دورية أكاديمية
B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4.
| العنوان: | B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4. |
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| المؤلفون: | Afzali AM; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany.; Department of Neurology, Technical University of Munich School of Medicine and Health, Munich, Germany.; Munich Cluster for Systems Neurology, Munich, Germany., Nirschl L; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany., Sie C; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany., Pfaller M; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany., Ulianov O; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany., Hassler T; Biomedical Center (BMC), Institute for Immunology, Faculty of Medicine, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany., Federle C; Biomedical Center (BMC), Institute for Immunology, Faculty of Medicine, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany., Petrozziello E; Biomedical Center (BMC), Institute for Immunology, Faculty of Medicine, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany., Kalluri SR; Department of Neurology, Technical University of Munich School of Medicine and Health, Munich, Germany., Chen HH; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany., Tyystjärvi S; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany., Muschaweckh A; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany., Lammens K; Department of Biochemistry at the Gene Center, Ludwig-Maximilians-University, Munich, Germany., Delbridge C; Institute of Pathology, Technical University of Munich School of Medicine and Health, Munich, Germany.; Department of Neuropathology, Institute of Pathology, Technical University of Munich School of Medicine and Health, Munich, Germany., Büttner A; Institute of Forensic Medicine, Rostock University Medical Center, Rostock, Germany., Steiger K; Institute of Pathology, Technical University of Munich School of Medicine and Health, Munich, Germany., Seyhan G; Institute for Experimental Hematology, TranslaTUM Cancer Center, Technical University of Munich School of Medicine and Health, Munich, Germany., Ottersen OP; Division of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway., Öllinger R; Institute of Molecular Oncology and Functional Genomics, TranslaTUM Cancer Center, Technical University of Munich School of Medicine and Health, Munich, Germany., Rad R; Institute of Molecular Oncology and Functional Genomics, TranslaTUM Cancer Center, Technical University of Munich School of Medicine and Health, Munich, Germany., Jarosch S; Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich School of Medicine and Health, Munich, Germany., Straub A; Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich School of Medicine and Health, Munich, Germany., Mühlbauer A; Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich School of Medicine and Health, Munich, Germany., Grassmann S; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Hemmer B; Department of Neurology, Technical University of Munich School of Medicine and Health, Munich, Germany.; Munich Cluster for Systems Neurology, Munich, Germany., Böttcher JP; Institute of Molecular Immunology, Technical University of Munich School of Medicine and Health, Munich, Germany., Wagner I; Department of Pathology and Immunology, Division of Clinical Pathology, Geneva Faculty of Medicine, Centre Médical Universitaire, Geneva, Switzerland., Kreutzfeldt M; Department of Pathology and Immunology, Division of Clinical Pathology, Geneva Faculty of Medicine, Centre Médical Universitaire, Geneva, Switzerland., Merkler D; Department of Pathology and Immunology, Division of Clinical Pathology, Geneva Faculty of Medicine, Centre Médical Universitaire, Geneva, Switzerland., Pardàs IB; Institute for Computational Biology, Helmholtz Munich, Neuherberg, Germany., Schmidt Supprian M; Institute for Experimental Hematology, TranslaTUM Cancer Center, Technical University of Munich School of Medicine and Health, Munich, Germany., Buchholz VR; Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich School of Medicine and Health, Munich, Germany., Heink S; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany., Busch DH; Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich School of Medicine and Health, Munich, Germany.; German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany., Klein L; Biomedical Center (BMC), Institute for Immunology, Faculty of Medicine, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany., Korn T; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany. thomas.korn@tum.de.; Department of Neurology, Technical University of Munich School of Medicine and Health, Munich, Germany. thomas.korn@tum.de.; Munich Cluster for Systems Neurology, Munich, Germany. thomas.korn@tum.de. |
| المصدر: | Nature [Nature] 2024 Mar; Vol. 627 (8003), pp. 407-415. Date of Electronic Publication: 2024 Feb 21. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Basingstoke : Nature Publishing Group Original Publication: London, Macmillan Journals ltd. |
| مواضيع طبية MeSH: | Aquaporin 4*/deficiency , Aquaporin 4*/genetics , Aquaporin 4*/immunology , Aquaporin 4*/metabolism , Autoantibodies*/immunology , Autoantigens*/immunology , B-Lymphocytes*/immunology , B-Lymphocytes*/metabolism , Immune Tolerance* , Neuromyelitis Optica*/immunology , Neuromyelitis Optica*/metabolism, Animals ; Humans ; Mice ; AIRE Protein ; CD40 Antigens/immunology ; Germinal Center/cytology ; Germinal Center/immunology ; Receptors, Antigen, T-Cell/immunology ; T-Lymphocytes/immunology ; Thymus Gland/cytology ; Thymus Gland/immunology ; Thyroid Epithelial Cells/immunology ; Thyroid Epithelial Cells/metabolism ; Transcriptome |
| مستخلص: | Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen 1 . The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP4 2 . However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of Aqp4 in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4. (© 2024. The Author(s).) |
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| معلومات مُعتمدة: | P30 CA008748 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (AIRE Protein) 0 (AQP4 protein, human) 0 (Aqp4 protein, mouse) 0 (Aquaporin 4) 0 (Autoantibodies) 0 (Autoantigens) 0 (CD40 Antigens) MKM3CA6LT1 (interleukin-21) 0 (Receptors, Antigen, T-Cell) |
| تواريخ الأحداث: | Date Created: 20240221 Date Completed: 20240315 Latest Revision: 20240727 |
| رمز التحديث: | 20240727 |
| مُعرف محوري في PubMed: | PMC10937377 |
| DOI: | 10.1038/s41586-024-07079-8 |
| PMID: | 38383779 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1476-4687 |
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| DOI: | 10.1038/s41586-024-07079-8 |