Maternal Gestational Immune Response and Autism Spectrum Disorder Phenotypes at 7 Years of Age in the Seychelles Child Development Study

Abstract

Background-Findings from observational and experimental studies suggest that maternal inflammation during pregnancy is associated with autism spectrum disorder (ASD). We report the first study in humans to examine this association in a large prospective birth cohort. Methods-We studied 788 mother-child pairs from the Seychelles Child Development Study Nutrition Cohort 2. Thirteen inflammatory markers were measured in mothers' serum at 28 weeks ' gestation, along with the sum of T-helper 1 (Th1) and 2 (Th2) cytokines. The Social Communication Questionnaire (SCQ) and Social Responsiveness Scale (SRS) were administered at age 7 years to obtain information on ASD phenotype. We evaluated associations between maternal inflammatory markers and ASD phenotype using multivariable linear regression. Results-For the SCQ, increased MCP-1 (a chemokine that is upregulated in response to proinflammatory cytokines) was associated with fewer ASD symptoms (B = −0.40; 95% CI = −0.72, −0.09). Increased IL-4 (a cytokine that is typically associated with an enhanced anti-inflammatory response) was associated with more ASD symptoms (B = 2.10; 95% CI = 0.78, 3.43). For the SRS, higher concentrations of the anti-inflammatory cytokine IL-10 were associated with fewer ASD symptoms (B = −0.18; 95% CI = −0.35, −0.01), but only after removal of outliers. No associations were observed for other markers.

Critical Role of the Maternal Immune System in the Pathogenesis of Autism Spectrum Disorder

“…Overall, MCAD had significantly increased levels of pro-inflammatory cytokines interferon gamma (INF-γ), interleukin-6 (IL-6) and interleukin-1 (IL-1), which may be indicative of an activation of the immune system and a shift from the usual anti-inflammatory cytokine pattern observed across pregnancy [98][99][100]. However, these cytokine profiles only reflect one particular time point during gestation and as they were determined from peripheral maternal blood samples, are not fully representative of the profile at the maternal-foetal interface [98,99,101]. To this regard, Abdallah et al's showed contradicting cytokine levels in amniotic fluid samples of MCAD, with increased anti-inflammatory interleukin-4 (IL-4) and interluekin-10 (IL-10) [102].…”

“…Although a variety of different maternal cytokines have been implicated in ASD [101][102][103]105,106], for the purpose of this literature review, only IL-1β, IL-6 and IL-17 will be discussed, as the pathological mechanisms by which they exert their effects on the prenatal environment are the most well understood.…”

Mid-gestation cytokine profiles in mothers of children affected by autism spectrum disorder: a case–control study

“…In demonstrating alterations in IL-4, we have corroborated findings in the small number of existing studies that have examined mid-gestational serum of mothers to autistic children. Across all of these studies (including our own), IL-4 is the only cytokine to consistently demonstrate altered expression 30 , 31 , 54 . Interestingly, while previous authors found levels of IL-4 to be elevated in the ASD affected group versus controls, in our study we found the opposite.…”

“…While the cytokine profiles of ASD affected individuals have been well characterised, very few studies have investigated the relationship between mid-gestation cytokine levels and ASD risk in offspring. To our knowledge, only three human studies have examined maternal serum 30 , 31 , 54 , and one more has examined amniotic fluid cytokine profiles in mothers of ASD affected children 86 . The findings from these studies, effectively provide all of our current understanding of gestational cytokine profiles in the setting of ASD.…”

“…Irwin et al (2018) demonstrated alterations in IL-4, MCP-1 and IL-10 levels in 28-week gestation serum of mothers who birthed ASD affected children 54 . Specifically, IL-4 (usually anti-inflammatory or involved in allergic type inflammation 87 ) was increased and associated with higher ASD symptomology (as measured by the Social Communication Questionnaire (SCQ)) in offspring.…”