Neuroimmunologic Investigations of Autism Spectrum Disorders (ASD)

自闭症谱系障碍 (ASD) 的神经免疫学研究

• 批准号: 8342179
• 负责人: Susan Swedo
• 金额: $ 26.47万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 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/8342179
• 关键词: Address; Affect; Age; American; Astrocytes; Autistic Disorder; Autopsy; Bacteria; Behavior; Behavioral; Biological Assay; Blood; Blood Circulation; Blood specimen; Brain; Cerebrospinal Fluid; Child; Chronic; Clinical; Communication; Development; Developmental Delay Disorders; Disease; Environmental Risk Factor; Family; Functional disorder; Gastrointestinal tract structure; Genetic; Immune System Diseases; Immune system; Impairment; Individual; Inflammation; Inflammatory; Injury; Investigation; Life; Link; Literature; MRI Scans; Microglia; Minocycline; NF-kappa B; Nature; Neuraxis; Neurotoxins; Nuclear Translocation; Paper; Pathologic; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Prevalence; Process; Production; Public Health; Recording of previous events; Reporting; Research; Research Priority; Role; Sampling; Scanning; Serum; Subgroup; Symptoms; Syndrome; Therapeutic Agents; Time; Universities; autism spectrum disorder; autistic behaviour; autistic children; chemokine; cohort; cytokine; effective therapy; gastrointestinal; gastrointestinal symptom; immune function; interest; microbial; neuroinflammation; neurotoxic; novel therapeutic intervention; novel therapeutics; open label; prevent; response; skills; social; social communication; suspected autism; therapeutic target; transcription factor

Autism is defined by its behavioral manifestations: social deficits, impairments in communication 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 (last reported to affect as many as 1 in 100 children) 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. Neuroimmune dysfunction is considered to be a potential etiologic factor in regressive autism where children are reported to have had a period of normal development and then began losing social and communication skills. The clinical course of regressive autism (particularly when it occurs acutely or semi-acutely) is consistent with alterations in immune function that are impacting on the central nervous system. If this hypothesis is correct, we would expect to find that at least some autistic children with a history of regression will have demonstrable abnormalities in immune function. These abnormalities are not expected to be found among autistic children without a regressive course; nor should they be present in the contrast groups of typically developing children or children with non-autistic developmental delays. 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. Minocycline has been shown to inhibit NF-kappaB production and has been used with modest benefit in a number of neuroinflammatory disorders. We undertook an open-label trial of minocycline to determine if the drug might have an effect on autistic behaviors or change patterns of distribution for the CSF or serum cytokines or chemokines. Minocycline produced no discernable improvements in the children's developmental trajectory or overall behavior; it also failed to significantly change the patterns of cytokines or chemokines in CSF or serum. Thus, no further investigations are planned for minocycline, but the search for novel therapeutic agents continues in other PDN projects. The phenotyping study is also continuing efforts to identify individuals with evidence of ongoing neuroinflammation as a potential cohort for targeted therapeutic efforts. A number of anecdotal reports have linked autism with gastrointestinal (GI) dysfunction; most notable among these are reports that autism is associated with "leaky gut" syndrome. Microbial translocation (MT) is the process by which bacteria or microbial byproducts permeate through the wall of the GI tract (or other abnormally porous mucosal barriers) into the bloodstream. The microbial byproducts would then stimulate the immune system, which could have secondary effects on CNS functioning, or the byproducts could have a direct neurotoxic effect. We conducted assays of MT products in children with autism (from blood and CSF), as well as typically developing children (blood samples only). MT markers were not found in the blood or CSF of children with autism and there were no overall differences found between children with autism and the age-matched typically developing children who served as their controls. Although these results would appear to rule out the "leaky gut" syndrome as a cause of autism, GI dysfunction was not a major problem for any of the children studied. Therefore, it is possible that our results were negative only because our sample didn't include patients with GI-neuro-immune dysfunction. Our ongoing phenotyping studies will be used to identify a cohort of children with autism who also have significant gastrointestinal symptoms in order to address this potentially important subgroup of patients.

自闭症由其行为表现形式定义：社会缺陷，沟通障碍以及存在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（上次据报道会影响100名儿童中多达1个），症状的终身性，常常使人衰弱的性质结合在一起，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。 神经免疫性功能障碍被认为是回归自闭症的潜在病因因素，据报道儿童患有正常发展，然后开始失去社会和沟通技巧。 回归自闭症的临床过程（尤其是在急性或半胃发生时）与影响中枢神经系统影响的免疫功能的改变是一致的。 如果这一假设是正确的，我们希望至少有一些具有回归史的自闭症儿童在免疫功能方面具有明显的异常。预计没有回归过程的自闭症儿童中不会发现这些异常。它们也不应出现在典型发展的儿童或非自主发展延迟的儿童的对比群体中。 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。 米诺环素已显示可抑制NF-kappab的产生，并在许多神经炎症性疾病中以适度的益处使用。 我们对米诺环素进行开放标签试验，以确定该药物是否可能对CSF或血清细胞因子或趋化因子或趋化因子的自闭症行为或变化分布模式产生影响。 米诺环素对儿童的发育轨迹或整体行为没有明显的改善。它也未能显着改变CSF或血清中细胞因子或趋化因子的模式。 因此，没有计划进一步研究米诺环素，但是在其他PDN项目中，对新型治疗剂的寻找仍在继续。 该表型研究也在继续努力，以确定具有持续神经炎症的证据的人，作为有针对性治疗的潜在队列。 许多轶事报告已将自闭症与胃肠道（GI）功能障碍联系起来；其中最值得注意的是自闭症与“漏水”综合征有关的报道。 微生物易位（MT）是细菌或微生物副产品通过胃肠道（或其他异常多孔粘膜屏障）渗透到血液中的过程。 然后，微生物副产品将刺激免疫系统，这可能会对中枢神经系统的功能产生次要影响，或者副产物可能具有直接的神经毒性作用。 我们对自闭症儿童（来自血液和CSF）以及通常患儿童（仅血液样本）进行了MT产品的测定。 在自闭症儿童的血液或CSF中未发现MT标记，自闭症儿童和年龄匹配的通常是作为对照的儿童匹配的儿童之间没有总体差异。 尽管这些结果似乎排除了“漏水”综合征是自闭症的原因，但对于任何研究的孩子来说，胃肠道功能障碍并不是主要问题。 因此，我们的结果可能仅是因为我们的样本不包括gi-neuro-免疫功能障碍的患者。 我们正在进行的表型研究将用于确定一群自闭症儿童，这些儿童也患有明显的胃肠道症状，以解决这种潜在的重要亚组患者。