Defensin gene copy number and mucosal innate immunity

描述（由申请人提供）：基因拷贝数（GCN）变异是一种新被描述的现象，它可能导致种群内显著的表型变异。大量GCN变异存在于编码防御素的基因中，防御素是在对传染病的先天免疫中起重要作用的阳离子抗菌肽。编码-防御素2的基因是皮肤和粘膜表面先天免疫反应的关键部分，每个二倍体基因组有2-12个拷贝。最近的证据表明，BD2 GCN的变异与特发性疾病的易感性有关：低GCN增加结肠克罗恩病的风险，而高GCN与牛皮癣的风险增加有关。我们最近使用恒河猴模型来证明，与人类一样，BD2的表达是由幽门螺杆菌诱导的，幽门螺杆菌是一种常见的胃病原体，是消化性溃疡的病原体，增加了胃癌的风险。此外，我们的初步数据表明恒河猴和人类一样，BD2 GCN也有明显的变异。我们假设BD2 GCN的变化反映在BD2的表达水平上，这些差异将影响幽门螺杆菌感染的结果。在Aim 1中，我们将表征GCN和猕猴BD2基因的等位基因多样性，并研究GCN与原代细胞培养中BD2表达之间的关系。在目标2中，我们将确定三组BD2 GNC低、中、高的猕猴，并比较它们的胃生物群和对幽门螺杆菌实验挑战的反应。由于只有约5%至10%的幽门螺杆菌感染的人会有临床后遗症，而其余的人只会有无症状的胃炎，因此人们对了解与疾病相关的宿主因素非常感兴趣。因此，了解BD2基因遗传变异与幽门螺杆菌感染之间的功能关系不仅将扩大我们对先天免疫反应与感染之间关系的认识，而且还可能提供一个翻译链接，以更好地了解谁可能从幽门螺杆菌治疗中受益，以预防消化性溃疡和胃癌。

DESCRIPTION (provided by applicant): Gene copy number (GCN) variation is a newly described phenomenon, which likely contributes significant phenotypic variability within populations. Substantial GCN variation is present in genes that encode defensins, cationic antimicrobial peptides that play an important role in innate immunity to infectious diseases. The gene encoding -defensin 2, which is a key part the innate immune response in skin and mucosal surfaces, varies from 2-12 copies per diploid genome. Recent evidence has linked variation in the BD2 GCN with susceptibility to idiopathic diseases: low GCN increases the risk for Crohn's disease of the colon, while high GCN is associated with increased risk of psoriasis. We recently used the rhesus macaque model to demonstrate that, like in humans, BD2 expression is induced by Helicobacter pylori, a common gastric pathogen that is the causative agent of peptic ulcer and increases the risk for gastric cancer. Furthermore, our preliminary data suggest that rhesus macaques, like humans, have marked variation in BD2 GCN. We hypothesize that variation in BD2 GCN is reflected in expression levels of BD2, and that these differences will affect the outcome of infection with H. pylori. In Aim 1 we will characterize GCN and allelic diversity in the BD2 gene of macaques, and examine the relationship between GCN and expression of BD2 in primary cell culture. In Aim 2 we will identify three groups of macaques with low, intermediate, or high BD2 GNC, and compare their gastric biota and response to experimental challenge with H. pylori. Since only about 5 to 10% of humans infected with H. pylori will have clinical sequelae, while the remainder will have only asymptomatic gastritis, there is considerable interest in understanding host factors that are associated with disease. Understanding the functional relationship between genetic variations in the BD2 gene and H. pylori infection will therefore not only expand our knowledge of the relationship between the innate immune response and infection, but may also provide a translational link to better understand who may benefit from treatment of H. pylori in order to prevent peptic ulcer and gastric cancer. PUBLIC HEALTH RELEVANCE: ?-defensin2 (BD2) is an important innate immune effectors at epithelial surfaces that shows variability in gene copy number (GCN) and is induced by infection with Helicobacter pylori, an important gastric pathogen. We hypothesize that differences in BD2 GCN affect the host inflammatory response, and thus the propensity to develop disease after infection with H. pylori.