Four different synthetic peptides of proteolipid protein induce a distinct antibody response in MP4-induced experimental autoimmune encephalomyelitis

- MP4-induced EAE is antibody-dependent.
- MP4-specific antibodies are directed against extra- and intracellular PLP.
- Antibodies against extracellular PLP are myelin-reactive in oligodendrocyte cultures.
- Antibodies against intracellular PLP bind to intact oligodendrocytes.
- Antibodies against intracellular PLP trigger EAE in MP4-immunized JHT mice.

Here we studied the autoantibody specificity elicited by proteolipid protein (PLP) in MP4-induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis (MS). In C57BL/6 (B6) mice, antibodies were induced by immunization with one of the two extracellular and by the intracellular PLP domain. Antibodies against extracellular PLP were myelin-reactive in oligodendrocyte cultures and induced mild spinal cord demyelination upon transfer into B cell-deficient JHT mice. Remarkably, also antibodies against intracellular PLP showed binding to intact oligodendrocytes and were capable of inducing myelin pathology upon transfer into JHT mice. In MP4-immunized mice peptide-specific TH1/TH17 responses were mainly directed against the extracellular PLP domains, but also involved the intracellular epitopes. These data suggest that both extracellular and intracellular epitopes of PLP contribute to the pathogenesis of MP4-induced EAE already in the setting of intact myelin. It remains to be elucidated if this concept also applies to MS itself.