CYTOKINE DYSREGULATION, VIRUSES, & CHILDHOOD ASTHMA

对于许多哮喘患者来说，这种综合征或疾病在婴儿期就有了根源。根据对人类的初步观察，以及我们实验室在病毒诱导的气道功能障碍啮齿动物模型中进行的实验，两个因素似乎影响了持续性喘息或哮喘表型的发展。首先是遗传因素，临床上表现为过敏性疾病的发展，免疫介导的是IgE抗体水平升高和/或细胞因子产生失调[很可能是干扰素γ (ifn - γ)产生减少]。其次，一个环境因素，它似乎与一种重要的病毒性下呼吸道疾病（很可能是呼吸道合胞病毒）的发展在生物学上有关，并且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，这些因素中的任何一个单独或联合的相对作用尚未明确确定。为了建立和提高我们对这些非常重要的关系的认识，本研究建议进行旨在回答以下问题的实验。ifn - γ在持续性喘息或哮喘儿童中是否失调？如果是这样，这些异常在生命的早期可以被证明吗？出生时?感染后?当孩子在不同时期遇到他/她的环境时？ifn - γ是唯一与这种结果相关的细胞因子，还是其他细胞因子也有关系？如果ifn - γ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？任何可证实的细胞因子反应或调节异常与临床明显过敏性疾病（如特应性皮炎、过敏性鼻炎和/或哮喘）的发展密切相关吗？为了回答这些问题，我们设计了一项前瞻性纵向研究，以评估相关免疫学、微生物学和临床参数的相互作用和时间依赖性。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.