Infection, fever and immune signatures in an autism birth cohort

描述（由申请人提供）：来自自闭症（ASD）流行病学和动物模型研究的证据支持产前和产后免疫和感染因素在自闭症发病机制中的作用。然而，与特定病原体、免疫反应模式、发热和接触抗生素、退烧药、止痛药和微量营养素的关系尚未得到严格处理。该项目将利用挪威自闭症出生队列（ABC）和感染和免疫中心（CII）的独特资源，通过追求三个互补的目标，不仅解决免疫激活，发烧和药物和微量营养素暴露在妊娠期间本身，而且这些现象的时间，深入了解感染，免疫和炎症在自闭症中的作用。在目标1中，我们将使用关于ASD和对照母子对的以下暴露的前瞻性问卷调查数据来调查感染、免疫和炎症事件与ASD风险的关系：a）感染; B）发热的存在、时间和持续时间，c）自身免疫性和过敏性疾病，d）退热药（对乙酰氨基酚、非甾体抗炎药[NSAID]）、镇痛药和抗生素，以及e）改变免疫功能（维生素D、锌）或减轻抗生素抗叶酸作用（叶酸）的微量营养素。在目标2中，我们将使用多重免疫测定（Luminex）来定义与ASD相关的免疫特征，以比较ASD和对照母亲（妊娠中期、出生）和儿童（脐带血）血浆样本中61种免疫/炎症分子的水平。在目标3中，我们将通过测量母亲和儿童对流感病毒、ToRCH病原体T.弓形虫、风疹病毒、巨细胞病毒和单纯疱疹病毒1型和2型;以及B组链球菌和E.大肠杆菌中，使用荧光素酶免疫沉淀系统（LIPS）和多重免疫测定（Luminex）。这些目标有可能确定ASD风险的因素和生物标志物，以促进早期诊断和干预。挪威研究理事会审查了该提案，并保证提供最多500万挪威克朗（834，000美元）的资金，以支持该项目的挪威部分，但前提是国家卫生研究院提供支持。

DESCRIPTION (provided by applicant): Evidence from epidemiologic and animal model studies of autism (ASD) supports a role for pre- and postnatal immune and infectious factors in autism pathogenesis. However, associations with specific pathogens, patterns of immune response, fever and exposure to antibiotics, antipyretics, analgesics and micronutrients have not been rigorously addressed. This project will leverage the unique resources of the Norwegian Autism Birth Cohort (ABC) and the Center for Infection and Immunity (CII) for insights into the role of infection, immunity and inflammation in autism through pursuit of three complementary aims that address not only immune activation, fever and drug and micronutrient exposures during gestation per se, but also the timing of these phenomena. In Aim 1 we will investigate the relationship of infectious, immune and inflammatory events to ASD risk using prospective questionnaire data about the following exposures in ASD and control mother- child pairs: a) infection; b) presence, timing and duration of fever, c) autoimmune and allergic conditions, d) antipyretics (acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]), analgesics and antibiotics, and e) micronutrients that modify immune function (vitamin D, zinc) or mitigate antibiotic anti-folate effects (folate). In Aim 2 we will define the immune signatures associated with ASD using multiplexed immunoassays (Luminex) to compare levels of 61 immune/inflammatory molecules in plasma samples from ASD and control mothers (mid-gestation, birth) and children (umbilical cord blood). In Aim 3 we will examine the role of specifi infectious agents in ASD by measuring maternal and child antibodies to influenza virus; ToRCH pathogens T. gondii, rubellavirus, cytomegalovirus and herpes simplex viruses 1 and 2; and Group B streptococcus and E. coli using luciferase immunoprecipitation systems (LIPS) and multiplexed immunoassays (Luminex). In concert these aims have the potential to identify factors and biomarkers for ASD risk that could facilitate early diagnosis and intervention. The Research Council of Norway has reviewed the proposal and guaranteed funding to a maximum of NOK 5 million ($834,000), to support the Norwegian segment of the project, contingent on NIH support.