Complement C3 Expression Is Decreased in Autism Spectrum Disorder Subjects and Contributes to Behavioral Deficits in Rodents.
Complement C3 Expression Is Decreased in Autism Spectrum Disorder Subjects and Contributes to Behavioral Deficits in Rodents.
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DOI：
10.1159/000465523
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发表时间：
2017-07-01
期刊：
影响因子：
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通讯作者：
Pillai, Anilkumar
中科院分区：
文献类型：
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作者：
Fagan, Kiley;Crider, Amanda;Pillai, Anilkumar
自闭症谱系障碍 (ASD) 是一种神经发育障碍，其标志性症状包括社交缺陷、沟通缺陷和重复行为。越来越多的证据表明免疫系统在自闭症谱系障碍的病理生理学中具有潜在作用。补体系统代表先天免疫系统的主要效应机制之一，调节炎症并协调针对病原体的防御。然而，中枢神经系统补体系统在 ASD 中的作用尚不清楚。在本研究中，我们发现与对照组相比，ASD 受试者额中回的 C2、C5 和 MASP1 显着增加，但 C1q、C3 和 C4 mRNA 水平下降。在 ASD 受试者中观察到 2 种关键促炎细胞因子 IL-17 和 IL-23 的 mRNA 水平显着降低。我们的研究进一步证明补体基因与 IL-17 和 IL-23 密切相关，表明补体系统在 ASD 免疫失调中可能发挥作用。我们观察到自闭症谱系障碍受试者的补体成分与发育评分异常之间存在显着关联。在啮齿类动物中，前额皮质中的 C3 敲低会导致小鼠的社交互动缺陷和重复行为。总之，这些研究表明 C3 在 ASD 的病理生理学中具有潜在作用。
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with hallmark symptoms including social deficits, communication deficits and repetitive behaviors. Accumulating evidence suggests a potential role of the immune system in the pathophysiology of ASD. The complement system represents one of the major effector mechanisms of the innate immune system, and regulates inflammation, and orchestrates defense against pathogens. However, the role of CNS complement system in ASD is not well understood. In the present study, we found a significant increase in C2, C5, and MASP1, but a decrease in C1q, C3, and C4 mRNA levels in the middle frontal gyrus of ASD subjects compared to controls. Significant decreases in the mRNA levels of 2 key proinflammatory cytokines, IL-17 and IL-23 were observed in ASD subjects. Our study further demonstrated a strong association of complement genes with IL-17 and IL-23, suggesting a possible role of the complement system in immune dysregulation in ASD. We observed significant associations between complement components and abnormality of development scores in subjects with ASD. In rodents, C3 knockdown in the prefrontal cortex induced social interaction deficits and repetitive behavior in mice. Together, these studies suggest a potential role of C3 in the pathophysiology of ASD.