Journal Article

Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population

Listì, Florinda, Fenoglio, Chiara, Scarpini, Elio, Franceschi, Claudio, Cellini, Elena, Kloetzel, Peter M., Bellavista, Elena, Ligorio, Claudia, Textoris-Taube, Kathrin, D'Alfonso, Sandra, Nacmias, Benedetta, Mishto, Michele, Leone, Maurizio, Caruso, Calogero, Giordano, Mara, Foschini, Maria P., Amato, Maria Pia, Martinelli-Boneschi, Filippo, Santoro, Aurelia, Galimberti, Daniela, Esposito, Federica, Seifert, Ulrike, Grimaldi, Luigi M.E.

2010

Overview

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. 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). 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Aging / Amino Acid Sequence / Antigenic determinants / Antigens / Arthritis / Autoimmune diseases / Autoimmunity / Biochemistry / Bioinformatics / Biophysics / Blood-brain barrier / Brain / Brain - metabolism / Brain - pathology / Brain research / CD4 antigen / CD8 antigen / Cell activation / Clinical trials / Cysteine Endopeptidases - genetics / Cysteine Endopeptidases - immunology / Cysteine Endopeptidases - metabolism / Cytokines / Disease / Endothelial cells / Epitopes / Epitopes - immunology / Epitopes - metabolism / Female / Females / Gene Frequency / Genotype / Glia / Hematology / Histocompatibility antigen HLA / HLA antigens / HLA-A Antigens - genetics / HLA-A Antigens - immunology / HLA-A Antigens - metabolism / HLA-A2 Antigen / Hospitals / Humans / Immunohistochemistry / Immunology/Antigen Processing and Recognition / Immunology/Autoimmunity / Italy / Lymphocytes / Lymphocytes T / Macrophages / Macrophages - metabolism / Macrophages - pathology / Major histocompatibility complex / Male / Microglia - metabolism / Microglia - pathology / Middle Aged / Molecular Sequence Data / Multiple myeloma / Multiple sclerosis / Multiple Sclerosis - genetics / Multiple Sclerosis - immunology / Multiple Sclerosis - metabolism / Muscle Proteins - metabolism / Myelin Basic Protein - immunology / Myelin Basic Protein - metabolism / Nervous system / Neurology / Neuroscience/Neurobiology of Disease and Regeneration / Oligodendrocytes / Oligodendroglia - metabolism / Oligodendroglia - pathology / Pathogenesis / Pathology / Physiology / Plaques / Population studies / Proteasome Endopeptidase Complex - metabolism / Proteasomes / Protein Binding / Proteins / Risk / Risk Factors / Risk reduction / Sex Factors / Studies / T cell receptors / T cells