Perinatal immune development and risk of childhood acute lymphoblastic leukemia

描述(申请人提供)：儿童白血病是最常见的儿童癌症，但在绝大多数病例中，病因尚不明确。流行病学研究指出，感染模式是白血病的有影响的危险因素--接触各种类型和数量的童年接触者(如托儿所和年长的兄弟姐妹)对白血病具有保护作用。这些关联对于白血病的前B细胞免疫表型是最强的，我们将在这里进行研究。新的流行病学证据表明，对感染的强烈反应是白血病的风险因素，这意味着需要医疗专业人员护理的感染。此外，与未患白血病的对照组儿童相比，患有白血病的儿童在出生时存在免疫抑制细胞因子IL10的缺陷，这意味着他们出生时带有先天性免疫异常。基于这些观察，我们假设新生儿免疫功能的特点，即缺乏免疫抑制，在前B细胞急性淋巴细胞白血病(Pre-B ALL)的风险中起重要作用。在目前的研究中，我们将进一步更详细地定义这种免疫抑制表型，并研究影响这种表型的发育、胎儿遗传交互作用和母体环境因素。我们将汇集500名ALL病例儿童及其母亲和500名对照儿童及其母亲，以评估在母亲体内为胎儿发展支持性免疫环境所起关键作用的两个遗传因素(人类白细胞抗原-C和KIR)是否会影响胎儿免疫状态和白血病病例/控制状态。我们还将评估200名病例母亲和500名对照母亲的新生儿免疫功能表型是否受母亲孕期免疫状态的影响。我们将通过除IL10水平以外的其他标记物来定义胎儿免疫表型，包括转化生长因子�、干扰素�和T调节细胞标记物-关键转录因子FOXP3的差异甲基化区域。在对照组中，首先将评估母亲细胞因子、免疫球蛋白E水平和KIR基因类型(以及新生儿中的人类白细胞抗原-C基因)对新生儿免疫功能的影响。然后将评估孕妇和胎儿的免疫表型在预测病例状态方面的影响。这项研究的结果将进一步挑战影响免疫系统癌症的免疫发展的关键特征。这些结果将有助于了解白血病的病因，并有助于儿童白血病的预测和预防方法，并为后续研究奠定基础，检查出生后因素与先天性免疫抑制相结合产生白血病。

DESCRIPTION (provided by applicant): Childhood leukemia is the most common childhood cancer but the causes of the disease are uncertain in the vast majority of cases. Epidemiology studies have pointed to patterns of infection being influential risk factors for leukemia - with exposure to a wide variety and number of childhood contacts (e.g., daycare and older siblings) being protective for leukemia. These associations are strongest for the pre-B cell immunophenotype of leukemia, which we will study here. New epidemiologic evidence suggests that vigorous response to infections, meaning infections that require care from medical professionals, is a risk factor for leukemia. Additionally, children who contract leukemia have a deficit of the immunosuppressive cytokine IL10 at birth when compared to control children who did not get leukemia, meaning that they enter the world with a congenital immune aberration. We hypothesize, based on these observations, that features of neonatal immune function, namely a lack of immunosuppression, are important in risk of pre-B cell acute lymphoblastic leukemia (pre-B ALL). In the current study we will further define this immunosuppressive phenotype in more detail and examine the developmental fetal genetic interaction and maternal environmental factors that influence this fetal phenotype. We will assemble a series of 500 ALL case children and their mothers, and 500 controls with their mothers to assess whether two genetic factors (HLA-C and KIR) critical in developing a supportive immune environment for a fetus within its mother can influence fetal immune status and leukemia case/control status. We will additionally assess, with 200 case mothers and 500 control mothers, whether neonatal immune function phenotype is influenced by maternal immune status during pregnancy. We will define fetal immune phenotype by additional markers besides only IL10 levels, including TGF-�, IFN-�, and T- regulatory cell marker - a differentially-methylated region of the critical transcription factor FOXP3. The impact of maternal cytokines and IGE levels, and KIR genotypes (along with HLA-C genotypes in the neonate) will first be assessed on neonatal immune function among controls. Both maternal and fetal immune phenotypes will then be assessed for their impact in prediction of case status. The results of this study will further defie critical characteristics in immune development that influence a cancer of the immune system. These results will benefit efforts to understand the etiology of leukemia as well aid predictive and preventative modalities for childhood leukemia, and set the stage for follow-up studies that examine postnatal factors that combine together with congenital immune immunosuppression to produce leukemia.