B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4

Afzali, Ali Maisam; Nirschl, Lucy; Sie, Christopher; Pfaller, Monika; Ulianov, Oleksii; Hassler, Tobias; Federle, Christine; Petrozziello, Elisabetta; Kalluri, Sudhakar Reddy; Chen, Hsin Hsiang; Tyystjaervi, Sofia; Muschaweckh, Andreas; Lammens, Katja; Delbridge, Claire; Buettner, Andreas; Steiger, Katja; Seyhan, Gonul; Ottersen, Ole Petter; Ollinger, Rupert; Rad, Roland; Jarosch, Sebastian; Straub, Adrian; Muehlbauer, Anton; Grassmann, Simon; Hemmer, Bernhard; Boettcher, Jan P.; Wagner, Ingrid; Kreutzfeldt, Mario; Merkler, Doron; Pardas, Irene Bonafonte; Supprian, Marc Schmidt; Buchholz, Veit R.; Heink, Sylvia; Busch, Dirk H.; Klein, Ludger und Korn, Thomas (2024): B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4. In: Nature, Nr. 627: S. 407-415

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. The immune system is tolerized against the neuromyelitis optica autoantigen AQP4 by thymic B cells, which present their endogenous AQP4 to AQP4-reactive thymocytes.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198