TLR7多态性，性别和慢性HBV感染通过TLR7配体影响浆细胞样DC成

StephenW

Antiviral Res. 2018 Jun 28. pii: S0166-3542(17)30840-9. doi: 10.1016/j.antiviral.2018.06.015. [Epub ahead of print]
TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands.
Buschow SI1, Biesta PJ1, Groothuismink ZMA1, Erler NS2, Vanwolleghem T3, Ho E4, Najera I5, Ait-Goughoulte M5, de Knegt RJ1, Boonstra A1, Woltman AM6.
Author information

1
    Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands.
2
    Department of Biostatistics, Erasmus MC University Medical Center Rotterdam, The Netherlands.
3
    Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands; Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp and Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.
4
    Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp and Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.
5
    Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, Switzerland.
6
    Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands. Electronic address: [email protected].

Abstract

TLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance. Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054). Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.
KEYWORDS:

Hepatitis B virus; Immunotherapy; Plasmacytoid dendritic cell; Sex; TLR7; rs179008

PMID:
    29964062
DOI:
    10.1016/j.antiviral.2018.06.015

StephenW

抗病毒药物2018年6月28日.pii：S0166-3542（17）30840-9。 doi：10.1016 / j.antiviral.2018.06.015。 [电子版提前打印]
TLR7多态性，性别和慢性HBV感染通过TLR7配体影响浆细胞样DC成熟。
Buschow SI1，Biesta PJ1，Groothuismink ZMA1，Erler NS2，Vanwolleghem T3，Ho E4，Najera I5，Ait-Goughoulte M5，de Knegt RJ1，Boonstra A1，Woltman AM6。
作者信息

1
    荷兰鹿特丹伊拉斯谟MC大学医学中心消化内科和肝病学系。
2
    荷兰鹿特丹伊拉斯谟MC大学医学中心生物统计学系。
3
    荷兰鹿特丹伊拉斯谟MC大学医学中心胃肠病学和肝病学系;安特卫普大学医学与健康科学学院实验医学与儿科实验室，比利时安特卫普安特卫普大学医院消化内科和肝病学系。
4
    安特卫普大学医学与健康科学学院实验医学与儿科实验室，比利时安特卫普安特卫普大学医院消化内科和肝病学系。
五
    罗氏制药研究与早期开发（pRED），罗氏瑞士巴塞尔创新中心。
6
    荷兰鹿特丹伊拉斯谟MC大学医学中心消化内科和肝病学系。电子地址：[email protected]。

抽象

TLR7激动剂对于治疗癌症，自身免疫和慢性病毒感染具有高度兴趣。已知它们激活浆细胞样树突细胞（pDC）以产生大量的I型干扰素（IFN）并促进T和B细胞应答，后者借助于成熟标志物如CD40，CD80和CD86。据报道，TLR7单核苷酸多态性（SNP）rs179008（GLn11Leu），性别和慢性病毒感染均影响pDC IFN的产生。然而，尚不清楚这些因子是否也影响pDC表型成熟，从而影响IFN非依赖性pDC功能。此外，尚不清楚SNP rs179008是否影响HBV易感性和/或清除率。在这里，我们调查SNP rs179008，性别和HBV感染是否影响来自38个健康个体和28个慢性HBV患者的pDC的表型成熟。此外，我们评估了一大群健康个体（n = 231）和慢性HBV患者（n = 1054）的SNP患病率。与之前的报道一致，rs179008变异等位基因在亚洲人中基本不存在，在高加索人群中更为普遍。在高加索人中，SNP在健康和慢性感染的男性中同样普遍。然而，健康女性的SNP显着高于慢性HBV感染者（42％对28％），这表明在女性中它可以提供免于慢性感染的保护。离体实验证明，TLR7配体而非TLR9配体对共刺激分子CD40和CD86的诱导在来自携带健康SNP的雌性的pDC中增强。此外，CD80和CD86上调在雌性中更明显，与SNP无关。最后，我们的数据表明慢性HBV感染会损害pDC的成熟。这些发现提供了对确定TLR7反应的因素的深入了解，这对于基于TLR7的疗法的进一步临床开发是重要的。
关键词：

乙型肝炎病毒;免疫治疗;浆细胞样树突状细胞;性别; TLR7; rs179008

结论：
    29964062
DOI：
    10.1016 / j.antiviral.2018.06.015

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newchinabok

单用都不行，靠药物组合治愈一部分人都是大进步