacted weakly to PLP in proliferation assays; however, these s ame lines were much more reactive to synthetic peptides of PLP. Thus, we established short-term T cell lines (TCL) from the peripheral blood lymphocytes (PBL) of MS patients in the presence of five separate syn thetic PLP peptides. In six out of seven MS patients, proliferative re sponses were elicited most often to PLP 40-60 compared to four other P LP peptides (PLP 89-106, 103-120, 125-143, and 139-154). Characterizat ion of PLP 40-60-responsive TCL from a single MS patient, MS1, indicat ed that six out of seven TCL proliferating to the peptide also lysed P LP 40-60 pulsed autologous targets. All cytolytic PLP 40-60 TCL were C D4+ and MHC class II restricted and further analysis of MS1 TCL showed that the PLP 40-60 TCL were restricted by DR4 whereas the MBP TCL fro m MS1 were restricted by DR6. These findings suggest that difficulties in examining the immune response to PLP have been due to the poor res ponse generated in vitro using the whole molecule and that the use of synthetic peptides may represent an alternative approach to the study of PLP. These results also suggest that MS PBL recognize several PLP p eptides, with the predominant response to PLP 40-60. Since these cells phenotypically resemble T cells known to mediate experimental autoimm une encephalomyelitis, it is possible that they may play a role in the pathogenesis of MS.