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Afzali, A.M.* ; Nirschl, L.* ; Sie, C.* ; Pfaller, M.* ; Ulianov, O.* ; Hassler, T.* ; Federle, C.* ; Petrozziello, E.* ; Kalluri, S.R.* ; Chen, H.H.* ; Tyystjärvi, S.* ; Muschaweckh, A.* ; Lammens, K.* ; Delbridge, C.* ; Büttner, A.* ; Steiger, K.* ; Seyhan, G.* ; Ottersen, O.P.* ; Öllinger, R.* ; Rad, R.* ; Jarosch, S.* ; Straub, A.* ; Mühlbauer, A.* ; Grassmann, S.* ; Hemmer, B.* ; Böttcher, J.P.* ; Wagner, I.* ; Kreutzfeldt, M.* ; Merkler, D.* ; Bonafonte Pardás, I. ; Schmidt Supprian, M.* ; Buchholz, V.R.* ; Heink, S.* ; Busch, D.H.* ; Klein, L.* ; Korn, T.*

B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4.

Nature 627, 407-415 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Mhc Class-ii; T-cells; Dendritic Cells; Self-antigens; Aquaporin 4; Expression; Thymus; Repertoire; Generation; Population
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 627, Issue: 8003, Pages: 407-415 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants Technische Universitaet Muenchen