B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4

Ali Maisam Afzali, Lucy Nirschl, Christopher Sie, Monika Pfaller, Oleksii Ulianov, Tobias Hassler, Christine Federle, Elisabetta Petrozziello, Sudhakar Reddy Kalluri, Hsin Hsiang Chen, Sofia Tyystjärvi, Andreas Muschaweckh, Katja Lammens, Claire Delbridge, Andreas Büttner, Katja Steiger, Gönül Seyhan, Ole Petter Ottersen, Rupert Öllinger, Roland Rad, Sebastian Jarosch, Adrian Straub, Anton Mühlbauer, Simon Grassmann, Bernhard Hemmer, Jan P. Böttcher, Ingrid Wagner, Mario Kreutzfeldt, Doron Merkler, Irene Bonafonte Pardàs, Marc Schmidt Supprian, Veit R. Buchholz, Sylvia Heink, Dirk H. Busch, Ludger Klein and Thomas Korn ()
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Ali Maisam Afzali: Technical University of Munich School of Medicine and Health
Lucy Nirschl: Technical University of Munich School of Medicine and Health
Christopher Sie: Technical University of Munich School of Medicine and Health
Monika Pfaller: Technical University of Munich School of Medicine and Health
Oleksii Ulianov: Technical University of Munich School of Medicine and Health
Tobias Hassler: Faculty of Medicine, Ludwig-Maximilians-University Munich
Christine Federle: Faculty of Medicine, Ludwig-Maximilians-University Munich
Elisabetta Petrozziello: Faculty of Medicine, Ludwig-Maximilians-University Munich
Sudhakar Reddy Kalluri: Technical University of Munich School of Medicine and Health
Hsin Hsiang Chen: Technical University of Munich School of Medicine and Health
Sofia Tyystjärvi: Technical University of Munich School of Medicine and Health
Andreas Muschaweckh: Technical University of Munich School of Medicine and Health
Katja Lammens: Ludwig-Maximilians-University
Claire Delbridge: Technical University of Munich School of Medicine and Health
Andreas Büttner: Rostock University Medical Center
Katja Steiger: Technical University of Munich School of Medicine and Health
Gönül Seyhan: Technical University of Munich School of Medicine and Health
Ole Petter Ottersen: University of Oslo
Rupert Öllinger: Technical University of Munich School of Medicine and Health
Roland Rad: Technical University of Munich School of Medicine and Health
Sebastian Jarosch: Technical University of Munich School of Medicine and Health
Adrian Straub: Technical University of Munich School of Medicine and Health
Anton Mühlbauer: Technical University of Munich School of Medicine and Health
Simon Grassmann: Memorial Sloan Kettering Cancer Center
Bernhard Hemmer: Technical University of Munich School of Medicine and Health
Jan P. Böttcher: Technical University of Munich School of Medicine and Health
Ingrid Wagner: Centre Médical Universitaire
Mario Kreutzfeldt: Centre Médical Universitaire
Doron Merkler: Centre Médical Universitaire
Irene Bonafonte Pardàs: Helmholtz Munich
Marc Schmidt Supprian: Technical University of Munich School of Medicine and Health
Veit R. Buchholz: Technical University of Munich School of Medicine and Health
Sylvia Heink: Technical University of Munich School of Medicine and Health
Dirk H. Busch: Technical University of Munich School of Medicine and Health
Ludger Klein: Faculty of Medicine, Ludwig-Maximilians-University Munich
Thomas Korn: Technical University of Munich School of Medicine and Health

Nature, 2024, vol. 627, issue 8003, 407-415

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07079-8

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