Inhibitors of Bruton's tyrosine kinase as emerging therapeutic strategy in autoimmune diseases

IF 9.2 1区 医学 Q1 IMMUNOLOGY Autoimmunity reviews Pub Date : 2024-03-22 DOI:10.1016/j.autrev.2024.103532
Mirre De Bondt , Janne Renders , Sofie Struyf , Niels Hellings
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Abstract

Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor signal transducer, initially identified as an essential signaling molecule for B cells, with genetic mutations resulting in a disorder characterized by disturbed B cell and antibody development. Subsequent research revealed the critical role of BTK in the functionality of monocytes, macrophages and neutrophils. Various immune cells, among which B cells and neutrophils, rely on BTK activity for diverse signaling pathways downstream of multiple receptors, which makes this kinase an ideal target to treat hematological malignancies and autoimmune diseases. First-generation BTK inhibitors are already on the market to treat hematological disorders. It has been demonstrated that B cells and myeloid cells play a significant role in the pathogenesis of different autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren's syndrome. Consequently, second-generation BTK inhibitors are currently being developed to treat these disorders. Despite the acknowledged involvement of BTK in various cell types, the focus on B cells often overshadows its impact on innate immune cells. Among these cell types, neutrophils are often underestimated in the pathogenesis of autoimmune diseases. In this narrative review, the function of BTK in different immune cell subsets is discussed, after which an overview is provided of different upcoming BTK inhibitors tested for treatment of autoimmune diseases. Special attention is paid to BTK inhibition and its effect on neutrophil biology.

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布鲁顿酪氨酸激酶抑制剂作为自身免疫性疾病的新兴治疗策略。
布鲁顿酪氨酸激酶(BTK)是一种细胞质非受体信号转换器,最初被认为是 B 细胞的重要信号分子,基因突变导致 B 细胞和抗体发育紊乱。随后的研究发现,BTK 对单核细胞、巨噬细胞和中性粒细胞的功能起着关键作用。各种免疫细胞,包括 B 细胞和中性粒细胞,都依赖 BTK 的活性来实现多种受体下游的信号通路,这使得这种激酶成为治疗血液恶性肿瘤和自身免疫性疾病的理想靶点。第一代 BTK 抑制剂已经上市,用于治疗血液病。研究表明,B 细胞和骨髓细胞在多发性硬化症、类风湿性关节炎、系统性红斑狼疮和原发性斯约格伦综合征等不同自身免疫性疾病的发病机制中起着重要作用。因此,目前正在开发第二代 BTK 抑制剂来治疗这些疾病。尽管 BTK 参与各种细胞类型的研究已得到公认,但对 B 细胞的关注往往掩盖了它对先天性免疫细胞的影响。在这些细胞类型中,中性粒细胞在自身免疫性疾病发病机制中的作用往往被低估。在这篇叙述性综述中,讨论了 BTK 在不同免疫细胞亚群中的功能,然后概述了即将测试用于治疗自身免疫性疾病的各种 BTK 抑制剂。其中特别关注 BTK 抑制及其对中性粒细胞生物学的影响。
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来源期刊
Autoimmunity reviews
Autoimmunity reviews 医学-免疫学
CiteScore
24.70
自引率
4.40%
发文量
164
审稿时长
21 days
期刊介绍: Autoimmunity Reviews is a publication that features up-to-date, structured reviews on various topics in the field of autoimmunity. These reviews are written by renowned experts and include demonstrative illustrations and tables. Each article will have a clear "take-home" message for readers. The selection of articles is primarily done by the Editors-in-Chief, based on recommendations from the international Editorial Board. The topics covered in the articles span all areas of autoimmunology, aiming to bridge the gap between basic and clinical sciences. In terms of content, the contributions in basic sciences delve into the pathophysiology and mechanisms of autoimmune disorders, as well as genomics and proteomics. On the other hand, clinical contributions focus on diseases related to autoimmunity, novel therapies, and clinical associations. Autoimmunity Reviews is internationally recognized, and its articles are indexed and abstracted in prestigious databases such as PubMed/Medline, Science Citation Index Expanded, Biosciences Information Services, and Chemical Abstracts.
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