An overview of JAK/STAT pathways and JAK inhibition in alopecia areata.
An overview of JAK/STAT pathways and JAK inhibition in alopecia areata.
复制标题
DOI：
10.3389/fimmu.2022.955035
复制
发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
斑秃（AA）是一种常见的自身免疫性疾病，其特征是非瘢痕性脱发，范围从头皮上的斑块到涉及整个身体的完全脱发。假设疾病发作是在毛囊免疫特权崩溃之后发生的，这导致自身肽/MHC表达沿着毛囊上皮增加。脱发与脓毒症自身反应性T细胞浸润毛囊有关。这一过程被认为使毛囊微环境从典型的稳态免疫状态向活跃的炎症状态倾斜。这种不平衡部分由特异性细胞因子的主导存在介导。虽然干扰素-γ（IFNγ）已被确定为AA发病机制中的关键参与者，但许多其他细胞因子也已被证明发挥关键作用。动物模型中的机制研究已经强调了常见γ链（γc）细胞因子（如IL-2、IL-7和IL-15）在加重疾病中的作用。IFNγ和γc细胞因子通过涉及Janus激酶（JAK）和信号转导子和转录激活子（STAT）的受体活化的途径进行信号传导。基于这些发现，JAK/STAT通路已被靶向用于临床环境中的治疗干预目的。病例报告和系列报道描述了使用小分子JAK抑制剂导致AA患者毛发再生。此外，新兴的临床试验结果显示出巨大的前景，并将JAK抑制剂定位为重度或难治性疾病患者的治疗策略。JAK抑制剂baricitinib的大规模临床试验证明了其疗效，导致FDA于2022年6月批准了首个治疗AA的药物。这篇综述旨在强调参与AA的各种细胞因子的JAK/STAT信号通路，以及靶向这些通路如何在实验室和临床环境中影响疾病结局。
Alopecia Areata (AA) is a common autoimmune disease characterized by non-scarring hair loss ranging from patches on the scalp to complete hair loss involving the entire body. Disease onset is hypothesized to follow the collapse of immune privilege of the hair follicle, which results in an increase in self-peptide/MHC expression along the follicular epithelium. Hair loss is associated with infiltration of the hair follicle with putatively self-reactive T cells. This process is thought to skew the hair follicle microenvironment away from a typically homeostatic immune state towards one of active inflammation. This imbalance is mediated in part by the dominating presence of specific cytokines. While interferon-γ (IFNγ) has been identified as the key player in AA pathogenesis, many other cytokines have also been shown to play pivotal roles. Mechanistic studies in animal models have highlighted the contribution of common gamma chain (γc) cytokines such as IL-2, IL-7, and IL-15 in augmenting disease. IFNγ and γc cytokines signal through pathways involving receptor activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Based on these findings, JAK/STAT pathways have been targeted for the purposes of therapeutic intervention in the clinical setting. Case reports and series have described use of small molecule JAK inhibitors leading to hair regrowth among AA patients. Furthermore, emerging clinical trial results show great promise and position JAK inhibitors as a treatment strategy for patients with severe or recalcitrant disease. Demonstrated efficacy from large-scale clinical trials of the JAK inhibitor baricitinib led to the first-in-disease FDA-approved treatment for AA in June of 2022. This review aims to highlight the JAK/STAT signaling pathways of various cytokines involved in AA and how targeting those pathways may impact disease outcomes in both laboratory and clinical settings.
登录
查看更多内容
影响因子：
3.6
作者：
Vandiver A;Girardi N;Alhariri J;Garza LA
通讯作者：
Garza LA
影响因子：
13.6
作者：
Dai, Zhenpeng;Wang, Eddy Hsi Chun;Christiano, Angela M.
通讯作者：
Christiano, Angela M.
影响因子：
--
作者：
Ebrahim, Adel Ali;Salem, Rehab Mohammed;Younis, Esraa Taha
通讯作者：
Younis, Esraa Taha
影响因子：
13.8
作者：
Damsky W;King BA
通讯作者：
King BA
影响因子：
13.6
作者：
Connell, Samuel J.;Jabbari, Ali
通讯作者：
Jabbari, Ali