PDF(Pubmed)
Abstract：
Systemic lupus erythematosus (SLE, lupus) is a debilitating, multisystem autoimmune disease that can affect any organ in the body. The disease is characterized by circulating autoantibodies that accumulate in organs and tissues, which triggers an inflammatory response that can cause permanent damage leading to significant morbidity and mortality. Lyn, a member of the Src family of non-receptor protein tyrosine kinases, is highly implicated in SLE as remarkably both mice lacking Lyn or expressing a gain-of-function mutation in Lyn develop spontaneous lupus-like disease due to altered signaling in B lymphocytes and myeloid cells, suggesting its expression or activation state plays a critical role in maintaining tolerance. The past 30 years of research has begun to elucidate the role of Lyn in a duplicitous signaling network of activating and inhibitory immunoreceptors and related targets, including interactions with the interferon regulatory factor family in the toll-like receptor pathway. Gain-of-function mutations in Lyn have now been identified in human cases and like mouse models, cause severe systemic autoinflammation. Studies of Lyn in SLE patients have presented mixed findings, which may reflect the heterogeneity of disease processes in SLE, with impairment or enhancement in Lyn function affecting subsets of SLE patients that may be a means of stratification. In this review, we present an overview of the phosphorylation and protein-binding targets of Lyn in B lymphocytes and myeloid cells, highlighting the structural domains of the protein that are involved in its function, and provide an update on studies of Lyn in SLE patients.
摘要：
系统性红斑狼疮（SLE，狼疮)是一种使人衰弱的疾病，可以影响体内任何器官的多系统自身免疫性疾病。该疾病的特征是循环自身抗体在器官和组织中积累，这会引发炎症反应，导致永久性损伤，导致显著的发病率和死亡率。林,非受体蛋白酪氨酸激酶Src家族的成员，与SLE密切相关，因为缺乏Lyn或在Lyn中表达功能获得突变的小鼠由于B淋巴细胞和骨髓细胞中的信号传导改变而发展为自发性狼疮样疾病，提示其表达或激活状态在维持耐受性中起关键作用。过去30年的研究已经开始阐明Lyn在激活和抑制免疫受体和相关靶标的双重信号网络中的作用。包括与toll样受体途径中干扰素调节因子家族的相互作用。现在已经在人类病例和小鼠模型中发现了Lyn的功能增益突变，引起严重的全身性自身炎症。对Lyn在SLE患者中的研究提出了不同的发现，这可能反映了SLE疾病过程的异质性，Lyn功能受损或增强会影响SLE患者的亚群，这可能是分层的一种手段。在这次审查中,我们概述了B淋巴细胞和骨髓细胞中Lyn的磷酸化和蛋白质结合靶标，突出蛋白质的结构域参与其功能，并提供Lyn在SLE患者中的最新研究。
