Layering of the human immune system, viral infections, and childhood asthma

人体免疫系统的分层、病毒感染和儿童哮喘

基本信息

批准号：
8298764
负责人：
JOSEPH M MCCUNE
金额：
$ 32.81万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-21 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298764
关键词：
Address Admixture Adult Anatomy Appearance Area Asthma Basophils Birds Birth Blood specimen Breathing CD4 Positive T Lymphocytes Cell Lineage Cells Child Childhood Childhood Asthma Chronic Dendritic Cells Development Diagnosis Disease Effector Cell Environment Environmental Risk Factor Equilibrium Event Fetus Functional disorder Gene Expression Generations Genetic Growth Helper-Inducer T-Lymphocyte Hematopoiesis Hematopoietic Human IgE Immune Immune response Immune system Individual Infectious Agent Inflammation Interleukin-13 Interleukin-4 Interleukin-5 Lead Life Literature Location Maintenance Mediating Mothers Mus Myeloid Cells Nature Neonatal Newborn Infant Pathway interactions Phenotype Physiological Predisposition Pregnancy Property Recurrence Regulatory T-Lymphocyte Reporting Respiratory Tract Infections Respiratory physiology Staging Stem cells Structure of parenchyma of lung System T-Lymphocyte Time Tissues Umbilical Cord Blood Variant Viral Virus Virus Diseases Wheezing airway epithelium airway hyperresponsiveness early childhood fetal in utero insight lymph nodes mast cell migration neonate novel research study respiratory response stem

项目摘要

DESCRIPTION (provided by applicant): The susceptibility of newborns to recurrent episodes of virus-induced wheezing and atopic disorders (such as asthma) has been associated with a combination of genetic and environmental factors that favor the generation of T helper 2 (Th2) cells over T helper 1 (Th1) cells. In ongoing experiments, we have discovered a governing feature of human immune system ontogeny that explains Th2 dominance in utero and that may also determine the propensity of some but not all neonates to preferentially sustain Th2-type responses after birth. Thus, the fetal immune system is derived from multi-lineage hematopoietic stem/progenitor cells (HSPCs) that give rise to tolerogenic regulatory T cells while the adult immune system is derived from distinct HSPCs that are more likely to give rise to immunoreactive T effector cells. We hypothesize that different neonates may have varying proportions of these two compartments and that those with a higher proportion of the fetal compartment may be more predisposed to sustaining Th2 responses for a longer period of time after birth. This hypothesis will be addressed in experiments of the following Specific Aims: (1) to confirm and extend previous findings that there are gene expression and functional differences that distinguish fetal and adult myeloid cells; (2) to determine whether there is inter individual variation in the admixture of fetal and adult T and/or myeloid cells in normal umbilical cord blood (UCB) samples; and (3) to determine whether skewed fetal-to-adult T and/or myeloid cell ratios in UCB are predictive of the development of viral respiratory illness and atopic disorders, e.g. asthma. These experiments should lead to a better understanding of the pathophysiology of viral respiratory illnesses and atopic disorders of childhood, and may also generate novel insights important for the diagnosis and treatment of such diseases. PUBLIC HEALTH RELEVANCE: Two hematopoietic stem/progenitor cells have been detected in the context of human ontogeny, one that gives rise to tolerogenic T cells in utero and another that gives rise to immunoreactive T cells after birth. The studies of this proposal address the possibility that sequential "layering" of fetal-type and adult-type T cells and myeloid cells may occur, that different children may be born with varying admixtures of the two, and that such variability may underlie susceptibility to viral respiratory infections and asthma after birth.

描述（由申请人提供）：新生儿对病毒引起的喘息和特应性疾病（例如哮喘）反复发作的易感性与有利于辅助 T 2 (Th2) 细胞生成的遗传和环境因素的组合有关超过 T 辅助细胞 1 (Th1) 细胞。在正在进行的实验中，我们发现了人类免疫系统个体发育的一个控制特征，它解释了 Th2 在子宫内的主导地位，也可能决定了一些但不是全部新生儿在出生后优先维持 Th2 型反应的倾向。因此，胎儿免疫系统源自多谱系造血干/祖细胞 (HSPC)，产生耐受性调节性 T 细胞，而成人免疫系统源自不同的 HSPC，更有可能产生免疫反应性 T 效应细胞。我们假设不同的新生儿这两个区室的比例可能不同，并且胎儿区室比例较高的新生儿可能更容易在出生后更长时间地维持 Th2 反应。这一假设将在以下具体目标的实验中得到解决：（1）证实和扩展先前的发现，即存在区分胎儿和成人骨髓细胞的基因表达和功能差异； (2)判断是否存在间正常脐带中胎儿和成人 T 细胞和/或骨髓细胞混合的个体差异脐带血（UCB）样本； (3) 确定 UCB 中胎儿与成人 T 细胞和/或骨髓细胞比例的偏差是否可以预测病毒性呼吸道疾病和特应性疾病（例如，呼吸道疾病）的发生。哮喘。这些实验应该有助于更好地了解病毒性呼吸道疾病和儿童特应性疾病的病理生理学，并且还可能产生对于此类疾病的诊断和治疗重要的新见解。公共健康相关性：在人类个体发育过程中检测到了两种造血干/祖细胞，一种在子宫内产生耐受性 T 细胞，另一种在出生后产生免疫反应性 T 细胞。该提案的研究解决了以下可能性：胎儿型和成人型 T 细胞和骨髓细胞可能会发生顺序“分层”，不同的孩子出生时可能具有不同的两者混合物，并且这种变异性可能是对以下疾病的易感性的基础：出生后病毒性呼吸道感染和哮喘。