Parental Expression of Immune Responses In Pediatric Crohn's Disease

描述（由申请人提供）： 儿童期发病的炎症性肠病，特别是克罗恩病，可能是导致更高发病率的遗传易感性增加的指标，并且通常被描述为具有更严重的疾病表型，即侵袭性或复杂的临床过程。我们的初步结果表明，微生物抗原的免疫反应的存在和幅度是更具侵略性的临床表型的亚临床标志物。很可能个体的遗传背景和他们的环境影响这些免疫应答的表达，这反过来又改变了儿童期克罗恩病（CD）的自然史。如果这些免疫应答确实代表了CD的遗传易感性，则这些免疫应答的定量和定性表达可作为CD的免疫风险标志物。在这个应用程序中，我提出，在未受影响的父母的CD后代的免疫反应的表达影响儿童期发病的CD的自然史。本提案的总体目标是确定未受影响的父母及其CD后代之间是否存在免疫应答表达相关性，以及这些相关性如何影响儿童期发病CD的自然史。具体目的包括目的1：检查CD后代未受影响亲本中血清学免疫应答的定量和定性表达，并确定亲本中的表达是否与受影响后代中的表达相关，目的2：证明未受影响亲本中免疫应答的定性和定量表达与其后代疾病自然史之间的相关性。将入组660名未受影响的父母，确定免疫应答的频率，并检测其免疫应答与其子代CD患者的免疫应答的相关性，以及这些免疫应答的表达如何影响其子女疾病的自然史。与疾病进展相关的风险因素的先验知识将导致在确定的高风险患者中进行干预研究，目的是预防临床疾病进展为临床并发症。如果这项研究的结果也可以确定疾病易感性的标志物，这将使我能够确定高风险的个人，并确认是否确实有疾病发展的免疫风险标志物，并考虑干预研究，以防止临床前疾病成为临床疾病。这项拟议的研究利用了这样一个事实，即小儿克罗恩病人群可能是一个具有加速自然史的高风险遗传群体。儿童父母亚临床水平免疫应答的存在所暗示的潜在风险环境的表征将提供关于免疫表型对临床结果影响的新信息。

DESCRIPTION (provided by applicant): Childhood-onset inflammatory bowel disease, Crohn's disease in particular, may be an indicator of increased genetic predisposition leading to a higher penetrance and is often described as having a more severe disease phenotype, i.e. an aggressive or complicated clinical course. Our preliminary results have demonstrated that the presence and magnitude of immune responses to microbial antigens are subclinical markers of a more aggressive clinical phenotype. It is likely than an individual's genetic background and their environment influence the expression of these immune responses, which i [sic] propose in turn alter the natural history of childhood onset Crohn's disease (CD). If indeed these immune responses represent a genetic susceptibility to CD, quantitative and qualitative expression of these immune responses may serve as an immunologic risk marker for CD. In this application I propose that the expression of immune responses in the unaffected parents of CD offspring influence the natural history of childhood-onset CD. The overall objective of this proposal is to determine if there is an association between unaffected parents and their CD offspring for immune response expression and how these associations influence the natural history of childhood-onset CD. The specific aims include Aim 1: To examine the quantitative and qualitative expression of serological immune responses in unaffected parents of offspring with CD and determine if expression in parents is associated with expression in affected offspring and Aim 2: To demonstrate an association between the qualitative and quantitative expression of immune responses in unaffected parents and the natural history of disease in their offspring. 660 unaffected parents will be enrolled and the frequency of immune responses will be determined and tested for associations of their immune responses with those in their offsring [sic] with CD and how the expression of these immune responses influence the natural history of their child's disease. The a priori knowledge of risk factors associated with disease progression, will lead to intervention studies in identified high risk patients with the goal of preventing progression of clinical disease to clinical complication. The results if this study may also identify markers of disease susceptibility, which will enable me to identify high risk individuals and confirm if indeed there are immunological risk markers of disease development and consider intervention studies to prevent pre-clinical disease from becoming clinical disease. The proposed research takes advantage of the fact that the pediatric Crohn's disease population is likely to be a high-risk genetic group with an accelerated natural history. The characterization of the potential risk milieu implied by the presence of immune responses at the sub clinical level in the child's' parents will offer new information on the influence of immune phenotypes on clinical outcomes.