B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4.

1. Nature. 2024 Mar;627(8003):407-415. doi: 10.1038/s41586-024-07079-8. Epub 2024 Feb 21.

B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4.

Afzali AM(1)(2)(3), Nirschl L(1), Sie C(1), Pfaller M(1), Ulianov O(1), Hassler T(4), Federle C(4), Petrozziello E(4), Kalluri SR(2), Chen HH(1), Tyystjärvi S(1), Muschaweckh A(1), Lammens K(5), Delbridge C(6)(7), Büttner A(8), Steiger K(6), Seyhan G(9), Ottersen OP(10), Öllinger R(11), Rad R(11), Jarosch S(12), Straub A(12), Mühlbauer A(12), Grassmann S(13), Hemmer B(2)(3), Böttcher JP(14), Wagner I(15), Kreutzfeldt M(15), Merkler D(15), Pardàs IB(16), Schmidt Supprian M(9), Buchholz VR(12), Heink S(1), Busch DH(12)(17), Klein L(4), Korn T(18)(19)(20).

Author information: (1)Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany. (2)Department of Neurology, Technical University of Munich School of Medicine and Health, Munich, Germany. (3)Munich Cluster for Systems Neurology, Munich, Germany. (4)Biomedical Center (BMC), Institute for Immunology, Faculty of Medicine, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany. (5)Department of Biochemistry at the Gene Center, Ludwig-Maximilians-University, Munich, Germany. (6)Institute of Pathology, Technical University of Munich School of Medicine and Health, Munich, Germany. (7)Department of Neuropathology, Institute of Pathology, Technical University of Munich School of Medicine and Health, Munich, Germany. (8)Institute of Forensic Medicine, Rostock University Medical Center, Rostock, Germany. (9)Institute for Experimental Hematology, TranslaTUM Cancer Center, Technical University of Munich School of Medicine and Health, Munich, Germany. (10)Division of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. (11)Institute of Molecular Oncology and Functional Genomics, TranslaTUM Cancer Center, Technical University of Munich School of Medicine and Health, Munich, Germany. (12)Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich School of Medicine and Health, Munich, Germany. (13)Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14)Institute of Molecular Immunology, Technical University of Munich School of Medicine and Health, Munich, Germany. (15)Department of Pathology and Immunology, Division of Clinical Pathology, Geneva Faculty of Medicine, Centre Médical Universitaire, Geneva, Switzerland. (16)Institute for Computational Biology, Helmholtz Munich, Neuherberg, Germany. (17)German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany. (18)Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Munich, Germany. thomas.korn@tum.de. (19)Department of Neurology, Technical University of Munich School of Medicine and Health, Munich, Germany. thomas.korn@tum.de. (20)Munich Cluster for Systems Neurology, Munich, Germany. thomas.korn@tum.de.

Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen1. The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP42. 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).

DOI: 10.1038/s41586-024-07079-8 PMCID: PMC10937377 PMID: 38383779 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.