Immunoproteasome LMP2 60HH variant alters MBP epitope generation and reduces the risk to develop multiple sclerosis in Italian female population.
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.
Mishto
Michele
M
Department of Experimental Pathology, University of Bologna, Bologna, Italy. michele.mishto@charite.de
Bellavista
Elena
E
Ligorio
Claudia
C
Textoris-Taube
Kathrin
K
Santoro
Aurelia
A
Giordano
Mara
M
D'Alfonso
Sandra
S
Listì
Florinda
F
Nacmias
Benedetta
B
Cellini
Elena
E
Leone
Maurizio
M
Grimaldi
Luigi M E
LM
Fenoglio
Chiara
C
Esposito
Federica
F
Martinelli-Boneschi
Filippo
F
Galimberti
Daniela
D
Scarpini
Elio
E
Seifert
Ulrike
U
Amato
Maria Pia
MP
Caruso
Calogero
C
Foschini
Maria P
MP
Kloetzel
Peter M
PM
Franceschi
Claudio
C
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
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