Project 2: Immunological Susceptibility of Autism

最近的研究表明，自闭症谱系障碍（ASD）儿童的免疫功能 与发育健康的对照组相比发生了深刻的变化。有一个强大的接口之间的 免疫系统和神经网络，成功的神经发育取决于一个 这两个系统之间的成功互动。我们已经确定了免疫的几个方面， 自闭症患者与正常发育对照组相比，其中包括减少 对细菌来源的疫苗抗原的应答，血浆中细胞因子水平的改变，以及 早发型孤独症患者外周血单个核细胞瘦素水平升高和脑抗原自身抗体 我们在第一个资助期注意到的这种广泛而复杂的免疫异常与 自闭症谱系所包含的广泛的表型。我将以我的初心， 免疫功能的血清学和细胞学变化。虽然我们在上一个项目中的研究 期间旨在广泛分析自闭症患者的免疫功能，目前的建议将 解决了我们的研究中发现的免疫稳态的许多改变的机制， 早期的研究。因此，我们的主要重点将是负责这种异常的机制， 通过深入分析细胞免疫功能来了解免疫功能。我们的总体假设是 自闭症患者在细胞水平上有一个根本性的缺陷， 免疫功能异常和对环境触发因素的敏感性增加。到 为了验证这一点，我们建议：（1）纵向检查ASD儿童的血清学特征，以确定 我们在第一次研究中注意到的各种免疫变化是否得到维持和/或进一步恶化; (2)确定哪些免疫细胞群在患者中观察到的免疫功能障碍中起关键作用 自闭症儿童;（3）充分表征ASD儿童亚群中的自身抗体反应 还有一些自闭症儿童的母亲必须指出的是，由于高度异质性， 自闭症，将有潜在的免疫差异，涉及自闭症患者的亚组。 因此，我们将根据我们现有的数据仔细定义研究组，以包括患有早期 初发性自闭症、迟发性/退行性自闭症儿童、一般人群对照组和 没有ASD的发育障碍。这些研究将在之前的CHARGE受试者中进行 我们的实验室分析（Charge-BACK研究）。这将使我们能够扩展我们先前的研究 以确定是否免疫失调，如早期发病时瘦素水平升高， 患者，随着时间的推移。以下目的涉及免疫调节的血清学和细胞学方面。 在自闭症患者中的作用。

Recent studies indicate that immune function in children with autism spectrum disorder (ASD) is profoundly altered compared to developmentally healthy controls. There is a strong interface between the immune system and the neurologic network, and successful neurodevelopment is contingent upon a successful interaction between these two systems. We have identified several aspects of immune dysfunction in patients with autism compared with typically developing controls. These include a reduced response to vaccine antigens of bacterial origin, altered cytokine levels in plasma and upon stimulation of PBMC, increased levels of leptin in patients with early onset autism, and autoantibodies to brain antigens. This wide and complex variety of immune anomalies noted in our first funding period is in keeping with the broad range of phenotypes encompassed by the autism spectrum. Thus, we will build upon our earlier findings of both serologic and cellular changes in immune function. While our studies in the previous project period were aimed at a broad analysis of immune function in patients with autism, the current proposal will address the mechanisms responsible for the numerous alterations in immune homeostasis uncovered in our earlier studies. Therefore, our primary focus will be on the mechanisms responsible for such anomalies in immune function through an in depth analysis of cellular immune function. Our overall hypothesis is that patients with autism have a fundamental defect at the cellular level that ultimately leads to abnormalities in immune function and heightened susceptibility to environmental triggers. To examine this, we propose to: (1) examine longitudinally the serologic profile of children with ASD to ascertain whether the various immune changes noted in our first studies are maintained and/or deteriorating further; (2) determine which immune cell population(s) plays a critical role in the immune dysfunction seen in patients with autism; and (3) fully characterize the autoantibody response in a subpopulation of children with ASD and some mothers of children with ASD. It must be noted that due to the highly heterogeneous nature of autism, there will potentially be immunologic differences that relate to sub-groups of patients with autism. Therefore, we will carefully define the study groups based on our current data to include children with early onset autism, children with delayed onset/regressive autism, general population controls, and children with developmental disorders without ASD. The studies will be performed on CHARGE subjects formerly analyzed by our laboratory (CHARGE-BACK study). This will allow us to extend our prior studies longitudinally to determine if the immune dysregulation, such as increased leptin levels in the early onset patients, remains over time. The following aims address both the serologic and cellular aspects of immune function in patients with autism.