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

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

  • Clin Immunol. 2023 Oct 10:256:109800. doi: 10.1016/j.clim.2023.109800.
Rui Chang 1 Yan Ji 1 Jing Xu 1 Yuxian Lai 1 Hang Zhang 1 Zhenyu Zhong 1 Guannan Su 1 Peizeng Yang 2
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, People's Republic of China.
  • 2 The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, People's Republic of China. Electronic address: peizengycmu@126.com.
Abstract

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.

Keywords

CLB; CsA & CS resistance; FCER1G; Female patients with VKH disease; Proteomics; Transcriptomics.

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