Bilbo Staci D, Block Carina L, Bolton Jessica L, Hanamsagar Richa, Tran Phuong K
Pediatrics and Neuroscience, Harvard Medical School, Lurie Center for Autism, Massachusetts General Hospital for Children, Boston, MA 02126, United States.
Psychology and Neuroscience, Duke University, Durham, NC 27708, United States.
Exp Neurol. 2018 Jan;299(Pt A):241-251. doi: 10.1016/j.expneurol.2017.07.002. Epub 2017 Jul 8.
Immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy, e.g. in response to infection, may disrupt the normal expression of immune molecules during critical stages of neural development and thereby contribute to the risk for neurodevelopmental disorders such as autism spectrum disorder (ASD). This hypothesis has in large part been shepherded by the work of Dr. Paul Patterson and colleagues, which has elegantly demonstrated that a single viral infection or injection of a viral mimetic to pregnant mice significantly and persistently impacts offspring immune and nervous system function, changes that underlie ASD-like behavioral dysfunction including social and communication deficits. Subsequent studies by many labs - in humans and in non-human animal models - have supported the hypothesis that ongoing disrupted immune molecule expression and/or neuroinflammation contributes to at least a significant subset of ASD. The heterogeneous clinical and biological phenotypes observed in ASD strongly suggest that in genetically susceptible individuals, environmental risk factors combine or synergize to create a tipping or threshold point for dysfunction. Importantly, animal studies showing a link between maternal immune activation (MIA) and ASD-like outcomes in offspring involve different species and diverse environmental factors associated with ASD in humans, beyond infection, including toxin exposures, maternal stress, and maternal obesity, all of which impact inflammatory or immune pathways. The goal of this review is to highlight the broader implications of Dr. Patterson's work for the field of autism, with a focus on the impact that MIA by diverse environmental factors has on fetal brain development, immune system development, and the pathophysiology of ASD.
细胞因子和趋化因子等免疫分子以及大脑中产生这些分子的细胞，尤其是小胶质细胞，对正常的大脑发育至关重要。近年来，这一认识引发了一个工作假设，即孕期的炎症事件，例如对感染的反应，可能会在神经发育的关键阶段扰乱免疫分子的正常表达，从而增加患神经发育障碍如自闭症谱系障碍（ASD）的风险。这一假设在很大程度上是由保罗·帕特森博士及其同事的工作推动的，他们巧妙地证明，单次病毒感染或向怀孕小鼠注射病毒模拟物会显著且持续地影响后代的免疫和神经系统功能，这些变化是ASD样行为功能障碍（包括社交和沟通缺陷）的基础。许多实验室随后在人类和非人类动物模型中的研究支持了这一假设，即持续的免疫分子表达紊乱和/或神经炎症至少导致了相当一部分ASD病例。在ASD中观察到的异质性临床和生物学表型强烈表明，在基因易感个体中，环境风险因素相互结合或协同作用，从而导致功能障碍的临界点或阈值。重要的是，动物研究表明母体免疫激活（MIA）与后代的ASD样结局之间存在联系，这些研究涉及不同物种以及与人类ASD相关的多种环境因素，除了感染之外，还包括接触毒素、母体压力和母体肥胖，所有这些都会影响炎症或免疫途径。本综述的目的是强调帕特森博士的工作对自闭症领域的更广泛影响，重点关注多种环境因素引起的MIA对胎儿大脑发育、免疫系统发育以及ASD病理生理学的影响。
