Effects of an FcγRIIA polymorphism on leukocyte gene expression and cytokine responses to anti-CD3 and anti-CD28 antibodies.,Genes and Immunity

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Effects of an FcγRIIA polymorphism on leukocyte gene expression and cytokine responses to anti-CD3 and anti-CD28 antibodies.
Genes and Immunity ( IF 5.0 ) Pub Date : 2018-07-06 , DOI: 10.1038/s41435-018-0038-8
Michelle M Stein ₁ , Cara L Hrusch ₂ , Anne I Sperling ₂ , Carole Ober ₁

Affiliation

The low affinity Fcγ receptor, FcγRIIA, harbors a common missense mutation, rs1801274 (G>A, Arg131His) that modifies binding affinity to human IgG2 and mouse IgG1 antibodies and is associated with increased risk of autoimmune disease. Despite the important role of the Arg131His variant, little is understood about heterozygous genotype effects on global gene expression and cytokine production during an FcγR-dependent response. To address this gap in knowledge, we treated human whole-blood samples from 130 individuals with mouse IgG1 anti-CD3 and anti-CD28 antibodies and characterized the genome-wide gene expression profiles and cytokine production among individuals stratified by rs1801274 genotype. Our analysis revealed that the levels of four cytokines (IFNγ, IL-12, IL-2, TNFα) and global gene expression patterns differed between all three genotype classes. Surprisingly, the heterozygotes showed suboptimal T cell activation compared to cells from individuals homozygous for the higher-affinity FcγRIIA allele (GG; Arg/Arg). The results of this study demonstrate that IgG response varies among all rs1801274 genotype classes and results in profound differences in both cytokine responses and gene expression patterns in blood leukocytes. Because even heterozygotes showed dampened global responses, our data may provide insight into the heterogeneity of outcomes in cytokine release assays and immunotherapy efficacy.

中文翻译：

FcγRIIA多态性对白细胞基因表达和细胞因子对抗CD3和抗CD28抗体的反应的影响。

低亲和力Fcγ受体FcγRIIA具有常见的错义突变rs1801274（G> A，Arg131His），可修饰与人IgG2和小鼠IgG1抗体的结合亲和力，并与自身免疫性疾病的风险增加相关。尽管Arg131His变体起着重要作用，但对于FcγR依赖性反应期间杂合基因型对整体基因表达和细胞因子产生的影响了解甚少。为了解决这一知识差距，我们用小鼠IgG1抗CD3和抗CD28抗体处理了130个个体的人全血样品，并表征了全基因组基因表达谱和rs1801274基因型分层个体中的细胞因子产生。我们的分析表明，四种细胞因子（IFNγ，IL-12，IL-2，TNFα）和整体基因表达模式在所有这三种基因型类别之间都不同。令人惊讶地，与来自具有较高亲和力的FcγRIIA等位基因（GG； Arg / Arg）纯合的个体的细胞相比，杂合子显示出次优的T细胞活化。这项研究的结果表明，IgG应答在所有rs1801274基因型类别之间均发生变化，并导致血液白细胞中细胞因子应答和基因表达模式的深刻差异。因为即使杂合子也显示出减弱的整体反应，所以我们的数据可能提供洞察细胞因子释放测定结果和免疫疗法疗效的异质性的见解。这项研究的结果表明，IgG应答在所有rs1801274基因型类别之间均发生变化，并导致血液白细胞中细胞因子应答和基因表达模式的深刻差异。因为即使杂合子也显示出减弱的整体反应，所以我们的数据可能提供洞察细胞因子释放测定结果和免疫疗法疗效的异质性的见解。这项研究的结果表明，IgG应答在所有rs1801274基因型类别之间均发生变化，并导致血液白细胞中细胞因子应答和基因表达模式的深刻差异。因为即使杂合子也显示出减弱的整体反应，所以我们的数据可能提供洞察细胞因子释放测定结果和免疫疗法疗效的异质性的见解。

更新日期：2019-05-16

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