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      Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases

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          Abstract

          DO (HLA-DO, in human; murine H2-O) is a highly conserved nonclassical major histocompatibility complex class II (MHC II) accessory molecule mainly expressed in the thymic medulla and B cells. Previous reports have suggested possible links between DO and autoimmunity, Hepatitis C (HCV) infection, and cancer, but the mechanism of how DO contributes to these diseases remains unclear. Here, using a combination of various in vivo approaches, including peptide elution, mixed lymphocyte reaction, T-cell receptor (TCR) deep sequencing, tetramer-guided naïve CD4 T-cell precursor enumeration, and whole-body imaging, we report that DO affects the repertoire of presented self-peptides by B cells and thymic epithelium. DO induces differential effects on epitope presentation and thymic selection, thereby altering CD4 T-cell precursor frequencies. Our findings were validated in two autoimmune disease models by demonstrating that lack of DO increases autoreactivity and susceptibility to autoimmune disease development.

          Abstract

          A combination of cellular, molecular and in vivo approaches reveals that the non-classical MHC class II chaperone DO controls CD4 T cell thymic selection; its absence leads to susceptibility to two murine autoimmune diseases, collagen-induced arthritis and experimental autoimmune encephalomyelitis.

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          Most cited references61

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          Myelin Oligodendrocyte Glycoprotein–specific T Cell Receptor Transgenic Mice Develop Spontaneous Autoimmune Optic Neuritis

          Multiple sclerosis (MS) is considered to be an autoimmune disease of the central nervous system (CNS) that in many patients first presents clinically as optic neuritis. The relationship of optic neuritis to MS is not well understood. We have generated novel T cell receptor (TCR) transgenic mice specific for myelin oligodendrocyte glycoprotein (MOG). MOG-specific transgenic T cells are not deleted nor tolerized and are functionally competent. A large proportion (>30%) of MOG-specific TCR transgenic mice spontaneously develop isolated optic neuritis without any clinical nor histological evidence of experimental autoimmune encephalomyelitis (EAE). Optic neuritis without EAE could also be induced in these mice by sensitization with suboptimal doses of MOG. The predilection of these mice to develop optic neuritis is associated with higher expression of MOG in the optic nerve than in the spinal cord. These results demonstrate that clinical manifestations of CNS autoimmune disease will vary depending on the identity of the target autoantigen and that MOG-specific T cell responses are involved in the genesis of isolated optic neuritis.
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            Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide.

            An influenza virus peptide binds to HLA-DR1 in an extended conformation with a pronounced twist. Thirty-five per cent of the peptide surface is accessible to solvent and potentially available for interaction with the antigen receptor on T cells. Pockets in the peptide-binding site accommodate five of the thirteen side chains of the bound peptide, and explain the peptide specificity of HLA-DR1. Twelve hydrogen bonds between conserved HLA-DR1 residues and the main chain of the peptide provide a universal mode of peptide binding, distinct from the strategy used by class I histocompatibility proteins.
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              The MHC locus and genetic susceptibility to autoimmune and infectious diseases

              In the past 50 years, variants in the major histocompatibility complex (MHC) locus, also known as the human leukocyte antigen (HLA), have been reported as major risk factors for complex diseases. Recent advances, including large genetic screens, imputation, and analyses of non-additive and epistatic effects, have contributed to a better understanding of the shared and specific roles of MHC variants in different diseases. We review these advances and discuss the relationships between MHC variants involved in autoimmune and infectious diseases. Further work in this area will help to distinguish between alternative hypotheses for the role of pathogens in autoimmune disease development. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1207-1) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: Resources
                Role: MethodologyRole: ResourcesRole: Validation
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Academic Editor
                Journal
                PLoS Biol
                PLoS Biol
                plos
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, CA USA )
                1544-9173
                1545-7885
                18 February 2020
                February 2020
                18 February 2020
                : 18
                : 2
                : e3000590
                Affiliations
                [1 ] Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [2 ] Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [3 ] Mass Spectrometry and Proteomics Core, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [4 ] Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                National Jewish Medical and Research Center/Howard Hughes Medical Institute, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-8870-5993
                http://orcid.org/0000-0001-5270-3849
                http://orcid.org/0000-0002-3096-4754
                http://orcid.org/0000-0002-8127-1720
                Article
                PBIOLOGY-D-19-02166
                10.1371/journal.pbio.3000590
                7028248
                32069316
                a329cff4-481f-42e5-9dd0-a5903fa9fd98
                © 2020 Welsh et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 26 July 2019
                : 13 January 2020
                Page count
                Figures: 8, Tables: 0, Pages: 29
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R21AI101987
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R01AI120634
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100002570, American Association of Immunologists;
                Award ID: AAI Careers in Immunology Fellowship Award
                Award Recipient :
                This work was funded by grants from the National Institutes of Allergy and Infection Diseases: R21AI101987, R01AI120634 (SS-N), and AAI Careers in Immunology Fellowship Award (SS-N). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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