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Bruton's tyrosine kinase is a possible therapeutic target in microscopic polyangiitis

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Title: Bruton's tyrosine kinase is a possible therapeutic target in microscopic polyangiitis
Authors: Nakade, Issei Browse this author
Tamura, Yuto Browse this author
Hashimoto, Fuyu Browse this author
Ariza, Yuko Browse this author
Hotta, Shingo Browse this author
Fujigaya, Hirofumi Browse this author
Arai, Suishin Browse this author
Taniguchi, Mai Browse this author
Ogawa, Hodaka Browse this author
Nishibata, Yuka Browse this author
Masuda, Sakiko Browse this author →KAKEN DB
Nakazawa, Daigo Browse this author →KAKEN DB
Tomaru, Utano Browse this author →KAKEN DB
Ishizu, Akihiro Browse this author →KAKEN DB
Keywords: MPO-ANCA
Btk inhibitor
Issue Date: 6-Nov-2023
Publisher: BMC
Journal Title: Arthritis Research & Therapy
Volume: 25
Start Page: 215
Publisher DOI: 10.1186/s13075-023-03201-9
PMID: 37932784
Abstract: Background: Bruton's tyrosine kinase (Btk) is an enzyme expressed in leukocytes other than T lymphocytes and plasma cells and involved in B-cell receptor- and Fcγ receptor (FcγR)-mediated signal transduction. Btk inhibitors potentially suppress autoantibody production due to the expected inhibitory ability of B lymphocyte differentiation into antibody-producing plasma cells and reduce FcγR-mediated neutrophil activation, including the release of neutrophil extracellular traps (NETs). Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis characterized by the pathogenic autoantibody, antineutrophil cytoplasmic antibody (ANCA) that reacts with myeloperoxidase (MPO). MPO and MPO-ANCA immune complex (IC)-induced FcγR-mediated NETs are critically involved in MPA pathogenesis. This study aimed to demonstrate the therapeutic efficacy of the Btk inhibitor tirabrutinib on MPA. Methods: Various doses of tirabrutinib or vehicle were orally administered to Sprague-Dawley rats daily. Four weeks later, the number of peripheral B lymphocytes was counted, and Btk phosphorylation in B lymphocytes was evaluated by flow cytometry. Human peripheral blood neutrophils were stimulated by MPO and anti-MPO antibody ICs (MPO and anti-MPO-ICs), and Btk and its downstream Vav phosphorylation were assessed by western blotting. The effects of tirabrutinib on MPO and anti-MPO-IC-induced NET formation were examined in vitro. Wistar Kyoto rats were immunized with human MPO to induce experimental MPA and given drug-free or tirabrutinib-containing feed (0.0037% or 0.012%) from day 0 or 28. All rats were euthanized on day 42 for serological and histological evaluation. Results: Tirabrutinib inhibited Btk phosphorylation without decreasing B lymphocytes in vivo. Neutrophil Btk and Vav were phosphorylated when stimulated with MPO and anti-MPO-ICs. Tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA in a dose-dependent manner in vivo. Although MPO-ANCA production was not affected, NET-forming neutrophils in the blood were significantly reduced by tirabrutinib. Conclusions: The Btk inhibitor tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA by reducing NET-forming neutrophils but not decreasing MPO-ANCA titer in vivo. This study suggests that Btk is a possible therapeutic target in MPA.
Type: article
Appears in Collections:保健科学院・保健科学研究院 (Graduate School of Health Sciences / Faculty of Health Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 石津 明洋

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