June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Hypermethylation of Interferon Regulatory Factor 8 (IRF8) confers risk to Vogt-Koyanagi-Harada Disease
Author Affiliations & Notes
  • Yiguo Qiu
    Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
  • Hongsong Yu
    Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
  • Yunyun Zhu
    Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
  • Zi Ye
    Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
  • Jing Deng
    Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
  • Wencheng Su
    Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
  • Qingfeng Cao
    Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
  • Gangxiang Yuan
    Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
  • Aize Kijlstra
    University Eye Clinic Maastricht, Maastricht, Netherlands
  • Peizeng Yang
    Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
  • Footnotes
    Commercial Relationships   Yiguo Qiu, None; Hongsong Yu, None; Yunyun Zhu, None; Zi Ye, None; Jing Deng, None; Wencheng Su, None; Qingfeng Cao, None; Gangxiang Yuan, None; Aize Kijlstra, None; Peizeng Yang, None
  • Footnotes
    Support  Natural Science Foundation Major International (Regional) Joint Research Project (81320108009), Key Project of Natural Science Foundation (81130019), National Natural Science Foundation Project (31370893), Basic Research program of Chongqing (cstc2013jcyjC10001), Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003), National Key Clinical Specialties Construction Program of China, Key Project of Health Bureau of Chongqing (2012-1-003), Chongqing Science & Technology Platform and Base Construction Program (cstc2014pt-sy10002) and the Major Research Development Program of China (2016YFC0904000)
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 506. doi:
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      Yiguo Qiu, Hongsong Yu, Yunyun Zhu, Zi Ye, Jing Deng, Wencheng Su, Qingfeng Cao, Gangxiang Yuan, Aize Kijlstra, Peizeng Yang; Hypermethylation of Interferon Regulatory Factor 8 (IRF8) confers risk to Vogt-Koyanagi-Harada Disease. Invest. Ophthalmol. Vis. Sci. 2017;58(8):506.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To investigate the methylation change of IRF8 in monocyte-derived dendritic cells (DCs) obtained from Vogt-Koyanagi-Harada (VKH) patients, and in the DCs incubated with conventional drugs, thus to study the effect of IRF8 demethylation on the in vitro function of DCs, and Th1/Th17 cell responses in patient group.

Methods : Monocyte-derived DCs from VKH patients were cultured with or without the presence of 5-Aza-2′-deoxycytidine (DAC), cyclosporin a (CsA) or dexamethasone (DEX). The mRNA expression of IRF8 was determined by real-time PCR. The methylation level of IRF8 promoter was detected by mass spectrometry. The demethylation effect of DAC on DCs and on Th1/Th17 responses was evaluated by ELISA and flow cytometry. Two-tailed Student's t test, Wilcoxon’s matched-pairs test or paired-samples t-test were used for the statistical analysis.

Results : A decreased IRF8 mRNA expression in association with a higher methylation level was observed in active VKH patients compared to controls (*p<0.05, **p<0.01). Inactive VKH patients that responded to treatments showed a down-regulated methylation level and increased mRNA expression of IRF8 compared to active VKH patients (*p<0.05, **p<0.01, ***p<0.001). The DCs from active untreated VKH patients which were incubated with CsA or DEX also showed a lower methylation and higher mRNA expression of IRF8 than untreated DCs (*p<0.05, **p<0.01, ***p<0.001). DAC showed a notable demethylation effect as evidenced by increasing the mRNA expression and reducing the methylation level of IRF8 (*p<0.05, **p<0.01, ***p<0.001). It also suppressed the Th1 and Th17 responses through down-regulating the expression of co-stimulatory molecules (CD86, CD80, and CD40), and reducing the expression of pro-inflammatory cytokines ( IL-6, IL-1β, IL-23 and IL-12) secreted by DCs (*p<0.05, **p<0.01, ***p<0.001). The frequencies of Th1, Th17 cells and the production of IFN-γ, IL-17 were also decreased with the treatment of DAC (*p<0.05, **p<0.01).

Conclusions : These findings show that hypermethylation of IRF8 in DCs confers risk to VKH disease. Demethylation of IRF8 may offer a novel therapeutic opportunity in the treatment of VKH disease.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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