Singh Umesh, Bernstein Jonathan A
University of Cincinnati College of Medicine Cincinnati Ohio USA.
Clin Transl Allergy. 2022 Oct 12;12(10):e12202. doi: 10.1002/clt2.12202. eCollection 2022 Oct.
Kallikrein-bradykinin-forming cascade is known to cause hereditary angioedema (HAE) acute angioedema (AE) attacks. Further research of HAE attacks is needed to explain disease heterogeneity, predict treatment response and identify biomarkers for monitoring HAE attacks. Differential expression of the microvascular endothelial cell-surface receptors for example, g-C1qR, cytokeratin-1, and plasminogen-activator-urokinase-receptor (PLAUR) were hypothesized as biomarkers of AE attacks.
To understand HAE attacks, the differentially expressed genes (DEGs) in RNAseq and mi-RNAseq data of total RNA extracted from skin biopsies of lesional versus non-lesional skin collected during and between attacks in Type-1 HAE patients ( = 11; F:M = 8:3) were compared. To understand the HAE variants, DEGs in skin biopsies from HAE with normal C1 inhibitor ( = 5, F:M = 5:0), and non-HAE ( = 7; F:M = 3:4) patients were compared. Gene-set enrichment analyses and regulator effects analysis of these DEGs identified biological pathways in HAE attacks and their regulators.
PLAUR gene, encoding urokinase-type plasminogen activator (u-PAR), was constitutively over-expressed in HAE-Type-1 versus non-HAE controls suggestive of overactive u-PAR-mediated signaling via binding to Factor-XII. Baseline PLAUR expression was associated with severe AE ( = 0.05). The 18 significant DEGs investigated between baseline and AE attack samples in Type1-HAE were enriched in beta1/beta3-integrin cell surface interactions and IL-6-mediated signaling. Regulator effects analysis suggests a role for IL-1b in HAE flares. AKT2, the mRNA regulated by the differentially-expressed miR-184A, was also associated with HAE attacks.
Angiopoetin-activated 1-integrin signaling pathways causing endothelial destabilization, and avid binding of factor XII to u-PAR are possible novel mechanisms for progression of the endothelial kinin-bradykinin-forming cascade in HAE attacks.
已知激肽释放酶-缓激肽形成级联反应会引发遗传性血管性水肿（HAE）急性血管性水肿（AE）发作。需要对HAE发作进行进一步研究，以解释疾病异质性、预测治疗反应并确定监测HAE发作的生物标志物。微血管内皮细胞表面受体（例如，g-C1qR、细胞角蛋白-1和纤溶酶原激活物-尿激酶受体（PLAUR））的差异表达被假定为AE发作的生物标志物。
为了解HAE发作情况，比较了1型HAE患者（n = 11；女性：男性 = 8:3）在发作期间和发作间隔期从病变皮肤与非病变皮肤活检组织中提取的总RNA的RNA测序和微小RNA测序数据中的差异表达基因（DEG）。为了解HAE变体，比较了C1抑制剂正常的HAE患者（n = 5；女性：男性 = 5:0）和非HAE患者（n = 7；女性：男性 = 3:4）皮肤活检组织中的DEG。对这些DEG进行基因集富集分析和调节因子效应分析，确定了HAE发作中的生物途径及其调节因子。
编码尿激酶型纤溶酶原激活物（u-PAR）的PLAUR基因在1型HAE中与非HAE对照相比持续过度表达，提示通过与因子XII结合，u-PAR介导的信号传导过度活跃。基线PLAUR表达与严重AE相关（P = 0.05）。在1型HAE基线样本与AE发作样本之间研究的18个显著DEG富含β1/β3整合素细胞表面相互作用和IL-6介导的信号传导。调节因子效应分析表明IL-1b在HAE发作中起作用。由差异表达的miR-184A调节的mRNA AKT2也与HAE发作相关。
血管生成素激活的1-整合素信号通路导致内皮细胞不稳定，以及因子XII与u-PAR的强烈结合，可能是HAE发作中内皮激肽释放酶-缓激肽形成级联反应进展的新机制。
