Genetic Variations of IL17F and IL23A Show Associations with Behçet’s Disease and Vogt-Koyanagi-Harada Syndrome

doi:10.1016/j.ophtha.2014.09.025

Ophthalmology

Volume 122, Issue 3, March 2015, Pages 518-523

https://doi.org/10.1016/j.ophtha.2014.09.025 Get rights and content

Purpose

To investigate the associations of IL17A, IL17F, IL23A, and IL23R copy number variants (CNVs) with Vogt-Koyanagi-Harada (VKH) syndrome and Behçet’s disease (BD) and the possible mechanisms involved.

Design

Two-stage case-control and functional studies.

Participants

A total of 1159 VKH patients, 1036 BD patients, and 2050 controls were enrolled.

Methods

TaqMan real-time polymerase chain reaction assay was used for genotyping of copy number variant. Cell proliferation was measured by colorimetric assay.

Main Outcome Measures

Association of CNVs in IL17A, IL17F, IL23A, and IL23R with BD and VKH syndrome and the functional roles of IL17F CNVs.

Results

Increased frequencies of more than 2 copies of IL17F and IL23A were found in BD patients as compared with controls (IL17F: P = 4.17 × 10⁻⁸; odds ratio [OR], 2.2; IL23A: P = 2.86 × 10⁻¹¹; OR, 2.8, respectively). A similar result was found for VKH syndrome (IL17F: P = 2.84 × 10⁻¹³; OR, 2.7; IL23A: P = 4.46 × 10⁻¹⁷; OR, 3.4, respectively). Interestingly, the association of IL17F and IL23A with BD was found only in male patients (IL17F: P = 1.06 × 10⁻⁶; OR, 2.3; IL23A, P = 3.81 × 10⁻⁸; OR, 2.8, respectively), but not in female patients. No association of CNVs in IL17A and IL23R was found for BD and VKH syndrome. IL17F protein levels were correlated positively with gene copy numbers (P = 3.43 × 10⁻⁷). Individuals with high IL17F copies showed enhanced peripheral blood mononuclear cells (PBMC) proliferation (P = 5.67 × 10⁻³).

Conclusions

High gene copy numbers of IL17F and IL23A were associated with BD and VKH syndrome. Enhanced IL17F protein production and PBMC proliferation were associated with high IL17F copy numbers.

Section snippets

Uveitis Patient and Normal Control Recruitment

A total of 1036 BD patients, 1159 VKH patients, and 2050 healthy individuals were recruited from the First Affiliated Hospital of Chongqing Medical University (Chongqing, China) or the Zhongshan Ophthalmic Center, Sun Yat-sen University (Guangzhou, China; Table 1, Table 2). The diagnoses of VKH syndrome and BD were based strictly on the revised diagnostic criteria 2001 for VKH syndrome¹⁶ and the International Study Group for BD,¹⁷ respectively. If there was any doubt about the diagnosis, the

Clinical Findings of Uveitis Patients and Controls

The clinical characteristics of the uveitis patients were assessed at the time of diagnosis and are summarized in Table 1, Table 2. The average age ± standard deviation of normal controls was 39.5 ± 11.0 years.

High Copy Number of IL17F and IL23A Confer Susceptibility to Behçet’s Disease and Vogt-Koyanagi-Harada Syndrome in Chinese Han Individuals

The association of CNVs in IL17A, IL17F, and IL23A and its receptor, including IL23R, in patients with BD and VKH syndrome was examined. The results showed that increased frequencies of more than 2 copies of IL17F and IL23A were found in BD patients as compared with controls (IL17F: P =

Discussion

Previous studies have shown that Th17 cells and Th17 cell-related genes were implicated as the critical agents in the pathogenesis of uveitis in such settings as VKH syndrome and BD.7, 20, 21 To our knowledge, this is the first study addressing copy number variants of Th17 cell-related genes with ocular disease. We identified 2 common risk CNVs of IL17F and IL23A for VKH syndrome and BD. More importantly, our study showed that high copies of IL17F were related positively with the expression of

Acknowledgments

The authors thank Meifen Zhang, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China; Xiuyun Zheng, Jinan Mingshui Eye Hospital, Jinan, China; and Minglian Zhang, Xingtai Eye Hospital, Xingtai, China, for their assistance in sample collection.

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Vogt-Koyanagi-Harada (VKH) disease and Behcet's uveitis (BU) are the two major vision-threatening uveitis entities. This study performed the first label-free quantitative proteomics on aqueous humor-derived exosomes from 84 patients with VKH or BU to determine their potential roles. Sixty-five differentially expressed proteins (DEPs) and 40 DEPs were detected in the VKH and BU groups, respectively. GO and KEGG analysis showed that DEPs were mainly enriched in the complement-related pathways. The complement C1q subcomponent subunit B (C1QB) was identified as a key exosomal protein, and its expression was significantly increased by western blotting in both diseases. Additionally, the integrated analysis based on the published scRNA-seq data showed that C1QB-containing exosomes were mainly produced by mononuclear macrophages in the anterior segment tissue. Overall, our proteomic profiling highlights that complement-related pathways may be actively involved in the pathogenesis of these two diseases. These pathways may also serve as treatment targets for both diseases.
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Autoimmune uveitis is a non-infectious, inflammatory intraocular disease that affects the uveal and adjacent tissues. It frequently causes varying degrees of visual loss. Evidence for the strong association between activated γδ T cells and the development of autoimmune uveitis is growing. The innate and adaptive immune response are connected in the early phases by the γδ T cells that contain the γ and δ chains. γδ T cells can identify antigens in a manner that is not constrained by the MHC. When activated by various pathways, γδ T cells can not only secrete pro-inflammatory factors early on (such as IL-17), but they can also promote Th17 cells responses, which ultimately exacerbates autoimmune uveitis. Therefore, we review the mechanisms by which γδ T cells affect autoimmune uveitis in different activation and disease states. Moreover, we also prospect for immunotherapies targeting different γδ T cell-related action pathways, providing a reference for exploring new drug for the treatment of autoimmune uveitis.
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2021, Progress in Retinal and Eye Research
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The function of ERAP1/2 involves trimming of peptides that are then loaded onto the MHC class I molecule, in this case dealing with processing of specific HLA-B51:01 ligands (Guasp et al., 2019). Besides the strong genetic predisposition of HLA-B51 to Behçet's disease, genome-wide association and replication analyses showed significant associations with genes encoding molecules related to the IL-23/IL-17 signalling pathway, such as IL23A, IL23R, IL12A, IL12B, IL12RB2, IL17A, IL17F, IL18RAP, IL6, IL10, IL37, STAT3, STAT4 and TNFAIP3 (Hou et al., 2012, 2015; Hu et al., 2010, 2012, 2015; Jiang et al., 2010a, 2015; Kappen et al., 2015; Kim et al., 2012; Li et al., 2013a, 2014b; Remmers et al., 2010; Tan et al., 2016; Yu et al., 2017). More importantly, the expressions of IL-23, IL-23R, IL-17, IFN-γ, IL-6 and TNF-α were observed to be considerably up-regulated in Behçet's disease (Çavuş et al., 2014; Chi et al., 2008).
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: Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

: Supported by the Natural Science Foundation (Major International [Regional] Joint Research Project of China (grant no.: 81320108009 [P.Y.]); National Basic Research Program of China (973 Program; grant no.: 2011CB510200 [P.Y.]); Key Project of Natural Science Foundation (grant no.: 81130019 [P.Y.]); National Natural Science Foundation Project (grant nos.: 31370893 [P.Y.] and 81270990 [S.H.]); Basic Research program of Chongqing (grant no.: cstc2013jcyjC10001 [P.Y., S.H.]); Chongqing Key Laboratory of Ophthalmology (grant no.: CSTC 2008CA5003 [P.Y.]); National Key Clinical Specialties Construction Program of China (P.Y.); Key Project of Health Bureau of Chongqing (2012-1-003) (P.Y), Fund for PAR-EU Scholars Program (P.Y.); and the Youth Talent Support Plan of Chongqing (S.H.).

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Original articleGenetic Variations of IL17F and IL23A Show Associations with Behçet’s Disease and Vogt-Koyanagi-Harada Syndrome

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Uveitis Patient and Normal Control Recruitment

Clinical Findings of Uveitis Patients and Controls

High Copy Number of IL17F and IL23A Confer Susceptibility to Behçet’s Disease and Vogt-Koyanagi-Harada Syndrome in Chinese Han Individuals

Discussion

Acknowledgments

Ophthalmology

J Allergy Clin Immunol

Am J Ophthalmol

Autoimmun Rev

Clin Immunol

The possible impact of uveitis in blindness: a literature survey

Br J Ophthalmol

Uveitis: a global perspective

Ocul Immunol Inflamm

Epidemiological survey of intraocular inflammation in Japan

Jpn J Ophthalmol

Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China

Curr Eye Res

Clinical characteristics of Vogt-Koyanagi-Harada syndrome in Chinese patients

Ophthalmology

p38{alpha} MAP kinase controls IL-17 synthesis in Vogt-Koyanagi-Harada syndrome and experimental autoimmune uveitis

Invest Ophthalmol Vis Sci

Imbalance of Th17 to Th1 cells in Behçet’s disease

Clin Exp Rheumatol

Th17 cells in Behçet’s disease: a new immunoregulatory axis

Clin Exp Rheumatol

Upregulated IL-23 and IL-17 in Behçet patients with active uveitis

Invest Ophthalmol Vis Sci

Copy number variation of beta-defensin genes in Behçet’s disease

Clin Exp Rheumatol

Copy number variations of complement component C4 are associated with Behçet’s disease but not with ankylosing spondylitis associated with acute anterior uveitis

Arthritis Rheum

Original article
Genetic Variations of IL17F and IL23A Show Associations with Behçet’s Disease and Vogt-Koyanagi-Harada Syndrome