与银屑病发病风险降低有关的 IL23R 基因突变会导致与银屑病有关的基因的差异表达

IF 3.5 3区 医学 Q1 DERMATOLOGY Experimental Dermatology Pub Date : 2024-09-22 DOI:10.1111/exd.15180
Shraddha S. Rane, Elan Shellard, Antony Adamson, Steve Eyre, Richard B. Warren
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引用次数: 0

摘要

银屑病是一种无法治愈的免疫介导型皮肤病,发病率约占总人口的 1%-3%。各种证据表明,IL23 在疾病中起着关键作用。IL23 受体(IL23R)的基因变异会增加罹患银屑病的风险,而专门针对 IL23 的生物疗法在治疗疾病方面具有很高的疗效。IL23 通过 IL23R 发挥作用,通过 STAT3 通路发出信号,介导一系列事件,最终导致银屑病的临床表现。鉴于 IL23R 在疾病中的重要作用,了解基因变异对受体功能和下游基因调控的影响非常重要。在这里,我们在 CD4+(Jurkat)和 CD8+(MyLa)T 细胞中开发了表达 IL23R 野生型风险或突变型(R381Q)保护形式的模型系统。在确认模型系统表达基因/蛋白并对 STAT3 磷酸化产生不同影响后,我们使用 RNAseq 对两种细胞类型在单个时间点以及 Jurkat CD4+ T 细胞在时间进程实验中的不同基因调控进行了探索,特别是与银屑病风险有关的基因。这些实验在表达野生型和突变型IL23R的细胞中发现了不同的调控基因,包括HLA-B、SOCS1、RUNX3、CCR5、CXCR3、CCR9、KLF3、CD28、IRF、SOCS6、TNFAIP和ICAM5,这些基因与IL23通路和银屑病都有关联。这些基因有可能定义疾病中的 IL23/银屑病通路,从而促进我们对疾病背后生物学的了解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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IL23R mutations associated with decreased risk of psoriasis lead to the differential expression of genes implicated in the disease

Psoriasis is an incurable immune-mediated skin disease, affecting around 1%–3% of the population. Various lines of evidence implicate IL23 as being pivotal in disease. Genetic variants within the IL23 receptor (IL23R) increase the risk of developing psoriasis, and biologic therapies specifically targeting IL23 demonstrated high efficacy in treating disease. IL23 acts via the IL23R, signalling through the STAT3 pathway, mediating the cascade of events that ultimately results in the clinical presentation of psoriasis. Given the essential role of IL23R in disease, it is important to understand the impact of genetic variants on receptor function with respect to downstream gene regulation. Here we developed model systems in CD4+ (Jurkat) and CD8+ (MyLa) T cells to express either the wild type risk or mutant (R381Q) protective form of IL23R. After confirmation that the model system expressed the genes/proteins and had a differential effect on the phosphorylation of STAT3, we used RNAseq to explore differential gene regulation, in particular for genes implicated with risk to psoriasis, at a single time point for both cell types, and in a time course experiment for Jurkat CD4+ T cells. These experiments discovered differentially regulated genes in the cells expressing wild type and mutant IL23R, including HLA-B, SOCS1, RUNX3, CCR5, CXCR3, CCR9, KLF3, CD28, IRF, SOCS6, TNFAIP and ICAM5, that have been implicated in both the IL23 pathway and psoriasis. These genes have the potential to define a IL23/psoriasis pathway in disease, advancing our understanding of the biology behind the disease.

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来源期刊
Experimental Dermatology
Experimental Dermatology 医学-皮肤病学
CiteScore
6.70
自引率
5.60%
发文量
201
审稿时长
2 months
期刊介绍: Experimental Dermatology provides a vehicle for the rapid publication of innovative and definitive reports, letters to the editor and review articles covering all aspects of experimental dermatology. Preference is given to papers of immediate importance to other investigators, either by virtue of their new methodology, experimental data or new ideas. The essential criteria for publication are clarity, experimental soundness and novelty. Letters to the editor related to published reports may also be accepted, provided that they are short and scientifically relevant to the reports mentioned, in order to provide a continuing forum for discussion. Review articles represent a state-of-the-art overview and are invited by the editors.
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