title: Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population.
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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Experimental Pathology, University of Bologna, Bologna, Italy. michele.mishto@charite.de
authors.forename: Michele
authors.initials: M
authors.lastname: Mishto
authors.forename: Elena
authors.initials: E
authors.lastname: Bellavista
authors.forename: Claudia
authors.initials: C
authors.lastname: Ligorio
authors.forename: Kathrin
authors.initials: K
authors.lastname: Textoris-Taube
authors.forename: Aurelia
authors.initials: A
authors.lastname: Santoro
authors.forename: Mara
authors.initials: M
authors.lastname: Giordano
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Alfonso
authors.forename: Florinda
authors.initials: F
authors.lastname: Listì
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nacmias
authors.forename: Elena
authors.initials: E
authors.lastname: Cellini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Leone
authors.forename: Luigi M E
authors.initials: LM
authors.lastname: Grimaldi
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenoglio
authors.forename: Federica
authors.initials: F
authors.lastname: Esposito
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli-Boneschi
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.forename: Ulrike
authors.initials: U
authors.lastname: Seifert
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Amato
authors.forename: Calogero
authors.initials: C
authors.lastname: Caruso
authors.forename: Maria P
authors.initials: MP
authors.lastname: Foschini
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kloetzel
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007150:Immunohistochemistry; D007558:Italy; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D012307:Risk Factors; D012737:Sex Factors
chemical_list: D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009124:Muscle Proteins; D004676:Myelin Basic Protein; C085047:PSME1 protein, human; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C486207:PSME2 protein, human; D046988:Proteasome Endopeptidase Complex