Identification of FCER1G as a cyclosporin A plus corticosteroid sensitization gene in female patients with Vogt-Koyanagi-Harada disease

作者全名："Chang, Rui; Ji, Yan; Xu, Jing; Lai, Yuxian; Zhang, Hang; Zhong, Zhenyu; Su, Guannan; Yang, Peizeng"

作者地址："[Chang, Rui; Ji, Yan; Xu, Jing; Lai, Yuxian; Zhang, Hang; Zhong, Zhenyu; Su, Guannan; Yang, Peizeng] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Eye Inst, Chongqing Key Lab Ophthalmol,Natl Clin Res Ctr Ocu, Chongqing, Peoples R China"

通信作者："Yang, PZ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing Eye Inst, Chongqing Key Lab Ophthalmol,Natl Clin Res Ctr Ocu, Chongqing, Peoples R China."

来源：CLINICAL IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001099898000001

JCR分区：Q2

影响因子：4.5

年份：2023

卷号：256

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Female patients with VKH disease; Transcriptomics; Proteomics; FCER1G; CLB; CsA & CS resistance

摘要："The resistance development of the combination regimen of corticosteroids (CS) with cyclosporin A (CsA) leads to therapeutic failure of some patients with autoimmune diseases. In the male patients with Vogt-Koyanagi-Harada (VKH) disease, we have identified RPS4Y1 as an important resistance gene of the regimen and a functional mediator of chlorambucil (CLB). However, it remains unclear what is responsible for the resistance in female patients. In the present study, we performed RNA sequencing, tandem mass tag (TMT) proteomics, gain-and loss of-function assays and rescue assays to screen and validate potential resistant mediators. The results showed that only Fc epsilon receptor Ig (FCER1G) exhibited significantly differential expression in CD4(+)T cells among female CsA & CS resistant, sensitive and CLB & CsA & CS treated patients at transcription and protein levels. Inhibition of FCER1G was demonstrated to modulate CD4+ T cell resistance to CsA & CS in female patients. Importantly, the inhibition was mediated by elevated DNA methylation in the promoter region of the FCER1G gene. Moreover, we found that the salvage effect of CLB on CsA & CS resistance was mediated by an increased FCER1G expression via DNA demethylation in female patients. Taken together, the downregulation of FCER1G due to DNA hypermethylation is responsible for the resistance to CsA & CS and CLB reverses this resistance by inducing FCER1G expression via DNA demethylation in female patients. Modulation of FCER1G would be a promising sensitization strategy in female patients with resistance to CsA & CS."

基金机构：Chongqing Key Laboratory of Ophthalmology (CSTC) [2018]; Natural Science Foundation of Chongqing [2008CA5003]; Chongqing Science & Technology Plat-form and Base Construction Program [CSTB2022NSCQ-BHX0680]; Project Foundation of Chongqing Science and Technology Commission of China [cstc2014pt-sy10002]; Chongqing Education Commission Project Fund of China [cstc2020jcyj-msxmX0829]; [KJQN202000445]

基金资助正文："This study was supported by the National Natural Science Foundation Key Program (82230032, 81930023), National Natural Science Foundation (82201167, 82000883), Key Project of Chongqing Science and Technology Bureau (CSTC2021jscx-gksb-N0010), Chongqing Outstanding Scientists Project (2019), Chongqing Chief MedicalScientist Project (2018), Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003), Natural Science Foundation of Chongqing (CSTB2022NSCQ-BHX0680), Chongqing Science & Technology Platform and Base Construction Program (cstc2014pt-sy10002), the Project Foundation of Chongqing Science and Technology Commission of China (cstc2020jcyj-msxmX0829) and Chongqing Education Commission Project Fund of China (KJQN202000445).r Scientist Project (2018) , Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003) , Natural Science Foundation of Chongqing (CSTB2022NSCQ-BHX0680) , Chongqing Science & Technology Plat-form and Base Construction Program (cstc2014pt-sy10002) , the Project Foundation of Chongqing Science and Technology Commission of China (cstc2020jcyj-msxmX0829) and Chongqing Education Commission Project Fund of China (KJQN202000445) ."