Kuo Kuang-Che, Yang Ya-Ling, Lo Mao-Hung, Cai Xin-Yuan, Guo Mindy Ming-Huey, Kuo Ho-Chang, Huang Ying-Hsien
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
Diagnostics (Basel). 2021 Nov 3;11(11):2035. doi: 10.3390/diagnostics11112035.
Kawasaki disease (KD) is a form of febrile vasculitis that primarily occurs in children. It can cause inflammation of the coronary arteries, which leads to aneurysms. The pathogenesis of coronary arteries may be associated with apoptosis or pyroptosis mediated by caspases activity, but this idea has not been discussed much in KD.
We enrolled 236 participants in this study. In the Affymetrix GeneChip Human Transcriptome Array 2.0 study, there were 18 KD patients analyzed prior to receiving intravenous immunoglobulin (IVIG) treatment, at least 3 weeks after IVIG treatment, and 36 non-KD control subjects. We also recruited 24 KD patients prior to receiving IVIG treatment, at least 3 weeks after IVIG treatment, and 24 non-KD control subjects for Illumina HumanMethylation450 BeadChip study. A separate cohort of 134 subjects was analyzed to validate real-time quantitative PCR.
The mRNA levels of caspase-1, -3, -4, and -5 were significantly increased in KD patients compared with control subjects ( < 0.05). After administration of IVIG, the expression of these genes decreased considerably. Of particular note, the methylation status of the CpG sites of the caspase-4 and -5 genes demonstrated significant opposite tendencies between the KD patients and controls. Furthermore, compared with patients who responded to IVIG, refractory KD patients had a lower expression of the caspase-3 gene prior to IVIG treatment.
Our study is the first to report the upregulation of pyroptotic caspase-1, -4, and -5 in peripheral leukocytes of KD patients. Moreover, the expression of caspase-3 may be associated with IVIG resistance in KD.
川崎病（KD）是一种主要发生于儿童的发热性血管炎。它可导致冠状动脉炎症，进而引发动脉瘤。冠状动脉的发病机制可能与半胱天冬酶活性介导的细胞凋亡或细胞焦亡有关，但这一观点在川崎病中尚未得到充分讨论。
本研究纳入了236名参与者。在Affymetrix基因芯片人类转录组阵列2.0研究中，有18名川崎病患者在接受静脉注射免疫球蛋白（IVIG）治疗前、IVIG治疗至少3周后进行了分析，还有36名非川崎病对照受试者。我们还招募了24名川崎病患者在接受IVIG治疗前、IVIG治疗至少3周后进行分析，以及24名非川崎病对照受试者进行Illumina HumanMethylation450 BeadChip研究。另外选取134名受试者组成队列进行分析，以验证实时定量PCR。
与对照受试者相比，川崎病患者中半胱天冬酶-1、-3、-4和-5的mRNA水平显著升高（<0.05）。给予IVIG后，这些基因的表达显著下降。特别值得注意的是，半胱天冬酶-4和-5基因的CpG位点甲基化状态在川崎病患者和对照之间呈现出明显相反的趋势。此外，与对IVIG有反应的患者相比，难治性川崎病患者在IVIG治疗前半胱天冬酶-3基因的表达较低。
我们的研究首次报道了川崎病患者外周血白细胞中细胞焦亡相关半胱天冬酶-1、-4和-5的上调。此外，半胱天冬酶-3的表达可能与川崎病患者对IVIG的耐药性有关。
