DEMYELINATING ANTIBODIES TO MYELIN OLIGODENDROCYTE GLYCOPROTEIN AND GALACTOCEREBROSIDE INDUCE DEGRADATION OF MYELIN BASIC-PROTEIN IN ISOLATED HUMAN MYELIN

Although the specificity of multiple sclerosis (MS) brain immunoglobul ins (Igs) remains unknown, the incubation of these Igs with human myel in can lead to myelin basic protein (MBP) degradation mediated by neut ral proteases. In this study, we demonstrate that monoclonal antibodie s (mAbs) specific to myelin components such as the CNS-specific myelin oligodendrocyte glycoprotein (MOG) and galactocerebroside (GalC) are found to induce a significant loss of MBP mediated by neutral protease s in myelin. By contrast, antibodies to periaxonal and structural comp onents of myelin, such as MBP and myelin-associated glycoprotein, are ineffective in inducing such MBP degradation. Among the 11 different a nti-MOG mAbs directed to externally located epitopes of MOG, only two were found to induce a significant degradation of MBP, suggesting that antibody-induced MBP degradation is not only antigen specific but als o epitope specific. Based on the inhibition of MBP degradation in the presence of EGTA and the analysis of the degradation products obtained following incubation of myelin with mAbs to GalC and MOG (8-18C5), th e neutral protease involved in this antibody-induced degradation of MB P could be calcium-activated neutral protease. Taken together, these r esults suggest that antibodies to GalC and MOG can play a major role i n destabilizing myelin through MBP breakdown mediated by neutral prote ases and thus have an important role to play in the pathogenesis of MS .