Neuroimmunologic Investigations of Autism Spectrum Disorders (ASD)

自闭症是由其行为表现来定义的：社交缺陷，沟通障碍以及存在限制或重复行为。 这些异常的原因尚不清楚，但强烈怀疑自闭症谱系障碍（ASD）是遗传和环境因素共同作用的结果。 自闭症谱系障碍的患病率不断上升（最新报告称，每100名儿童中就有1名受到影响），加上这些症状的终身性，往往使人衰弱，这些因素结合在一起联合收割机使自闭症谱系障碍成为一个主要的公共卫生问题。 增加我们对症状的原因和性质的理解的研究，以及调查新的治疗干预措施的潜在作用的研究，有望使数百万美国家庭受益。 越来越多的文献支持神经免疫功能障碍在自闭症谱系障碍（ASD）中的作用，包括CSF细胞因子和趋化因子异常模式的观察，以及ASD患者慢性神经炎症变化的病理报告。 神经免疫功能障碍被认为是退行性自闭症的一个潜在病因因素，据报道，儿童有一段正常发育期，然后开始失去社交和沟通技能。 退行性自闭症的临床过程（特别是当它急性或半急性发生时）与影响中枢神经系统的免疫功能改变一致。 如果这一假设是正确的，我们将期望发现至少一些有退化史的自闭症儿童将有明显的免疫功能异常。这些异常预计不会在没有退化过程的自闭症儿童中发现，也不应该存在于正常发育的儿童或非自闭症发育迟缓的儿童的对照组中。 寻找新的有效的自闭症治疗方法是PDN的最高研究优先事项之一。约翰霍普金斯大学的一篇论文（D. Vargas等人，2005年）报告说，自闭症患者的尸检材料显示慢性脑神经炎症的证据，如小胶质细胞和星形胶质细胞的活化所示。 作者指出，慢性小胶质细胞激活似乎是导致持续神经炎症反应的原因，而这种反应可能产生神经毒性因子。 （或者，神经胶质细胞的激活可能是对神经毒素存在的反应，因此代表了损伤的结果，而不是原因。 与神经胶质细胞活化相关的神经炎症变化可以通过阻断促炎转录因子NF-κ B的核转位来预防。 米诺环素已被证明可以抑制NF-κ B的产生，并已被用于许多神经炎性疾病中，并具有适度的益处。 我们进行了一项米诺环素的开放标签试验，以确定该药物是否可能对自闭症行为或CSF或血清细胞因子或趋化因子的分布模式产生影响。 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，没有计划对米诺环素进行进一步的研究，但在其他PDN项目中继续寻找新的治疗药物。 表型研究也在继续努力，以确定具有持续神经炎症证据的个体作为靶向治疗工作的潜在队列。 许多轶事报道将自闭症与胃肠功能障碍联系起来;其中最值得注意的是自闭症与“漏肠”综合征有关的报道。 微生物易位（MT）是细菌或微生物副产物通过胃肠道壁（或其他异常多孔的粘膜屏障）渗透到血流中的过程。 微生物的副产物会刺激免疫系统，这可能对中枢神经系统的功能产生继发性影响，或者副产物可能具有直接的神经毒性作用。 我们在自闭症儿童（来自血液和CSF）以及典型发育儿童（仅血液样本）中进行了MT产品的测定。 在自闭症儿童的血液或CSF中没有发现MT标记物，并且在自闭症儿童和作为其对照的年龄匹配的典型发育儿童之间没有发现总体差异。 尽管这些结果似乎排除了“漏肠”综合征是自闭症的原因，但GI功能障碍并不是研究中任何儿童的主要问题。 因此，我们的结果可能是阴性的，只是因为我们的样本不包括GI神经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组自闭症儿童，他们也有显著的胃肠道症状，以解决这个潜在的重要患者亚组。

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.