Department of Pulmonary & Allergy, University Children's Hospital Munich, LMU Munich, Germany.
Allergy. 2011 Aug;66(8):1020-9. doi: 10.1111/j.1398-9995.2011.02573.x. Epub 2011 Mar 4.
Toll-like receptor (TLR) polymorphisms have been associated with atopic diseases in children and adults. Development of atopic diseases may be modified by TLR-mediated signals that modulate T-regulatory cells (Tregs) early in life when maternal influences are still present and relevant. The aim of this study was to assess whether genetic TLR variants influence Tregs in neonates.
Twelve single nucleotide polymorphisms located in TLR1, TLR2, TLR4, TLR6, and TLR10 were genotyped in 200 cord blood samples (72 samples from atopic, 128 from nonatopic mothers). Cord blood mononuclear cells were cultured without or with stimulation [lipid A (LpA), peptidoglycan (Ppg), phytohemagglutinin, house dust mite]. mRNA expression of Treg marker genes [forkhead box protein P3 (FOXP3), glucocorticoid-induced tumor necrosis factor receptor (GITR), lymphocyte activation gene 3 (LAG3)], TLR2, Th1/Th2 cytokines, and tumor necrosis factor alpha (TNF-α) was measured.
In children with the AA genotype of the TLR2 promoter variant rs4696480, gene expression of FOXP3 and Treg marker genes GITR and LAG3 as well as Th2 cytokines and TNF-α secretion was significantly increased in the presence of maternal atopy and Tregs decreased without maternal atopy. In carriers of the GG genotype for TLR2 rs1898830, gene expression of Treg marker genes was significantly decreased with and increased without maternal atopy. FOXP3 expression was also modified by TLR1 rs4833095 (P ≤ 0.03) and trendwise by TLR10 rs4129009 after LpA and Ppg stimulation.
Genetic variations of TLR2, TLR1, and TLR10 affect Treg marker gene expression in cord blood. Gene-immunological interactions of the TLR pathway influence Tregs early in life, modulated by maternal atopy. This may be relevant for immune maturation in the development of atopic diseases in childhood.
Toll 样受体 (TLR) 多态性与儿童和成人的特应性疾病有关。特应性疾病的发展可能受到 TLR 介导的信号的调节，这些信号在生命早期调节 T 调节细胞 (Tregs)，此时母体的影响仍然存在且相关。本研究旨在评估遗传 TLR 变体是否影响新生儿的 Tregs。
在 200 份脐带血样本（72 份来自特应性母亲，128 份来自非特应性母亲）中，对位于 TLR1、TLR2、TLR4、TLR6 和 TLR10 中的 12 个单核苷酸多态性进行基因分型。培养脐带血单核细胞，不刺激或用脂多糖 (LpA)、肽聚糖 (Ppg)、植物血凝素、屋尘螨刺激。测量 Treg 标记基因 [叉头框蛋白 P3 (FOXP3)、糖皮质激素诱导的肿瘤坏死因子受体 (GITR)、淋巴细胞激活基因 3 (LAG3)]、TLR2、Th1/Th2 细胞因子和肿瘤坏死因子 α (TNF-α) 的 mRNA 表达。
在 TLR2 启动子变异 rs4696480 的 AA 基因型儿童中，FOXP3 和 Treg 标记基因 GITR 和 LAG3 的基因表达以及 Th2 细胞因子和 TNF-α 的分泌在母体特应性存在时显著增加，而在母体特应性不存在时 Tregs 减少。TLR2 rs1898830 的 GG 基因型携带者，Treg 标记基因的表达在母体特应性存在和不存在时均显著降低。TLR1 rs4833095（P≤0.03）和 TLR10 rs4129009 也可调节 FOXP3 的表达，在 LpA 和 Ppg 刺激后呈趋势。
TLR2、TLR1 和 TLR10 的遗传变异影响脐带血中 Treg 标记基因的表达。TLR 途径的基因-免疫相互作用影响生命早期的 Tregs，受母体特应性的调节。这可能与儿童特应性疾病发展过程中的免疫成熟有关。
