Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population

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

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Abstract

Background: Albeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis. Methodology/Principal Findings:Immunoproteasomes and PA28-ab regulator are present in MS affected brain area and accumulated 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 1262 Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2 codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H allele produce 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 HLA-A* 02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specific MBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement of immunoproteasome in the MS pathogenesis.

Original languageEnglish
Article numbere9287
JournalPLoS One
Volume5
Issue number2
DOIs
Publication statusPublished - Feb 18 2010

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mishto, M., Bellavista, E., Ligorio, C., Textoris-Taube, K., Santoro, A., Giordano, M., D'Alfonso, S., Listì, F., Nacmias, B., Cellini, E., Leone, M., Grimaldi, L. M. E., Fenoglio, C., Esposito, F., Martinelli-Boneschi, F., Galimberti, D., Scarpini, E., Seifert, U., Amato, M. P., ... Franceschi, C. (2010). Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population. PLoS One, 5(2), [e9287]. https://doi.org/10.1371/journal.pone.0009287