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

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 LM, Fenoglio C, Esposito F, Martinelli-Boneschi F, Galimberti D, Scarpini E, Seifert U, Amato MP, Caruso C, Foschini MP, Kloetzel PM, Franceschi C - PLoS ONE (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Pathology, University of Bologna, Bologna, Italy. michele.mishto@charite.de

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-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).

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.

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Related in: MedlinePlus

20S immunoproteasomes (+ PA28-αβ) carrying LMP2 60H allele have a lower SP of the MBP111–119 epitope.(A) Chart shows the time-dependent kinetics of MBP102–129 degradation increased in presence of PA28-αβ. (B) Specific production (SP) [expressed as: (peptide signal/consumed substrate signal)*1000] of the MBP111–119 epitope (peptide 10–18 of MBP102–129) and of the two flanking peptides 1–9 and 19–28 in absence or presence of PA28-αβ. The values are the average of the SPs measured at different time points. (C) In presence of PA28-αβ, H-carrier 20S immunoproteasomes have a significant lower epitope SP in all three selected ranges of substrate consumption. No significant difference emerged, on the contrary, in absence of PA28-αβ (D). (E) The similar rate constant K1 of MBP102–129 digestion by 20S immunoproteasomes (in presence of PA28-αβ) carrying the three LMP2 codon 60 variants. All values are given as mean+S.E.M. Statistical significance (p<0.05) is marked with *.
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pone-0009287-g004: 20S immunoproteasomes (+ PA28-αβ) carrying LMP2 60H allele have a lower SP of the MBP111–119 epitope.(A) Chart shows the time-dependent kinetics of MBP102–129 degradation increased in presence of PA28-αβ. (B) Specific production (SP) [expressed as: (peptide signal/consumed substrate signal)*1000] of the MBP111–119 epitope (peptide 10–18 of MBP102–129) and of the two flanking peptides 1–9 and 19–28 in absence or presence of PA28-αβ. The values are the average of the SPs measured at different time points. (C) In presence of PA28-αβ, H-carrier 20S immunoproteasomes have a significant lower epitope SP in all three selected ranges of substrate consumption. No significant difference emerged, on the contrary, in absence of PA28-αβ (D). (E) The similar rate constant K1 of MBP102–129 digestion by 20S immunoproteasomes (in presence of PA28-αβ) carrying the three LMP2 codon 60 variants. All values are given as mean+S.E.M. Statistical significance (p<0.05) is marked with *.

Mentions: We observed that this regulatory complex increased the degradation rate of MBP102–129 (Fig. 4A) as well as the MBP111–119 specific production (SP) (M-W U = 0; p = 0.002), as also indirectly confirmed by the concomitant higher SP of the flanking peptide 1–9 ( M-W U = 0; p = 0.002) (Fig. 4B).


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

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 LM, Fenoglio C, Esposito F, Martinelli-Boneschi F, Galimberti D, Scarpini E, Seifert U, Amato MP, Caruso C, Foschini MP, Kloetzel PM, Franceschi C - PLoS ONE (2010)

20S immunoproteasomes (+ PA28-αβ) carrying LMP2 60H allele have a lower SP of the MBP111–119 epitope.(A) Chart shows the time-dependent kinetics of MBP102–129 degradation increased in presence of PA28-αβ. (B) Specific production (SP) [expressed as: (peptide signal/consumed substrate signal)*1000] of the MBP111–119 epitope (peptide 10–18 of MBP102–129) and of the two flanking peptides 1–9 and 19–28 in absence or presence of PA28-αβ. The values are the average of the SPs measured at different time points. (C) In presence of PA28-αβ, H-carrier 20S immunoproteasomes have a significant lower epitope SP in all three selected ranges of substrate consumption. No significant difference emerged, on the contrary, in absence of PA28-αβ (D). (E) The similar rate constant K1 of MBP102–129 digestion by 20S immunoproteasomes (in presence of PA28-αβ) carrying the three LMP2 codon 60 variants. All values are given as mean+S.E.M. Statistical significance (p<0.05) is marked with *.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2823778&req=5

pone-0009287-g004: 20S immunoproteasomes (+ PA28-αβ) carrying LMP2 60H allele have a lower SP of the MBP111–119 epitope.(A) Chart shows the time-dependent kinetics of MBP102–129 degradation increased in presence of PA28-αβ. (B) Specific production (SP) [expressed as: (peptide signal/consumed substrate signal)*1000] of the MBP111–119 epitope (peptide 10–18 of MBP102–129) and of the two flanking peptides 1–9 and 19–28 in absence or presence of PA28-αβ. The values are the average of the SPs measured at different time points. (C) In presence of PA28-αβ, H-carrier 20S immunoproteasomes have a significant lower epitope SP in all three selected ranges of substrate consumption. No significant difference emerged, on the contrary, in absence of PA28-αβ (D). (E) The similar rate constant K1 of MBP102–129 digestion by 20S immunoproteasomes (in presence of PA28-αβ) carrying the three LMP2 codon 60 variants. All values are given as mean+S.E.M. Statistical significance (p<0.05) is marked with *.
Mentions: We observed that this regulatory complex increased the degradation rate of MBP102–129 (Fig. 4A) as well as the MBP111–119 specific production (SP) (M-W U = 0; p = 0.002), as also indirectly confirmed by the concomitant higher SP of the flanking peptide 1–9 ( M-W U = 0; p = 0.002) (Fig. 4B).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Pathology, University of Bologna, Bologna, Italy. michele.mishto@charite.de

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-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).

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.

Show MeSH
Related in: MedlinePlus