Dataset Information

A functional variant of PTPN22 confers risk for Vogt-Koyanagi-Harada syndrome but not for ankylosing spondylitis.

ABSTRACT:

Background

Protein tyrosine phosphatase non-receptor 22 (PTPN22) is a key negative regulator of T lymphocytes and has emerged as an important candidate susceptibility factor for a number of immune-related diseases. This study aimed to examine the predisposition of PTPN22 SNPs to Vogt-Koyanagi-Harada (VKH) syndrome and acute anterior uveitis (AAU) associated with ankylosing spondylitis (AS).

Methods

A total of 1005 VKH syndrome, 302 AAU+AS+ patients and 2010 normal controls among the Chinese Han population were enrolled in the study. Genotyping, PTPN22 expression, cell proliferation, cytokine production and cell activation were examined by PCR-RFLP, Real-time PCR, CCK8, ELISA and Flow cytometry.

Results

The results showed significantly increased frequencies of the rs2488457 CC genotype and C allele but a decreased frequency of the GG genotype in VKH syndrome patients (PBonferroni correction (Pc)?=?3.47×10(-7), OR?=?1.54; Pc?=?3.83×10(-8), OR?=?1.40; Pc?=?6.35×10(-4), OR?=?0.62; respectively). No significant association of the tested SNPs with AAU+AS+ patients was observed. Functional studies showed a decreased PTPN22 expression, impaired cell proliferation and lower production of IL-10 in rs2488457 CC cases compared to GG cases (Pc?=?0.009, Pc?=?0.015 and Pc?=?0.048 respectively). No significant association was observed concerning T cell activation and rs2488457 genotype.

Conclusions

The study showed that a functional variant of PTPN22 confers risk for VKH syndrome but not for AAU+AS+ in a Chinese Han population, which may be due to a modulation of the PTPN22 expression, PBMC proliferation and IL-10 production.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC4016172 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

A functional variant of PTPN22 confers risk for Vogt-Koyanagi-Harada syndrome but not for ankylosing spondylitis.

Zhang Qi Q Qi Jian J Hou Shengping S Du Liping L Yu Hongsong H Cao Qingfeng Q Zhou Yan Y Liao Dan D Kijlstra Aize A Yang Peizeng P

PloS one 20140509 5

<h4>Background</h4>Protein tyrosine phosphatase non-receptor 22 (PTPN22) is a key negative regulator of T lymphocytes and has emerged as an important candidate susceptibility factor for a number of immune-related diseases. This study aimed to examine the predisposition of PTPN22 SNPs to Vogt-Koyanagi-Harada (VKH) syndrome and acute anterior uveitis (AAU) associated with ankylosing spondylitis (AS).<h4>Methods</h4>A total of 1005 VKH syndrome, 302 AAU+AS+ patients and 2010 normal controls among t ...[more]

PMID: 24816862

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Project description:Purpose:This study was designed to systemically characterize and compare the immunological profiles of peripheral blood from patients with VKH and healthy controls. The influence of MP, which has been the most widely prescribed GC in VKH therapy, on immune phenotypes in peripheral blood from VKH patients was also evaluated. Our investigation will offer a better understanding of the function, activation and differentiation status of the leukocyte subpopulations during autoimmune VKH and after GC therapy, and may facilitate a more specific therapeutic regimen for this particular disease, which is a major cause of visual impairment. Methods:Total RNAs of whole blood cells were extracted in accordance with the manual of PAXgene tube (BD bioscience, San Jose, CA, USA). Preparation of library and transcriptomic sequencing were carried out using Illumina novaseq 6000 (Novogene Bioinformatics Technology Co., Ltd., Beijing, China). Differential expression analysis of two conditions/groups (two biological replicates per condition) was performed using the DESeq2 R package (1.16.1). DESeq2 provide statistical routines for determining differential expression in digital gene expression data using a model based on the negative binomial distribution. The resulting P values were adjusted using the Benjamini and Hochberg’s approach for controlling the false discovery rate. Genes with an adjusted P value <0.05 found by DESeq2 were assigned as differentially expressed. Results:The lymphocyte composition in the blood was different in VKH patients and HCs. VKH patients had significantly higher numbers of T cells with more activated, polarized and differentiated phenotype, more unswitched memory B cells and monocytes, as compared to HCs. MP treatment resulted in decreased frequencies of T cells and NK cells, inhibited NK cell activation and T cell differentiation, and more profoundly, a marked shift of monocytes toward an anti-inflammatory phenotype. Collectively, our findings suggest that the occurrence of VKH mainly affects the activation status and numbers of peripheral lymphocytes, and GC therapy with MP not only inhibits T cell activation directly, but also affects monocyte subsets and polarizes monocyte toward a suppressive phenotype, endowing them with the capacity to inhibit the pathogenic immune response. Conclusion:The comprehensive analysis of blood leukocytes from VKH patients and HCs described in this study reveals a perturbation of the lymphocyte compartment in VKH, exemplified by the increased activation and proliferation of T cells in VKH patients. GC therapy not only affects the proliferation and apoptosis of lymphocytes, especially T cells, but also affects the distribution of monocyte subsets. Our results also indicate that CD56+ monocytes may be regulatory and contribute to the remission of inflammatory autoimmune diseases such as VKH, suggesting that this monocyte subset could represent a potentially useful cellular therapeutic target in certain inflammatory diseases, especially when patients have strong side effects in response to GC therapy.

Dataset Information

A functional variant of PTPN22 confers risk for Vogt-Koyanagi-Harada syndrome but not for ankylosing spondylitis.

Background

Methods

Results

Conclusions

Publications

A functional variant of PTPN22 confers risk for Vogt-Koyanagi-Harada syndrome but not for ankylosing spondylitis.

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