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      MHC Class II Protein Turnover In vivo and Its Relevance for Autoimmunity in Non-Obese Diabetic Mice

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          Abstract

          Major histocompatibility complex class II (MHCII) proteins are loaded with endosomal peptides and reside at the surface of antigen-presenting cells (APCs) for a time before being degraded. In vitro, MHCII protein levels and turnover are affected by peptide loading and by rates of ubiquitin-dependent internalization from the cell surface, which is in turn affected by APC type and activation state. Prior work suggested that fast turnover of disease-associated MHCII alleles may contribute to autoimmunity. We recently developed novel stable isotope tracer techniques to test this hypothesis in vivo. In non-obese diabetic (NOD) mice, a model of type 1 diabetes (T1D), MHCII turnover was affected by APC type, but unaffected by disease-associated structural polymorphism. Differences in MHCII turnover were observed between NOD colonies with high and low T1D incidence, but fast turnover was dispensable for autoimmunity. Moreover, NOD mice with gene knockouts of peptide loading cofactors do not develop T1D. Thus, fast turnover does not appear pathogenic, and conventional antigen presentation is critical for autoimmunity in NOD mice. However, shared environmental factors may underpin colony differences in MHCII protein turnover, immune regulation, and pathogenesis.

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          Most cited references57

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          Organ-specific disease provoked by systemic autoimmunity.

          Rheumatoid arthritis (RA) is a chronic joint disease characterized by leukocyte invasion and synoviocyte activation followed by cartilage and bone destruction. Its etiology and pathogenesis are poorly understood. We describe a spontaneous mouse model of this syndrome, generated fortuitously by crossing a T cell receptor (TCR) transgenic line with the NOD strain. All offspring develop a joint disease highly reminiscent of RA in man. The trigger for the murine disorder is chance recognition of a NOD-derived major histocompatibility complex (MHC) class II molecule by the transgenic TCR; progression to arthritis involves CD4+ T, B, and probably myeloid cells. Thus, a joint-specific disease need not arise from response to a joint-specific antigen but can be precipitated by a breakdown in general mechanisms of self-tolerance resulting in systemic self-reactivity. We suggest that human RA develops by an analogous mechanism.
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            Functional and quantitative proteomics using SILAC.

            Researchers in many biological areas now routinely characterize proteins by mass spectrometry. Among the many formats for quantitative proteomics, stable-isotope labelling by amino acids in cell culture (SILAC) has emerged as a simple and powerful one. SILAC removes false positives in protein-interaction studies, reveals large-scale kinetics of proteomes and - as a quantitative phosphoproteomics technology - directly uncovers important points in the signalling pathways that control cellular decisions.
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              Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells.

              Dendritic cells have the remarkable property of presenting any incoming antigen. To do so they must not only capture antigens with high efficiency and broad specificity, but must also maximize their capacity to load class II molecules of the major histocompatibility complex (MHC) with antigenic peptides in order to present a large array of epitopes from different proteins, each at a sufficient copy number. Here we show that formation of peptide-MHC class II complexes is boosted by inflammatory stimuli that induce maturation of dendritic cells. In immature dendritic cells, class II molecules are rapidly internalized and recycled, turning over with a half-life of about 10 hours. Inflammatory stimuli induce a rapid and transient boost of class II synthesis, while the half-life of class II molecules increases to over 100 hours. These coordinated changes result in the rapid accumulation of a large number of long-lived peptide-loaded MHC class II molecules capable of stimulating T cells even after several days. The capacity of dendritic cells to load many antigenic peptides over a short period of initial exposure to inflammatory stimuli could favour presentation of infectious antigens.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                25 November 2013
                2013
                : 4
                : 399
                Affiliations
                [1] 1Department of Medicine, University of Cambridge , Cambridge, UK
                Author notes

                Edited by: Laura Santambrogio, Albert Einstein College of Medicine, USA

                Reviewed by: Masaaki Murakami, Osaka University, Japan; M. Karen Newell-Rogers, Texas A&M University, USA

                *Correspondence: Robert Busch, Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Box 157, Level 5, Hills Road, Cambridge CB2 0QQ, UK e-mail: rb468@ 123456medschl.cam.ac.uk

                Present address: Robert Busch, Department of Life Sciences, Whitelands College, University of Roehampton, Parkstead House, London SW15 4JD, UK e-mail: robert.busch@roehampton.ac.uk

                This article was submitted to Antigen Presenting Cell Biology, a section of the journal Frontiers in Immunology.

                Article
                10.3389/fimmu.2013.00399
                3839011
                dcb018ed-f3c6-46d8-9636-7a40cb1e381d
                Copyright © 2013 De Riva and Busch.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 August 2013
                : 08 November 2013
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 59, Pages: 7, Words: 5416
                Categories
                Immunology
                Mini Review

                Immunology
                antigen-presenting cell,mass spectrometry,protein turnover,major histocompatibility complex class ii,autoimmune pathogenesis,type 1 diabetes mellitus

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