Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero

al-Haddad, Benjamin J.S.; Jacobsson, Bo; Chabra, Shilpi; Modzelewska, Dominika; Olson, Edwin S.; Bernier, Raphael; Enquobahrie, Daniel A.; Hagberg, Henrik; Östling, Svante; Rajagopal, Lakshmi; Waldorf, Kristina M. Adams; Sengpiel, Verena

doi:10.1001/jamapsychiatry.2019.0029

Cited by 223 publications

(185 citation statements)

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“…ASD is characterized by social and language deficits that present in early childhood, although the literature on several fronts seems to indicate that the aberrant neurodevelopment begins much earlier, in early to mid‐fetal stages .The genetics of autism are complex, but so far the evidence of immune involvement is less clear than for schizophrenia . Some epidemiological data suggest links between maternal infections during pregnancy and later risk for autism . There is some clinical evidence of alterations in immune function in autism, both in peripheral blood (decreased TGF‐β1 and increased IL‐1β) and in brain gene expression , reviewed in .…”

Section: The Immune System and Psychiatric Diagnoses: What Human Studmentioning

confidence: 99%

The immune system and psychiatric disease: a basic science perspective

Bennett

Molofsky

2019

Clinical and Experimental Immunology

101

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Summary Mental illness exerts a major burden on human health, yet evidence‐based treatments are rudimentary due to a limited understanding of the underlying pathologies. Clinical studies point to roles for the immune system in psychiatric diseases, while basic science has revealed that the brain has an active and multi‐cellular resident immune system that interacts with peripheral immunity and impacts behavior. In this perspective, we highlight evidence of immune involvement in human psychiatric disease and review data from animal models that link immune signaling to neuronal function and behavior. We propose a conceptual framework for linking advances in basic neuroimmunology to their potential relevance for psychiatric diseases, based on the subtypes of immune responses defined in peripheral tissues. Our goal is to identify novel areas of focus for future basic and translational studies that may reveal the potential of the immune system for diagnosing and treating mental illnesses

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Section: The Immune System and Psychiatric Diagnoses: What Human Studmentioning

confidence: 99%

The immune system and psychiatric disease: a basic science perspective

Bennett

Molofsky

2019

Clinical and Experimental Immunology

101

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“…Risk factors most consistently associated with neurodevelopmental problems, such as ASD, are prenatal and include male sex [Loomes, Hull, & Mandy, 2017], advanced parental age [Guinchat et al, 2012;Huang, Zhu, Qu, & Mu, 2016], premature birth [Guinchat et al, 2012;Huang et al, 2016], low birth weight [Guinchat et al, 2012;Huang et al, 2016], birth order [Guinchat et al, 2012;Huang et al, 2016], delivery by caesarean section [Guinchat et al, 2012], and pregnancy complications, such as breech presentation [Guinchat et al, 2012], gestational diabetes [Guinchat et al, 2012;Huang et al, 2016], blood loss [Guinchat et al, 2012], and preeclampsia [Guinchat et al, 2012;Huang et al, 2016]. Further risk factors include maternal obesity [Sanchez et al, 2018], smoking [Wehby, Prater, McCarthy, Castilla, & Murray, 2011], alcohol use [Landgren, Svensson, Stromland, & Andersson Gronlund, 2010], certain medications [Ng et al, 2017], infections [Al-Haddad et al, 2019], and exposure to toxic substances [Ng et al, 2017]. Maternal stress and poor mental health in pregnancy are also suspected to be related to neurodevelopment, but the level of evidence is less conclusive [Ibanez et al, 2015;van den Bergh et al, 2017].…”

Section: Introductionmentioning

confidence: 99%

Maternal immigrant status and signs of neurodevelopmental problems in early childhood: The French representative ELFE birth cohort

et al. 2019

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A growing body of evidence suggests that children of immigrants may have increased risks of neurodevelopmental disorders. However, evidence based on parent report and on very young children is lacking. We therefore investigated the association between maternal immigrant status and early signs of neurodevelopmental problems in a population‐based sample of 2‐year‐old children using standardized parent‐report instruments. We used data from the French representative Étude Longitudinale Française depuis l'Enfance birth cohort, initiated in 2011. The study sample included 9,900 children of nonimmigrant French, 1,403 children of second, and 1,171 children of first generation immigrant women followed‐up to age 2 years. Neurodevelopment was assessed using the Modified Checklist for Autism in Toddlers (M‐CHAT) and an adaptation of the MacArthur‐Bates Communicative Development Inventories (MB‐CDI). In fully adjusted linear regression models, maternal immigrant status was associated with M‐CHAT scores, with stronger associations in children of first (β‐coefficient: 0.19; 95% CI 0.08–0.29) than second generation immigrants (0.09; 0.01–0.17). This association was especially strong among children of first generation immigrant mothers native of North Africa (vs. nonimmigrant French: 0.33; 0.16–0.49) and French‐speaking Sub‐Saharan Africa (0.26; 0.07–0.45). MB‐CDI scores were lowest among children of first generation immigrant mothers, particularly from mostly non‐francophone regions. Children of first generation immigrant mothers were most likely to have simultaneously low MB‐CDI and high M‐CHAT scores. Our findings suggest that maternal immigrant status is associated with early signs of neurodevelopmental difficulties, with strong variations according to maternal region of origin. Further research is necessary to test whether these associations persist and to determine the underlying mechanisms. Autism Res 2019, 12: 1845–1859. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary We asked immigrant and nonimmigrant mothers in France about early signs of neurodevelopmental problems in their 2‐year‐old children. Overall, we found that children of immigrants may be at higher risk of showing these early warning signs, as compared to children of nonimmigrants. This is in line with previous studies, which were based on doctors' diagnoses at later ages. However, our results differed depending on the mothers' regions of origin. We found the highest risks in children of first generation immigrants from North and French‐speaking Sub‐Saharan Africa, who also seemed especially at risk of neurodevelopmental problems combined with low language development.

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“…These alterations can impact forebrain wiring, influence functional connectivity across limbic and cortical neural networks, and induce behavioral deficits that are characteristic of neuropsychiatric illnesses like autism spectrum disorder (ASD) (3,6,7). Maternal infections during pregnancy have been linked to increased risk of ASD (8)(9)(10), and animal models of maternal immune activation (MIA) indicate that increased maternal cytokines perturb embryonic microglia, shifting their phenotype to a more proinflammatory state (1,11,12).…”

mentioning

confidence: 99%

Maternal viral infection causes global alterations in porcine fetal microglia

Antonson

Lawson

Caputo

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Maternal infections during pregnancy are associated with increased risk of neurodevelopmental disorders, although the precise mechanisms remain to be elucidated. Previously, we established a maternal immune activation (MIA) model using swine, which results in altered social behaviors of piglet offspring. These behavioral abnormalities occurred in the absence of microglia priming. Thus, we examined fetal microglial activity during prenatal development in response to maternal infection with live porcine reproductive and respiratory syndrome virus. Fetuses were obtained by cesarean sections performed 7 and 21 d postinoculation (dpi). MIA fetuses had reduced brain weights at 21 dpi compared to controls. Furthermore, MIA microglia increased expression of major histocompatibility complex class II that was coupled with reduced phagocytic and chemotactic activity compared to controls. High-throughput gene-expression analysis of microglial-enriched genes involved in neurodevelopment, the microglia sensome, and inflammation revealed differential regulation in primary microglia and in whole amygdala tissue. Microglia density was increased in the fetal amygdala at 7 dpi. Our data also reveal widespread sexual dimorphisms in microglial gene expression and demonstrate that the consequences of MIA are sex dependent. Overall, these results indicate that fetal microglia are significantly altered by maternal viral infection, presenting a potential mechanism through which MIA impacts prenatal brain development and function. maternal immune activation | microglia | neurodevelopment | prenatal inflammation | pig Author contributions: A.M.A., M.A.L., and R.W.J. designed research; A.M.A., M.A.L., M.P.C., S.M.M., and B.J.L. performed research; A.M.A., M.P.C., and S.M.M. analyzed data; A.M.A., M.A.L., and R.W.J. interpreted data; and A.M.A. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission.Published under the PNAS license. NEUROSCIENCEDownloaded by guest on July 10, 2020 3 symbols = P < 0.001, 2 symbols = P < 0.01, and 1 symbol = P < 0.05.Antonson et al.

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Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero

Cited by 223 publications

References 51 publications

The immune system and psychiatric disease: a basic science perspective

The immune system and psychiatric disease: a basic science perspective

Maternal immigrant status and signs of neurodevelopmental problems in early childhood: The French representative ELFE birth cohort

Maternal viral infection causes global alterations in porcine fetal microglia

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