Neuroimmunologic Investigations of Autism Spectrum Disorders (ASD)

自闭症谱系障碍 (ASD) 的神经免疫学研究

基本信息

批准号：
8940001
负责人：
Susan Swedo
金额：
$ 16.55万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8940001
关键词：
Age American Antibodies Astrocytes Autistic Disorder Autopsy Behavior Behavioral Borrelia burgdorferi Brain Cerebrospinal Fluid Child Chronic Data Development Developmental Delay Disorders Environmental Risk Factor Etiology Family Functional disorder Genetic Immune System Diseases Immune system Immunologic Markers Individual Inflammation Inflammatory Injury Intervention Intestines Investigation Life Literature Lyme Disease MRI Scans Maternal antibody Microglia Minocycline Mothers NF-kappa B Nature Neurotoxins Nuclear Translocation Paper Pathologic Pattern Pharmacologic Substance Phenotype Play Prevalence Protocols documentation Public Health Recording of previous events Reporting Research Research Priority Role Sampling Scanning Serum Symptoms Testing Time Universities autism spectrum disorder autistic children chemokine cohort cytokine effective therapy immune function interest microbial neuroinflammation neurotoxic novel therapeutic intervention open label prevent response skills social communication suspected autism therapeutic target transcription factor

项目摘要

Autism is defined by its behavioral manifestations: social-communication deficits and the presence of restricted or repetitive behaviors. The cause of these abnormalities is unknown, but it is strongly suspected that autism spectrum disorders (ASD) result from a combination of genetic and environmental factors. The rising prevalence rates of ASD and the life-long, often debilitating nature of the symptoms combine to make autism spectrum disorders a major public health problem. Research that increases our understanding of the causes and nature of the symptoms, and studies that investigate the potential role for novel therapeutic interventions hold the promise of benefit for millions of American families. A growing literature supports a role for neuroimmune dysfunction in autism spectrum disorders (ASD), including observations of abnormal patterns of CSF cytokines and chemokines, and pathological reports of chronic neuroinflammatory changes among individuals with ASD. Evidence thus far supports that neuroimmune dysfunction may play prominent role in certain cases of autism, including those with a history of significant regression. If this hypothesis is correct, we would expect to find that at least some autistic children, particularly those with a history of regression, will have demonstrable abnormalities in immune function. Thus, we are continuing to collect data on a cohort of young children with autism that have been well-characterized and studied longitudinally. We are exploring immune markers in the CNS as well as peripherally. Finding new and effective treatments for autism is one of PDN's highest research priorities. One potential target was provided by a paper from Johns Hopkins University (D. Vargas et al, 2005) reporting that autopsy material from individuals with autism showed evidence of chronic brain neuroinflammation, as exemplified by activation of microglia and astroglia. The authors remarked that chronic microglia activation appeared to be responsible for a sustained neuroinflammatory response which could be producing neurotoxic factors. (Alternatively, neuroglial activation could occur in response to the presence of neurotoxins and thus represent the result, rather than the cause, of the injury.) The neuroinflammatory changes associated with neuroglial activation can be prevented by blocking nuclear translocation of the pro-inflammatory transcription factor NF-kappaB. Having completed an open-label trial of minocycline, an agent shown to inhibit NF KappaB, wherein neither immune markers (e.g. CSF and serum cytokines and chemokines) nor behavioral status changed, we continue to explore targets for further pharmaceutical intervention. The phenotyping study (Protocol 06-M-0102, NCT 00298246) is also continuing efforts to identify individuals with evidence of ongoing neuroinflammation as a potential cohort for targeted therapeutic efforts. Markers under investigation include those that relate to direct evidence of immune dysfunction in relation to core symptoms of autism, as well as in relation to associated features, such as gastro-intestinal problems in a subset of children. Previously collected samples have also been used to demonstrate that, contrary to a highly publicized report, children with autism do not have circulating antibodies against Borrelia burgdorferi (as would be seen in Lyme Disease); nor was there any evidence of microbial translocation, which had been proposed as an etiologic factor in autism (the so-called "leaky gut" hypothesis). In both studies, there were no discernable differences between samples obtained from typically developing children and those from children with autism. More recently, serum samples have been obtained from mothers of children with autism or typical development in order to evaluate recent reports that maternal antibodies play a role in the etiology of autism. Samples of children with autism are also being tested for a variety of autoreactive antibodies.

自闭症由其行为表现形式定义：社会通信缺陷以及受限制或重复行为的存在。这些异常的原因尚不清楚，但强烈怀疑自闭症谱系障碍（ASD）是由于遗传和环境因素的组合引起的。 ASD的患病率上升和终身症状的终身性，使人衰弱的性质结合起来，使自闭症谱系成为一个主要的公共卫生问题。提高了我们对症状原因和性质的理解以及研究新型治疗干预措施的潜在作用的研究使人对数百万美国家庭有利。越来越多的文献支持自闭症谱系障碍（ASD）中神经免疫功能障碍的作用，包括观察到CSF细胞因子和趋化因子异常模式，以及ASD患者中慢性神经炎性变化的病理报道。迄今为止，有证据表明，神经免疫功能障碍可能在某些自闭症病例中起着重要作用，包括具有重大回归史的自闭症。如果这个假设是正确的，我们希望至少有一些自闭症儿童，尤其是那些具有回归史的儿童，将在免疫功能方面具有明显的异常。因此，我们将继续收集有关自闭症的幼儿的数据，这些儿童经过了充分的表征和纵向研究。我们正在中枢神经系统和外围探索免疫标记。为自闭症寻找新的有效治疗方法是PDN的最高研究重点之一。约翰·霍普金斯大学（D. Vargas等，2005）的一篇论文提供了一个潜在的目标，该论文报告说，自闭症患者的尸检材料显示出慢性脑神经炎症的证据，这是通过小胶质细胞和星形胶质细胞激活的例证。作者指出，慢性小胶质细胞活化似乎是导致持续的神经炎症反应，可能会产生神经毒性因子。（或者，可以通过神经毒素的存在来响应神经毒素的存在，从而代表损伤的结果而不是原因。）可以通过阻断促脑膜炎转录因子NF-Kappab的核易位来预防与神经元激活相关的神经炎症变化。在完成了米诺环素的开放标签试验后，该试验显示了抑制NF Kappab的药物，其中免疫标记物（例如CSF和血清细胞因子和趋化因子和趋化因子）均未改变，我们继续探索目标进一步药物干预的靶标。表型研究（方案06-M-0102，NCT 00298246）也在继续努力，以确定具有持续神经炎症证据的人，作为有针对性的治疗努力的潜在队列。正在调查的标记包括与自闭症核心症状有关的直接证据以及与相关特征有关的直接证据，例如儿童子集中的胃肠道问题。以前收集的样品还被用来证明，与高度公开的报告相反，自闭症儿童没有针对Borrelia burgdorferi的循环抗体（如莱姆病中所见）；也没有任何微生物易位的证据，这些易位是自闭症的病因学因素（所谓的“肠道肠道”假设）。在这两项研究中，从通常发育的儿童和自闭症儿童获得的样本之间没有明显的差异。最近，已经从患有自闭症或典型发育的儿童的母亲那里获得了血清样本，以评估最近的报道，即母体抗体在自闭症的病因学中起作用。自闭症儿童的样本也正在测试各种自身反应性抗体。