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Scientific article
Open access
English

B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4

Published inNature, vol. 627, no. 8003, p. 407-415
Publication date2024-03
First online date2024-02-21
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.

eng
Keywords
  • Animals
  • Humans
  • Mice
  • AIRE Protein
  • Aquaporin 4 / deficiency
  • Aquaporin 4 / genetics
  • Aquaporin 4 / immunology
  • Aquaporin 4 / metabolism
  • Autoantibodies / immunology
  • Autoantigens / immunology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • CD40 Antigens / immunology
  • Germinal Center / cytology
  • Germinal Center / immunology
  • Immune Tolerance
  • Neuromyelitis Optica / immunology
  • Neuromyelitis Optica / metabolism
  • Receptors, Antigen, T-Cell / immunology
  • T-Lymphocytes / immunology
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Thyroid Epithelial Cells / immunology
  • Thyroid Epithelial Cells / metabolism
  • Transcriptome
Citation (ISO format)
AFZALI, Ali Maisam et al. B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4. In: Nature, 2024, vol. 627, n° 8003, p. 407–415. doi: 10.1038/s41586-024-07079-8
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Article (Published version)
Identifiers
ISSN of the journal0028-0836
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