Immunoproteasome LMP2 60HH Variant Alters MBPEpitope Generation and Reduces the Risk to DevelopMultiple Sclerosis in Italian Female Population

Calogero Caruso, Kathrin Textoris-Taube, Federica Esposito, Sandra D'Alfonso, Claudio Franceschi, Filippo Martinelli-Boneschi, Maria P. Foschini, Elio Scarpini, Elio Scarpini, Michele Mishto, Claudia Ligorio, Elena Cellini, Daniela Galimberti, Benedetta Nacmias, Peter M. Kloetzel, Ulrike Seifert, Luigi M. E. Grimaldi, Maria Pia Amato, Mara Giordano, Chiara FenoglioMaurizio Leone, Elena Bellavista, Aurelia Santoro, Florinda Listi'

Risultato della ricerca: Articlepeer review

45 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
Numero di pagine0
RivistaPLoS One
Volume5
Stato di pubblicazionePublished - 2010

All Science Journal Classification (ASJC) codes

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  • General

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