ИСТИНА

Triggering of autoimmune diseases by autoantigens is poorly understood. One of the crucial steps in antigen presentation on MHC I is degradation of antigenic protein by proteasome. We studied proteasome-mediated degradation of myelin basic protein (MBP), one of major autoantigenes in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). We have demonstrated a dramatic shift in the balance between constitutive and immuno proteasomes in the CNS of SJL mice with EAE, with immunoproteasome subunit LMP2 localized mainly in oligodendrocytes. Patterns of MBP degradation by proteasome from brain of EAE mice and control nontreated mice were compared by MS spectra using 16O/18O labeling and isotope-labeled synthetic peptides. Elevated levels of immunoproteasome in brain of mice with EAE result in an increased production of several peptides, including peptide ENPVVHFF, a part of encephalitogenic MBP region. Peptidyl epoxyketone inhibitor of LMP2 immunoproteasome subunit affects catalytic activity of brain-derived immunoproteasome in vitro and ameliorates ongoing demyelination in vivo, suggesting a novel treatment modality of autoimmune neurological diseases.