寻常型天疱疮(PV)是一种潜在致命的自身免疫性水疱疾病,其特征是细胞-细胞脱离(或棘皮松解)和水疱形成。虽然与皮肤/粘膜起泡相关的信号机制正在阐明,针对PV特异性病理机制的特定治疗策略,特别是激酶信号,尚未建立。因此,本综述的目的是系统评估对棘皮松解和水疱形成至关重要的激酶类分子,因此是靶向治疗的候选分子。搜索了PubMed和Scopus数据库中的英文文章,包括在体外,在体内,以及研究激酶在PV中的作用的人体研究。我们选择了研究,重复提取数据并评估偏倚风险,根据系统评价和荟萃分析的首选报告项目(PRISMA)概述的方法报告结果.使用SYRCLE的偏倚风险工具对体内研究进行偏倚风险评估。纳入了35项符合PV激酶致病性标准的研究,绝大多数是使用PV血清(n=13)和PV-IgG(n=22)的实验模型。抑制激酶活性(p38MAPK,PKC,TK,c-Src,EGFR,ERK,mTOR,BTK,和CDK2)主要是通过药理学手段实现的。总的来说,我们发现大量证据表明,激酶抑制减少PV相关的磷酸化事件和角质形成细胞解离,防止棘层松解,并阻止水泡形成。然而,缺乏对标准化报告系统和所使用的实验方案/模型的坚持,确实限制了这些研究的内部和外部有效性.总之,这篇系统综述强调了PV棘层松解中激酶介导的致病细胞内事件,并提出了激酶信号作为转化研究的有希望的途径。特别是,本研究中鉴定和讨论的分子代表了PV中基于机制的干预措施开发的潜在候选物.
Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease characterized by cell-cell detachment (or acantholysis) and blister formation. While the signaling mechanisms that associate with skin/mucosal blistering are being elucidated, specific treatment strategies targeting PV-specific pathomechanisms, particularly kinase signaling, have yet to be established. Hence, the aim of this
review was to systematically evaluate molecules in the class of kinases that are essential for acantholysis and blister formation and are therefore candidates for targeted therapy. English articles from PubMed and Scopus databases were searched, and included in vitro, in vivo, and human studies that investigated the role of kinases in PV. We selected studies, extracted data and assessed risk of bias in duplicates and the results were reported according to the methodology outlined by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The risk of bias assessment was performed on in vivo studies utilizing SYRCLE\'s risk of bias tool. Thirty-five studies were included that satisfied the pathogenicity criterion of kinases in PV, the vast majority being experimental models that used PV sera (n = 13) and PV-IgG (n = 22). Inhibition of kinase activity (p38MAPK, PKC, TK, c-Src, EGFR, ERK, mTOR, BTK, and CDK2) was achieved mostly by pharmacological means. Overall, we found substantial evidence that kinase inhibition reduced PV-associated phosphorylation events and keratinocyte disassociation, prevented acantholysis, and blocked blister formation. However, the scarce adherence to standardized reporting systems and the experimental protocols/models used did limit the internal and external validity of these studies. In summary, this systematic
review highlighted the pathogenic intracellular events mediated by kinases in PV acantholysis and presented kinase signaling as a promising avenue for translational research. In particular, the molecules identified and discussed in this study represent potential candidates for the development of mechanism-based interventions in PV.