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

• 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
• 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

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）：新生儿对病毒诱导的喘息和特应性疾病（如哮喘）的复发性发作的易感性与遗传和环境因素的组合有关，这些因素有利于T辅助细胞2（Th 2）细胞而不是T辅助细胞1（Th 1）细胞的产生。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主要特征，它解释了Th 2在子宫内的优势，也可能决定了一些但不是所有新生儿出生后优先维持Th 2型反应的倾向。因此，胎儿免疫系统源自产生致耐受性调节性T细胞的多谱系造血干/祖细胞（HSPC），而成人免疫系统源自更可能产生免疫反应性T效应细胞的不同HSPC。我们假设，不同的新生儿可能有不同的比例，这两个隔间，那些与胎儿隔间的比例较高，可能更倾向于维持Th 2反应出生后的一段较长的时间。这一假设将在以下特定目的的实验中得到解决：（1）证实和扩展先前的发现，即存在区分胎儿和成人髓样细胞的基因表达和功能差异;（2）确定是否存在基因表达和功能差异。 正常脐带血中胎儿和成人T细胞和/或骨髓细胞混合物的个体差异 脐带血（UCB）样本;和（3）确定UCB中偏斜的胎儿与成人T和/或骨髓细胞比率是否预示病毒性呼吸道疾病和特应性疾病（例如哮喘）的发展。这些实验应导致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，也可能产生新的见解重要的诊断和治疗这些疾病。 公共卫生相关性：在人类个体发育的背景下已经检测到两种造血干/祖细胞，一种在子宫内产生致耐受性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发生顺序“分层”，不同的儿童可能出生时具有不同的两种混合物，并且这种可变性可能是出生后对病毒性呼吸道感染和哮喘的易感性的基础。