CYTOKINE DYSREGULATION, VIRUSES, & CHILDHOOD ASTHMA

对于许多哮喘患者来说，这种综合征或疾病的根源是在婴儿时期。根据对人类的初步观察，以及我们实验室在病毒诱导的呼吸道功能障碍的啮齿动物模型上进行的实验，似乎有两个因素影响持续性喘息或哮喘表型的发展。首先是一种遗传性成分，临床上表现为变态反应性疾病的发展，免疫学上由IgE抗体水平升高和/或细胞因子产生失调[最可能是干扰素-γ产生减少]介导。第二，环境成分，它似乎在生物学上与一种重要的病毒性下呼吸道疾病(最有可能是呼吸道合胞病毒)的发展有关，并在时间上与下呼吸道生理发育的关键阶段有关。然而，在婴儿期和/或幼儿期，这两个因素中的任何一个单独或结合在一起的相对贡献尚未明确确定。为了建立和促进我们对这些非常重要的关系的了解，本研究建议进行旨在回答以下问题的实验。持续性喘息症或哮喘儿童是否存在干扰素-γ调节失调？如果是这样的话，这些异常在多早的时候可以被证明？出生的时候？在感染之后？当孩子在不同的时间里遇到他/她的环境时？干扰素-γ是唯一可以与这种结果相关的细胞因子吗，或者其他细胞因子是否也参与其中？如果干扰素-γ调节失调可以被证明与各种结果有因果关系，那么这种缺陷的机制是什么？细胞因子反应或调节的任何明显异常与临床上明显的过敏性疾病(如特应性皮炎、过敏性鼻炎和/或哮喘)的发展有多密切的关系？为了回答这些问题，设计了一项前瞻性的纵向研究，评估相关免疫学、微生物学和临床参数的相互作用和时间相关性。这些研究的结果将为我们理解遗传和环境风险因素对儿童哮喘发展的相对影响提供重要的信息。

For many asthmatic patients, the syndrome or disease has its roots in infancy. From preliminary observations in humans, and from experiments performed in a rodent model of virus-induced airway dysfunction in our laboratory, two factors appear to influence the development of persistent wheezing or the asthmatic phenotype. First a hereditary component which is clinically manifested by the development of allergic diseases, and immunologically mediated by the presence of increased levels of IgE antibody and/or a dysregulation in cytokine production [most likely a decreased production of interferon gamma (IFN-gamma)]. Second, an environmental component, which appears biologically related to the development of a significant viral lower respiratory tract illness (most likely respiratory syncytial virus), and temporally related to a critical stage in the physiological development of the lower airway. However, the relative contribution of either of these factors, either alone or in combination, has yet to be clearly established during infancy and/or early childhood. To establish and advance our knowledge about these very important relationships, this study proposes to conduct experiments designed to answer the following questions. Is IFN-gamma dysregulated in persistent wheezers or asthmatic children? If so, how early in life can these abnormalities be demonstrated? At birth? Following infection? As the child encounters his/her environment for various periods of time? Is IFN-gamma the only cytokine that can be linked with such outcomes, or can other cytokines be involved as well? If IFN-gamma dysregulation can be shown to be causally linked with various outcomes, what is the mechanism of the defect? How closely do any demonstrable abnormalities in cytokine responses or regulation track with the development of clinically apparent allergic disease such as atopic dermatitis, allergic rhinitis, and or asthma? To answer these questions, a prospective longitudinal study has been designed that will evaluate the interactions and time dependencies of relevant immunological, microbiological, and clinical parameters. The results of these studies will provide information that will be a major step forward in our understanding of the relative influences that genetic and environmental risk factors have on the development of childhood asthma.