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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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LMP2 subunit and PA28-αβ are expressed in CNS cortex and white matter of MS but not of young controls.Example of cortex (A, C) and plaque into white matter (B, D) of MS parietal lobe, stained with anti-LMP2 (A, B) and anti-PA28-α (C, D) Abs are shown. Different cell types, positive to the staining, are marked as following: 1. neurons; 2. luminal endothelial cells; 3. astrocytes; 4. oligodendrocytes (putative). Example of a parietal lobe cortex (E, G) and white matter (F, H) of young control stained with anti-LMP2 (E, F) and anti-PA28-α (G, H) Abs, which bind only luminal endothelial cells (see arrow). In (I) and (L) example of a parietal lobe white matter of a MS patient stained with anti-β1 and anti-α4 Abs are shown, respectively. As expected, all cells are positive to both stainings. The representative samples here reported derived from gender- and age-matched MS and control samples. A, C, D, F, G, H, I scale bars = 50 µm; B, E, L scale bars = 25 µm.
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pone-0009287-g001: LMP2 subunit and PA28-αβ are expressed in CNS cortex and white matter of MS but not of young controls.Example of cortex (A, C) and plaque into white matter (B, D) of MS parietal lobe, stained with anti-LMP2 (A, B) and anti-PA28-α (C, D) Abs are shown. Different cell types, positive to the staining, are marked as following: 1. neurons; 2. luminal endothelial cells; 3. astrocytes; 4. oligodendrocytes (putative). Example of a parietal lobe cortex (E, G) and white matter (F, H) of young control stained with anti-LMP2 (E, F) and anti-PA28-α (G, H) Abs, which bind only luminal endothelial cells (see arrow). In (I) and (L) example of a parietal lobe white matter of a MS patient stained with anti-β1 and anti-α4 Abs are shown, respectively. As expected, all cells are positive to both stainings. The representative samples here reported derived from gender- and age-matched MS and control samples. A, C, D, F, G, H, I scale bars = 50 µm; B, E, L scale bars = 25 µm.

Mentions: In the present study we described “immunoproteasomes” as any iso-form of proteasome that contains immunosubunits, thereby also including intermediate-types [18], [19]. IHC assays were performed on parietal lobes and rostral medulla (with MS plaques) of three MS patients (2 males, 37 and 49 years old; 1 female, 49 years old) and two young controls (females, 21 and 42 years old), provided by the Department of Hematology and Oncology, “L. and A. Seragnoli” Section of Anatomic Pathology, University of Bologna at Bellaria Hospital, Bologna, Italy. The IHC showed in Figure 1, 2 and 3 referred to autopsy samples derived from MS and control donors (respectively 49 and 42 years old) died by lung embolus and gastric hemorrhage, respectively. Both autopsies were carried out after 24 h from the death and almost all brain was included for histological examination and diagnostic definition of the disease. For the present study we selected brain areas carrying the histopathological features of active chronic plaques. These plaques, included for our immunohistochemical examination, were characterized by area of myelin reduction containing numerous macrophages with clear and foamy cytoplasm, positive with acid periodic Schiff staining (PAS) after diastase digestion. The same macrophages contained myelin degradation products, which reacted with the Luxol Fast Blue (LFB) staining and were mainly located in the peripheral part of the plaque as previously described [20]. The presence of macrophages and microglial cells has been evidenced by anti-CD68 immunostaining. In addition small venules, surrounded by mature lymphocytes, were present within the plaques. The lymphocyte population, characterized at the time of the diagnosis, consisted mainly of mature T cells, CD8 positive. The other MS and controls samples were biopsies obtained during surgery to investigate the presence of possible cancers. In the brain of subjects classified as MS patients characteristic MS lesions, were identified, instead of cancer markers; in contrast, neither cancer nor MS plaques were observed in the control sample.


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)

LMP2 subunit and PA28-αβ are expressed in CNS cortex and white matter of MS but not of young controls.Example of cortex (A, C) and plaque into white matter (B, D) of MS parietal lobe, stained with anti-LMP2 (A, B) and anti-PA28-α (C, D) Abs are shown. Different cell types, positive to the staining, are marked as following: 1. neurons; 2. luminal endothelial cells; 3. astrocytes; 4. oligodendrocytes (putative). Example of a parietal lobe cortex (E, G) and white matter (F, H) of young control stained with anti-LMP2 (E, F) and anti-PA28-α (G, H) Abs, which bind only luminal endothelial cells (see arrow). In (I) and (L) example of a parietal lobe white matter of a MS patient stained with anti-β1 and anti-α4 Abs are shown, respectively. As expected, all cells are positive to both stainings. The representative samples here reported derived from gender- and age-matched MS and control samples. A, C, D, F, G, H, I scale bars = 50 µm; B, E, L scale bars = 25 µm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2823778&req=5

pone-0009287-g001: LMP2 subunit and PA28-αβ are expressed in CNS cortex and white matter of MS but not of young controls.Example of cortex (A, C) and plaque into white matter (B, D) of MS parietal lobe, stained with anti-LMP2 (A, B) and anti-PA28-α (C, D) Abs are shown. Different cell types, positive to the staining, are marked as following: 1. neurons; 2. luminal endothelial cells; 3. astrocytes; 4. oligodendrocytes (putative). Example of a parietal lobe cortex (E, G) and white matter (F, H) of young control stained with anti-LMP2 (E, F) and anti-PA28-α (G, H) Abs, which bind only luminal endothelial cells (see arrow). In (I) and (L) example of a parietal lobe white matter of a MS patient stained with anti-β1 and anti-α4 Abs are shown, respectively. As expected, all cells are positive to both stainings. The representative samples here reported derived from gender- and age-matched MS and control samples. A, C, D, F, G, H, I scale bars = 50 µm; B, E, L scale bars = 25 µm.
Mentions: In the present study we described “immunoproteasomes” as any iso-form of proteasome that contains immunosubunits, thereby also including intermediate-types [18], [19]. IHC assays were performed on parietal lobes and rostral medulla (with MS plaques) of three MS patients (2 males, 37 and 49 years old; 1 female, 49 years old) and two young controls (females, 21 and 42 years old), provided by the Department of Hematology and Oncology, “L. and A. Seragnoli” Section of Anatomic Pathology, University of Bologna at Bellaria Hospital, Bologna, Italy. The IHC showed in Figure 1, 2 and 3 referred to autopsy samples derived from MS and control donors (respectively 49 and 42 years old) died by lung embolus and gastric hemorrhage, respectively. Both autopsies were carried out after 24 h from the death and almost all brain was included for histological examination and diagnostic definition of the disease. For the present study we selected brain areas carrying the histopathological features of active chronic plaques. These plaques, included for our immunohistochemical examination, were characterized by area of myelin reduction containing numerous macrophages with clear and foamy cytoplasm, positive with acid periodic Schiff staining (PAS) after diastase digestion. The same macrophages contained myelin degradation products, which reacted with the Luxol Fast Blue (LFB) staining and were mainly located in the peripheral part of the plaque as previously described [20]. The presence of macrophages and microglial cells has been evidenced by anti-CD68 immunostaining. In addition small venules, surrounded by mature lymphocytes, were present within the plaques. The lymphocyte population, characterized at the time of the diagnosis, consisted mainly of mature T cells, CD8 positive. The other MS and controls samples were biopsies obtained during surgery to investigate the presence of possible cancers. In the brain of subjects classified as MS patients characteristic MS lesions, were identified, instead of cancer markers; in contrast, neither cancer nor MS plaques were observed in the control sample.

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