Prenatal Autoimmune and Inflammatory Risk Factors for Autism Spectrum Disorders

摘要 这项建议的重点是子宫内暴露于母体自身免疫性的作用， 决定后代的神经发育结果。我们的初步数据显示 支持这一假设，即母亲体内的抗脑抗体在 自闭症谱系障碍（ASD）的发展。我们特别关注ASD， 因为这种疾病的发病率在过去几十年中急剧增加。 虽然已经提出了许多环境触发因素，但越来越多的证据表明， 母体自身免疫和母体免疫激活。动物研究表明 子宫内暴露于母体抗脑抗体在疾病发病机制中起作用。 当从患有脑反应抗体的妇女和患有ASD的儿童中提取血清或纯化IgG时， 给怀孕的老鼠或猴子，后代表现出社会异常， 焦虑增加或运动活动增加。在横向研究中，我们有 有ASD孩子的女性患脑反应性痴呆的可能性是其他女性的4-5倍， 血清学比育龄妇女高。这些抗体在女性体内富集 母亲的自身免疫性已被证明易患ASD 结果。尽管有这些有趣的观察结果，但缺乏人类的前瞻性数据 显示了妊娠期间自身免疫和/或炎症与 后代出现神经发育异常。该项目将调查一个 前瞻性队列，以解决这一问题，方法是为有证据表明 自身免疫，并将其儿童神经发育障碍的发病率与 没有自身免疫证据的对照组母亲的孩子。在具体目标1中，我们将测试 母亲在怀孕时出现临床或亚临床自身免疫的假设 容易导致自闭症儿童我们将在一个4500人的队列中监测ASD相关的结果 自身免疫性疾病的母亲。具体目标2： 检验怀孕期间母体抗脑抗体的存在 更容易使孩子患上自闭症或神经发育问题。在特定 目的3，我们将检验母体免疫激活或细胞因子水平升高的假设， 在怀孕期间容易导致ASD的孩子。我们将跟踪细胞因子水平和模块 在第二和第三孕期母体全血基因表达的模式， 评估母体免疫和炎症因子对ASD相关性 后代的表型。支持宫内环境对风险作用的前瞻性数据 将从根本上改变我们对ASD发病机制的理解，并将直接导致 潜在的诊断以及预防疾病的新方法。

ABSTRACT This proposal focuses on the role of in utero exposure to maternal autoimmunity in determining neurodevelopmental outcomes of the offspring. Our preliminary data provide strong support for the hypothesis that anti-brain antibodies in mothers have a contributory role in the development of autism spectrum disorders (ASD). We focus particularly on ASD, in part because the incidence of this disorder has increased dramatically over the past few decades. While many environmental triggers have been suggested, growing evidence indicates roles for maternal autoimmunity and maternal immune activation. There is evidence from animal studies that exposure in utero to maternal anti-brain antibodies plays a role in disease pathogenesis. When serum or purified IgG from women with brain-reactive antibodies and a child with ASD are administered to pregnant mice or monkeys, the offspring exhibit abnormalities in social behavior, increased anxiety or increased motor activity. In cross sectional studies, we have shown that women with a child with ASD are 4-5 times more likely to have brain-reactive serology than unselected women of child-bearing age. These antibodies are enriched in women with autoimmunity, and autoimmunity in a mother has been shown to predispose to ASD outcome. Despite these intriguing observations, there is a lack of prospective data in humans showing a relationship between autoimmunity and/or inflammation during gestation and the presence of neurodevelopmental abnormalities in offspring. This project will investigate a prospective cohort to address this issue by enriching for mothers who have evidence of autoimmunity, and comparing the incidence of neurodevelopmental disorders in their children to the children of control mothers without evidence of autoimmunity. In specific aim 1, we will test the hypothesis that clinical or subclinical autoimmunity in the mother at the time of pregnancy predisposes to a child with ASD. We will monitor ASD related outcomes in a cohort of 4,500 mothers who are enriched for the presence of autoimmune disease. In specific aim 2, we will test the hypothesis that the presence of maternal anti-brain antibodies during pregnancy predisposes to a greater risk of a child with ASD or neurodevelopmental problems. In specific aim 3, we will test the hypothesis that maternal immune activation or increased cytokine levels at during pregnancy predisposes to ASD in the child. We will follow cytokine levels and modular patterns of maternal whole blood gene expression in the second and third trimesters in order to assess the contribution of maternal immune and inflammatory factors to ASD-related phenotypes in offspring. Prospective data supporting a role for intrauterine environment on risk for ASD will fundamentally alter our understanding of ASD pathogenesis and will lead directly to potential diagnostics as well as new approaches to disease prevention.