系统性红斑狼疮患者中祖先及功能相关CD5变体的分析。
Analysis of ancestral and functionally relevant CD5 variants in systemic lupus erythematosus patients.
作者信息
Cenit Maria Carmen, Martínez-Florensa Mario, Consuegra Marta, Bonet Lizette, Carnero-Montoro Elena, Armiger Noelia, Caballero-Baños Miguel, Arias Maria Teresa, Benitez Daniel, Ortego-Centeno Norberto, de Ramón Enrique, Sabio José Mario, García-Hernández Francisco J, Tolosa Carles, Suárez Ana, González-Gay Miguel A, Bosch Elena, Martín Javier, Lozano Francisco
机构信息
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.
ImmunNovative Developments, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
出版信息
PLoS One. 2014 Nov 17;9(11):e113090. doi: 10.1371/journal.pone.0113090. eCollection 2014.
OBJECTIVE
CD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis.
METHODS
The CD5 SNPs rs2241002 (C/T; Pro224Leu) and rs2229177 (C/T; Ala471Val) were genotyped using TaqMan allelic discrimination assays in a total of 1,324 controls and 681 SLE patients of Spanish origin. In vitro analysis of CD3-mediated T cell proliferative and cytokine response profiles of healthy volunteers homozygous for the above mentioned CD5 haplotypes were also analyzed.
RESULTS
T-cell proliferation and cytokine release were significantly increased showing a bias towards to a Th2 profile after CD3 cross-linking of peripheral mononuclear cells from healthy individuals homozygous for the ancestral Pro224-Ala471 (CC) haplotype, compared to the more recently derived Pro224-Val471 (CT). The same allelic combination was statistically associated with Lupus nephritis.
CONCLUSION
The ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients.
目的
CD5在自身免疫中起关键作用，是类风湿关节炎（RA）发病的一个公认的遗传风险因素。最近，东亚人群中已发现CD5基因Pro224-Val471单倍型存在正选择证据。本研究旨在进一步分析构成祖先型和新衍生型单倍型（分别为Pro224-Ala471和Pro224-Val471）的非同义CD5多态性的功能相关性，以及探讨CD5在系统性红斑狼疮（SLE）和/或狼疮性肾炎发病中的潜在作用。
方法
采用TaqMan等位基因鉴别分析法对1324名对照者和681名西班牙裔SLE患者进行CD5单核苷酸多态性（SNP）rs2241002（C/T；Pro224Leu）和rs2229177（C/T；Ala471Val）基因分型。同时对上述CD5单倍型纯合的健康志愿者进行体外CD3介导的T细胞增殖和细胞因子反应谱分析。
结果
与新衍生的Pro224-Val471（CT）单倍型相比，祖先型Pro224-Ala471（CC）单倍型纯合的健康个体外周单个核细胞经CD3交联后，T细胞增殖和细胞因子释放显著增加，且表现出向Th2型的偏向性。相同的等位基因组合与狼疮性肾炎存在统计学关联。
结论
祖先型Ala471 CD5等位基因使淋巴细胞对TCR/CD3交联反应过度，且与SLE患者的肾炎相关。
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