Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population.
<h4>Background</h4>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-restric...
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2010
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oai:doaj.org-article:4cb4cbf2336142ff9d2394e21649e6912021-11-25T06:25:44ZImmunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population.1932-620310.1371/journal.pone.0009287https://doaj.org/article/4cb4cbf2336142ff9d2394e21649e6912010-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20174631/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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).<h4>Conclusion/significance</h4>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.Michele MishtoElena BellavistaClaudia LigorioKathrin Textoris-TaubeAurelia SantoroMara GiordanoSandra D'AlfonsoFlorinda ListìBenedetta NacmiasElena CelliniMaurizio LeoneLuigi M E GrimaldiChiara FenoglioFederica EspositoFilippo Martinelli-BoneschiDaniela GalimbertiElio ScarpiniUlrike SeifertMaria Pia AmatoCalogero CarusoMaria P FoschiniPeter M KloetzelClaudio FranceschiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 2, p e9287 (2010) |
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Medicine R Science Q 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 Caruso Maria P Foschini Peter M Kloetzel Claudio Franceschi Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population. |
| description |
<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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).<h4>Conclusion/significance</h4>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. |
| format |
article |
| author |
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 Caruso Maria P Foschini Peter M Kloetzel Claudio Franceschi |
| author_facet |
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 Caruso Maria P Foschini Peter M Kloetzel Claudio Franceschi |
| author_sort |
Michele Mishto |
| title |
Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population. |
| title_short |
Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population. |
| title_full |
Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population. |
| title_fullStr |
Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population. |
| title_full_unstemmed |
Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population. |
| title_sort |
immunoproteasome lmp2 60hh variant alters mbp epitope generation and reduces the risk to develop multiple sclerosis in italian female population. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2010 |
| url |
https://doaj.org/article/4cb4cbf2336142ff9d2394e21649e691 |
| work_keys_str_mv |
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