Maternal Mid-Gestation Cytokine Dysregulation in Mothers of Children with Autism Spectrum Disorder

Casey, Sophie; Carter, M.; Looney, Ann-Marie; Livingstone, Vicki; Moloney, Gerard M.; O’Keeffe, Gerard W.; Taylor, Rennae S.; Kenny, Louise C.; McCarthy, Fergus P.; McCowan, Lesley; Thompson, John M. D.; Murray, Deirdre M.

doi:10.1007/s10803-021-05271-7

Cited by 12 publications

(5 citation statements)

References 81 publications

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“…Decreased levels of mid-gestational IL-4 were associated with ASD, which contradicts the findings by Goines et al and Irwin et al ( 23 , 25 ). Casey et al combined maternal serum samples from two mother-child cohorts including 25 mothers to ASD-cases and 38 mothers to controls, and investigated associations between eight maternal cytokines at 15 and 20 weeks of gestation and odds of ASD in offspring ( 47 ). Decreased levels of IL-17A at 20 weeks of gestation were associated with increased odds of ASD.…”

Section: Discussionmentioning

confidence: 99%

Maternal Levels of Cytokines in Early Pregnancy and Risk of Autism Spectrum Disorders in Offspring

Brynge

Gardner

Sjöqvist

et al. 2022

Front. Public Health

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Previous studies indicate a role of immune disturbances during early development in the etiology of autism spectrum disorders (ASD). Any potential disturbances during fetal development are best addressed by prospective evaluation of maternal markers of inflammation. Previous studies have investigated maternal cytokines, a group of powerful effectors of the immune system, with inconsistent results. In this study, we aimed to clarify the relationship between maternal cytokines and ASD by evaluating levels of 17 cytokines in first trimester maternal serum samples, from 318 mothers to ASD-cases and 429 mothers to ASD-unaffected controls, nested within the register-based Stockholm Youth Cohort. Overall, we observed no consistent associations between levels of maternal cytokines and ASD. While we observed a number of individual associations, the patterns varied across the diagnostic sub-groups. Levels above the 90th percentile of IL-1β (OR = 2.31, 95% CI 1.16–4.60), IL-7 (OR = 2.28, 95% CI 1.20–4.33), IL-13 (OR = 2.42, 95% CI 1.29–4.55), and MCP-1 (OR = 2.09, 95% CI 1.03–4.24) were associated with increased odds of ASD with co-occurring intellectual disability (ID), whereas GMCSF (OR = 2.06, 95% CI 1.03–4.11) and TNF-α (OR = 2.31, 95% CI 1.18–4.50) were associated with increased odds of ASD with ADHD but none survived correction for multiple comparisons. Also, none of the measured maternal cytokines were associated with ASD without co-occurring ID or ADHD. Implementing a data-driven approach using machine learning (Random Forest's Variable Importance measurement), we found no evidence to suggest that adding these cytokines and other markers of maternal immunity, to register-based maternal factors (e.g., psychiatric history) improves prediction of ASD. In summary, we found no robust evidence of an association between maternal immune markers during early pregnancy and ASD.

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Section: Discussionmentioning

confidence: 99%

Maternal Levels of Cytokines in Early Pregnancy and Risk of Autism Spectrum Disorders in Offspring

Brynge

Gardner

Sjöqvist

et al. 2022

Front. Public Health

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“…A growing body of evidence supports a role in ASD pathogenesis for Th17 cells and their product cytokine, IL-17A (Figure 1) (79,82). The IL17A gene itself has been identified by a small genome-wide CNV study to have amplified CNVs in ASD affected cohorts (83).…”

Section: Alterations In Cytokine Expression In Human Studiesmentioning

confidence: 99%

Maternal Immune Activation and Interleukin 17A in the Pathogenesis of Autistic Spectrum Disorder and Why It Matters in the COVID-19 Era

et al. 2022

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Autism spectrum disorder (ASD) is the commonest neurodevelopmental disability. It is a highly complex disorder with an increasing prevalence and an unclear etiology. Consensus indicates that ASD arises as a genetically modulated, and environmentally influenced condition. Although pathogenic rare genetic variants are detected in around 20% of cases of ASD, no single factor is responsible for the vast majority of ASD cases or that explains their characteristic clinical heterogeneity. However, a growing body of evidence suggests that ASD susceptibility involves an interplay between genetic factors and environmental exposures. One such environmental exposure which has received significant attention in this regard is maternal immune activation (MIA) resulting from bacterial or viral infection during pregnancy. Reproducible rodent models of ASD are well-established whereby induction of MIA in pregnant dams, leads to offspring displaying neuroanatomical, functional, and behavioral changes analogous to those seen in ASD. Blockade of specific inflammatory cytokines such as interleukin-17A during gestation remediates many of these observed behavioral effects, suggesting a causative or contributory role. Here, we review the growing body of animal and human-based evidence indicating that interleukin-17A may mediate the observed effects of MIA on neurodevelopmental outcomes in the offspring. This is particularly important given the current corona virus disease-2019 (COVID-19) pandemic as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is a potent stimulator of the maternal immune response, however the long-term effects of maternal SARS-CoV-2 infection on neurodevelopmental outcomes is unclear. This underscores the importance of monitoring neurodevelopmental outcomes in children exposed to SARS-CoV-2-induced MIA during gestation.

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“…These effects of systemic inflammation, and the difference in effect sizes between girls and boys, were most pronounced in mid-gestation 20 . Previous research examining immune signatures associated with ASD was limited: only a few studies had examined maternal immune molecules in mid-gestation 44 – 46 and a handful had examined immune molecules in dried blood spots 47 – 51 . Most of these studies examined only a small number of analytes, and although most had controlled for sex, sex-specific differences were not detailed 44 – 51 .…”

Section: Prospective Birth Cohortsmentioning

confidence: 99%

Cohort-guided insights into gene–environment interactions in autism spectrum disorders

2023

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Prospective birth cohorts offer unprecedented opportunities to investigate the pathogenesis of complex disorders such as autism, in which gene–environment interactions must be appreciated in a temporal context. This Perspective article considers the history of autism research, including missteps that reflected an incomplete understanding of the epidemiology of autistic spectrum disorders, the effects of advocacy and philanthropy on the trajectory of scientific inquiry, and the current and future roles of prospective birth cohort research in illuminating the pathology of these and other complex disorders wherein exposures during gestation might not manifest until later in life.

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Maternal Mid-Gestation Cytokine Dysregulation in Mothers of Children with Autism Spectrum Disorder

Cited by 12 publications

References 81 publications

Maternal Levels of Cytokines in Early Pregnancy and Risk of Autism Spectrum Disorders in Offspring

Maternal Levels of Cytokines in Early Pregnancy and Risk of Autism Spectrum Disorders in Offspring

Maternal Immune Activation and Interleukin 17A in the Pathogenesis of Autistic Spectrum Disorder and Why It Matters in the COVID-19 Era

Cohort-guided insights into gene–environment interactions in autism spectrum disorders

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