Immune regulation and autism

免疫调节与自闭症

• 批准号: 10152381
• 负责人: Paul Ashwood
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152381
• 关键词: 3 year old; ASD patient; Address; Adult; Affect; Amygdaloid structure; Anxiety; Area; Autoimmune; Autoimmunity; Autopsy; Behavior; Behavioral; Biological Response Modifiers; Blood; Blood specimen; Brain; Cell Lineage; Cell physiology; Cell surface; Cells; Cerebrospinal Fluid; Child; Childhood; Clinical Research; Coculture Techniques; DNA Methylation; Data; Defect; Development; Diagnosis; Disease; Epigenetic Process; Exhibits; FOXP3 gene; Flow Cytometry; Frequencies; Functional disorder; Genetic Transcription; Growth; Human; Immune; Immune System Diseases; Immune Targeting; Immune Tolerance; Immune response; Immunologics; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Innate Immune Response; Interleukin-10; Interleukin-17; Investigation; Knowledge; Lead; Life; Link; Longevity; Maps; Measures; Mediating; Molecular; Neurodevelopmental Disorder; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Perinatal; Phenotype; Plasma; Play; Population; Process; Proteomics; Public Health; Quantitative Reverse Transcriptase PCR; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Risk; Risk Factors; Role; Sampling; Severities; Signal Pathway; Signal Transduction; Social Behavior; Social Interaction; Structure; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Umbilical Cord Blood; atopy; autism spectrum disorder; autistic children; behavioral impairment; behavioral outcome; behavioral phenotyping; bisulfite; cellular targeting; cohort; comorbidity; cytokine; demethylation; drug discovery; epidemiology study; epigenetic regulation; experimental study; forkhead protein; genetic signature; immune activation; immune function; immunoregulation; improved; individuals with autism spectrum disorder; innovation; insight; neurodevelopment; neuroinflammation; neuron loss; novel; population based; prospective; pyrosequencing; receptor; receptor function; social anxiety; stem; therapeutic target

Project Summary/Abstract: Many in vitro studies, post-mortem brain studies, and proteomic studies in plasma and cerebral spinal fluid have described the presence of increased immune activation in ASD, whilst clinical and epidemiological studies suggest that there is an increase in immune mediated conditions such as atopy and autoimmunity. Activation of these immune responses is more prominent in individuals with exacerbated behavioral impairments in ASD. Despite recent advances, there is a large gap in our knowledge regarding pathophysiological pathways in ASD. We hypothesize that an underlying mechanism common to this diverse array of findings is the lack of immune control or regulation that can lead to immune activation and inflammation. Regulatory T cells (Tregs) are key mediators of immune tolerance that maintain their lineage commitment and function through epigenetic regulation, and restrain inappropriate inflammation. We and others have previously demonstrated decreased frequencies of Tregs-and immunosuppressive cytokines including transforming growth factor (TGF)1 and interleukin (IL)-10.Our new preliminary data shows that these immune regulatory deficits are associated with more severe behavioral phenotypes. However, no studies have yet to address the functional cellular mechanisms of Tregs in ASD. We will test the innovative hypothesis that a lack of cellular immune regulation is an early predictive risk factor for ASD, and that it endures in children with ASD who have received a diagnosis. Considering that impairments in social interaction and anxiety are key features of ASD, the amygdala has been extensively implicated in ASD pathophysiology. We will also address the absence of immune regulation in the amygdala of individuals with ASD and matched controls over development. This is an important area of investigation since therapeutic targeting of immune control mechanisms might improve immune function, address abnormal amygdala development and alleviate behavioral abnormalities. The proposed studies will determine immune regulation, Treg cellular function and epigenetic mechanisms controlling Tregs commitment and stability (Aim #1) in children with ASD and typically developing (TD) controls. In two prospective, population based cohorts we will examine immune regulatory mechanisms in cord blood samples from children that later receive a diagnosis of ASD, or TD (Aim #2). The proposal will directly assess the relationship of predictive and longitudinal measures of immune dysregulation and behavior abnormalities in ASD. We will examine amygdala growth over development into adulthood and immune regulation in human samples from ASD and TD controls (Aim #3). If successful, this research will validate the transformative concept that ASD is, for some, a disorder due to defects in immune regulation and will validate a novel mechanism for one of the most visible public health concerns of our time. .

项目摘要/摘要：许多体外研究，死后大脑研究和蛋白质组学研究， 血浆和脑脊髓液已经描述了ASD中免疫激活增加的存在， 临床和流行病学研究表明，免疫介导的病症增加， 特应性和自身免疫。这些免疫反应的激活在患有以下疾病的个体中更为突出： 加剧了自闭症谱系障碍的行为障碍。尽管最近取得了一些进展，但我们的知识仍有很大的差距， 关于ASD的病理生理途径。我们假设，一个共同的潜在机制， 一系列不同的发现是缺乏免疫控制或调节，这可能导致免疫激活， 炎症调节性T细胞（Regulatory T cells，Tcells）是维持免疫耐受的关键介质 承诺和功能通过表观遗传调节，并抑制不适当的炎症。我们和 其他人先前已经证明Tregs和免疫抑制细胞因子的频率降低 包括转化生长因子（TGF）β 1和白细胞介素（IL）-10。我们新的初步数据显示， 这些免疫调节缺陷与更严重的行为表型有关。然而，没有研究 还没有解决ASD中TdR的功能性细胞机制。我们将检验创新假设 缺乏细胞免疫调节是ASD的早期预测风险因素， 患有ASD的患者。考虑到社会交往和焦虑的障碍 作为ASD的关键特征，杏仁核已广泛涉及ASD病理生理学。我们还将 解决ASD患者和匹配对照组杏仁核中免疫调节缺失的问题， 发展这是一个重要的研究领域，因为免疫控制的治疗靶向 机制可能会改善免疫功能，解决异常杏仁核发育和减轻 行为异常拟议的研究将确定免疫调节、Treg细胞功能和 在ASD儿童中控制Tendon承诺和稳定性的表观遗传机制（目标#1）， 开发（TD）控制。在两个前瞻性的，基于人群的队列中，我们将研究免疫调节 在后来接受ASD或TD诊断的儿童的脐带血样本中发现了一种机制（目标#2）。的 该提案将直接评估免疫失调的预测性和纵向测量的关系 和行为异常我们将研究杏仁核在成年期的生长情况， 来自ASD和TD对照的人样品中的免疫调节（目标#3）。如果成功，这项研究将 验证了ASD是一种由于免疫调节缺陷引起的疾病的变革性概念， 将为我们这个时代最明显的公共卫生问题之一验证一种新的机制。 .