Parental Expression of Immune Responses In Pediatric Crohn's Disease

描述(由申请人提供)： 儿童期起病的炎症性肠病，特别是克罗恩病，可能是遗传易感性增加导致更高外显性的指标，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病程。我们的初步结果表明，对微生物抗原的免疫反应的存在和程度是更具侵袭性的临床表型的亚临床标志。一个人的遗传背景和他们的环境很可能会影响这些免疫反应的表达，我[原创]提出，这反过来又改变了儿童发病的克罗恩病(CD)的自然病史。如果这些免疫反应确实代表了CD的遗传易感性，那么这些免疫反应的定量和定性表达可能作为CD的免疫危险标记。在这一应用中，我认为CD子代未受影响的父母的免疫反应的表达影响了儿童起病CD的自然病程。这项建议的总体目标是确定未受影响的父母和他们的CD后代之间是否存在免疫反应表达的关联，以及这些关联如何影响儿童起病CD的自然历史。目的1：检测CD患儿父母血清免疫反应的定量和定性表达，并确定父母的表达是否与患病子女的表达有关；目的2：证明未患病父母的免疫反应定性和定量表达与其子女的自然病史之间的关系。660名未受影响的父母将被登记，免疫反应的频率将被确定和测试，以确定他们的免疫反应与他们患有CD的后代的联系，以及这些免疫反应的表达如何影响他们孩子的疾病的自然病史。对与疾病进展相关的危险因素的先验知识，将导致对已确定的高危患者进行干预研究，目的是防止临床疾病的进展到临床并发症。这项研究的结果可能还会确定疾病易感性的标志，这将使我能够识别高危个体，确认是否确实存在疾病发展的免疫风险标志，并考虑进行干预研究，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，即儿童克罗恩病人群很可能是具有加速自然病史的高危遗传组。儿童父母亚临床水平的免疫反应所隐含的潜在危险环境的特征将为免疫表型对临床结果的影响提供新的信息。

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.