Brescacin Adriano, Baig Zunaira, Bhinder Jaspreet, Lin Sen, Brar Lovejot, Cirillo Nicola
Melbourne Dental School, Faculty of Medicine, Dentistry & Health Sciences, University of Melbourne, Carlton, Victoria, Australia.
J Cell Physiol. 2022 Jul;237(7):2825-2837. doi: 10.1002/jcp.30784. Epub 2022 May 26.
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.
寻常型天疱疮（PV）是一种潜在致命的自身免疫性水疱病，其特征为细胞间分离（或棘层松解）和水疱形成。虽然与皮肤/黏膜水疱形成相关的信号传导机制正在逐步阐明，但针对PV特异性发病机制，尤其是激酶信号传导的特异性治疗策略尚未确立。因此，本综述的目的是系统评估激酶类分子，这些分子对于棘层松解和水疱形成至关重要，因此是靶向治疗的候选分子。检索了来自PubMed和Scopus数据库的英文文章，纳入了研究激酶在PV中作用的体外、体内和人体研究。我们筛选了研究，提取了数据，并评估了重复研究中的偏倚风险，结果根据系统评价和Meta分析的首选报告项目（PRISMA）概述的方法进行报告。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中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。激酶活性（p38丝裂原活化蛋白激酶、蛋白激酶C、酪氨酸激酶、c-Src、表皮生长因子受体、细胞外信号调节激酶、哺乳动物雷帕霉素靶蛋白、布鲁顿酪氨酸激酶和细胞周期蛋白依赖性激酶2）的抑制大多通过药理学方法实现。总体而言，我们发现大量证据表明激酶抑制可减少与PV相关的磷酸化事件和角质形成细胞解离，预防棘层松解，并阻止水疱形成。然而，对标准化报告系统和所使用的实验方案/模型的缺乏严格遵循确实限制了这些研究的内部和外部有效性。总之，本系统综述突出了激酶在PV棘层松解中介导的致病性细胞内事件，并将激酶信号传导作为转化研究的一个有前景的途径。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分子。
