Background: Albeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cellsinvolvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in theproduction of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation andregulation of autoreactive CD8+ T cells in Multiple Sclerosis.Methodology/Principal Findings: Immunoproteasomes and PA28-ab regulator are present in MS affected brain area andaccumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons,endothelial cells, oligodendrocytes, macrophages/macroglia and lymphocytes. Furthermore, in a genetic study on 1262Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H alleleproduce in vitro a lower amount of the HLA-A*0201 restricted immunodominant epitope MBP111–119.Conclusion/Significance: The immunoproteasome LMP2 60HH variant reduces the risk to develop MS amongst Italian HLAA*02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specificMBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement ofimmunoproteasome in the MS pathogenesis.
|Numero di pagine||0|
|Stato di pubblicazione||Published - 2010|