Neys Stefan F H, Hendriks Rudi W, Corneth Odilia B J
Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands.
Front Cell Dev Biol. 2021 Jun 4;9:668131. doi: 10.3389/fcell.2021.668131. eCollection 2021.
Bruton's tyrosine kinase (BTK) was discovered due to its importance in B cell development, and it has a critical role in signal transduction downstream of the B cell receptor (BCR). Targeting of BTK with small molecule inhibitors has proven to be efficacious in several B cell malignancies. Interestingly, recent studies reveal increased BTK protein expression in circulating resting B cells of patients with systemic autoimmune disease (AID) compared with healthy controls. Moreover, BTK phosphorylation following BCR stimulation was enhanced. In addition to its role in BCR signaling, BTK is involved in many other pathways, including pattern recognition, Fc, and chemokine receptor signaling in B cells and myeloid cells. This broad involvement in several immunological pathways provides a rationale for the targeting of BTK in the context of inflammatory and systemic AID. Accordingly, numerous and preclinical studies support the potential of BTK targeting in these conditions. Efficacy of BTK inhibitors in various inflammatory and AID has been demonstrated or is currently evaluated in clinical trials. In addition, very recent reports suggest that BTK inhibition may be effective as immunosuppressive therapy to diminish pulmonary hyperinflammation in coronavirus disease 2019 (COVID-19). Here, we review BTK's function in key signaling pathways in B cells and myeloid cells. Further, we discuss recent advances in targeting BTK in inflammatory and autoimmune pathologies.
布鲁顿酪氨酸激酶（BTK）因其在B细胞发育中的重要性而被发现，它在B细胞受体（BCR）下游的信号转导中起关键作用。事实证明，用小分子抑制剂靶向BTK在几种B细胞恶性肿瘤中是有效的。有趣的是，最近的研究表明，与健康对照相比，系统性自身免疫性疾病（AID）患者循环静止B细胞中的BTK蛋白表达增加。此外，BCR刺激后BTK的磷酸化增强。除了在BCR信号传导中的作用外，BTK还参与许多其他途径，包括B细胞和髓系细胞中的模式识别、Fc和趋化因子受体信号传导。BTK在多种免疫途径中的广泛参与为在炎症性和全身性AID背景下靶向BTK提供了理论依据。因此，大量的临床前研究支持了在这些情况下靶向BTK的潜力。BTK抑制剂在各种炎症和AID中的疗效已在临床试验中得到证实或正在评估。此外，最近的报道表明，BTK抑制作为免疫抑制疗法可能有效减轻2019冠状病毒病（COVID-19）中的肺部过度炎症。在这里，我们综述了BTK在B细胞和髓系细胞关键信号通路中的功能。此外，我们讨论了在炎症和自身免疫性疾病中靶向BTK的最新进展。
