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Open Access 01-12-2023 | Neuromyelitis Optica Spectrum Disease | Research

Bruton’s tyrosine kinase-bearing B cells and microglia in neuromyelitis optica spectrum disorder

Authors: Ye Liu, Zhenning Huang, Tian-Xiang Zhang, Bin Han, Guili Yang, Dongmei Jia, Li Yang, Qiang Liu, Alexander Y. L. Lau, Friedemann Paul, Alexei Verkhratsky, Fu-Dong Shi, Chao Zhang

Published in: Journal of Neuroinflammation | Issue 1/2023

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte–microglia interaction, which both contribute to evolution of NMOSD lesions.

Main body

Through transcriptomic and flow cytometry analyses, we found that Bruton’s tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes–microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes.

Conclusions

Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target.

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Title: Bruton’s tyrosine kinase-bearing B cells and microglia in neuromyelitis optica spectrum disorder
Authors: Ye Liu
Zhenning Huang
Tian-Xiang Zhang
Bin Han
Guili Yang
Dongmei Jia
Li Yang
Qiang Liu
Alexander Y. L. Lau
Friedemann Paul
Alexei Verkhratsky
Fu-Dong Shi
Chao Zhang
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Neuromyelitis Optica Spectrum Disease
Zanubrutinib
Published in: Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-023-02997-2

2024 ASCO Annual Meeting

Springer Medicine

Bruton’s tyrosine kinase-bearing B cells and microglia in neuromyelitis optica spectrum disorder

Abstract

Background

Main body

Conclusions

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Main body

Conclusions

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