Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population
Copyright policy )Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population
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.Immunoproteasomes and PA28-alphabeta 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 MBP(111-119).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.
- University of Palermo Italy
- King's College London United Kingdom
- University of Florence Italy
- Fondazione Istituto G. Giglio di Cefalù Italy
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Italy
Adult, Male, Proteasome Endopeptidase Complex, 570, T cells, proteasomes, multiple sclerosis, parietal lobe, Multiple Sclerosis, Genotype, Science, Molecular Sequence Data, 610, Muscle Proteins, Research Support, multiple sclerosis, Immunoproteasome, Epitopes, Sex Factors, Gene Frequency, Risk Factors, HLA-A2 Antigen, Journal Article, Humans, Funding: This work was financed in part by the grant Giovani Ricercatori 2007 from Italian Ministry of Health to MM, DG and FMB, by a grant from the European Commission Integrated Project PROTEOMAGE (FP6) to CF, by the finalized projects of Fondazione Italiana Sclerosi Multipla (FISM) cod. 2003/R26 and BioPharmaNet to CF and 2002/R/40 and 2005/R/10, 2008/R/11 (Genoa) to SD'A, by the University of Bologna (FRO) to MPF, by the Regione Piemonte (Ricerca Sanitaria Finalizzata Project and Ricerca Sanitaria Applicata-CIPE Project) to SD'A, by Associazione Amici del Centro Dino Ferrari and IRCCS Ospedale Maggiore Policlinico, Milano to DG and by the grants Sonderforschungsbereich (SFB-507, SFB-421) to PMK and US, the grants TR43 and Neurocure to PMK. MM benefited from the A.V. Humboldt PostDoc fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Amino Acid Sequence, Non-U.S. Gov't, HLA-A Antigens, Macrophages, Q, R, Brain, Myelin Basic Protein, Middle Aged, Immunohistochemistry, Oligodendroglia, Cysteine Endopeptidases, Italy, Immunoproteasome; multiple sclerosis; italian population, Medicine, Female, Microglia, italian population, Protein Binding, Research Article
Adult, Male, Proteasome Endopeptidase Complex, 570, T cells, proteasomes, multiple sclerosis, parietal lobe, Multiple Sclerosis, Genotype, Science, Molecular Sequence Data, 610, Muscle Proteins, Research Support, multiple sclerosis, Immunoproteasome, Epitopes, Sex Factors, Gene Frequency, Risk Factors, HLA-A2 Antigen, Journal Article, Humans, Funding: This work was financed in part by the grant Giovani Ricercatori 2007 from Italian Ministry of Health to MM, DG and FMB, by a grant from the European Commission Integrated Project PROTEOMAGE (FP6) to CF, by the finalized projects of Fondazione Italiana Sclerosi Multipla (FISM) cod. 2003/R26 and BioPharmaNet to CF and 2002/R/40 and 2005/R/10, 2008/R/11 (Genoa) to SD'A, by the University of Bologna (FRO) to MPF, by the Regione Piemonte (Ricerca Sanitaria Finalizzata Project and Ricerca Sanitaria Applicata-CIPE Project) to SD'A, by Associazione Amici del Centro Dino Ferrari and IRCCS Ospedale Maggiore Policlinico, Milano to DG and by the grants Sonderforschungsbereich (SFB-507, SFB-421) to PMK and US, the grants TR43 and Neurocure to PMK. MM benefited from the A.V. Humboldt PostDoc fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Amino Acid Sequence, Non-U.S. Gov't, HLA-A Antigens, Macrophages, Q, R, Brain, Myelin Basic Protein, Middle Aged, Immunohistochemistry, Oligodendroglia, Cysteine Endopeptidases, Italy, Immunoproteasome; multiple sclerosis; italian population, Medicine, Female, Microglia, italian population, Protein Binding, Research Article
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