The relationship of immune cells with autism spectrum disorder: a bidirectional Mendelian randomization study.

BACKGROUND: Observational studies have indicated a correlation between immunological inflammation and the risk of autism spectrum disorder (ASD). However, the causal relationship between immunological inflammation and ASD remains uncertain. METHODS: Immunity-wide data sources were retrieved from the GWAS catalog. Genetic summary data on ASD were retrieved from two independent GWAS. We performed two independent bi-directional, two-sample Mendelian randomization (MR) analyses and a meta-analysis based on the two independent MR estimates to assess the causal relationship between ASD and immune cell signatures. RESULTS: We have discovered 26 potential correlations between genetic predisposition in the immunophenotypes and ASD. The meta-analysis of the two inverse variance weighted (IVW)-produced estimates provided further evidence supporting the potential causal relationship between immunophenotypes and ASD. Based on the findings of the reverse MR analysis, it was determined that there are two potential negative causal relationships between ASD and immunophenotypes. However, the meta-analysis of the two IVW-derived MR estimates indicated that immunophenotypes were not significantly influenced by ASD (OR = 0.87, 95% CI = 0.73 -1.03, P = 0.09; OR = 0.91, 95% CI = 0.81-1.01, P = 0.08). CONCLUSIONS: This study expanded immune cell subtypes that were potentially causally associated with ASD risk as well as identified ASD-specific immune cell subtypes. The discovery has the potential to lead to earlier detection and more effective treatment techniques.

Interactions between circulating inflammatory factors and autism spectrum disorder: a bidirectional Mendelian randomization study in European population.

Background: Extensive observational studies have reported an association between inflammatory factors and autism spectrum disorder (ASD), but their causal relationships remain unclear. This study aims to offer deeper insight into causal relationships between circulating inflammatory factors and ASD. Methods: Two-sample bidirectional Mendelian randomization (MR) analysis method was used in this study. The genetic variation of 91 circulating inflammatory factors was obtained from the genome-wide association study (GWAS) database of European ancestry. The germline GWAS summary data for ASD were also obtained (18,381 ASD cases and 27,969 controls). Single nucleotide polymorphisms robustly associated with the 91 inflammatory factors were used as instrumental variables. The random-effects inverse-variance weighted method was used as the primary analysis, and the Bonferroni correction for multiple comparisons was applied. Sensitivity tests were carried out to assess the validity of the causal relationship. Results: The forward MR analysis results suggest that levels of sulfotransferase 1A1, natural killer cell receptor 2B4, T-cell surface glycoprotein CD5, Fms-related tyrosine kinase 3 ligand, and tumor necrosis factor-related apoptosis-inducing ligand are positively associated with the occurrence of ASD, while levels of interleukin-7, interleukin-2 receptor subunit beta, and interleukin-2 are inversely associated with the occurrence of ASD. In addition, matrix metalloproteinase-10, caspase 8, tumor necrosis factor-related activation-induced cytokine, and C-C motif chemokine 19 were considered downstream consequences of ASD. Conclusion: This MR study identified additional inflammatory factors in patients with ASD relative to previous studies, and raised a possibility of ASD-caused immune abnormalities. These identified inflammatory factors may be potential biomarkers of immunologic dysfunction in ASD.

Unraveling the immunogenetic landscape of autism spectrum disorder: a comprehensive bioinformatics approach.

Background: Autism spectrum disorder (ASD) is a disease characterized by social disorder. Recently, the population affected by ASD has gradually increased around the world. There are great difficulties in diagnosis and treatment at present. Methods: The ASD datasets were obtained from the Gene Expression Omnibus database and the immune-relevant genes were downloaded from a previously published compilation. Subsequently, we used WGCNA to screen the modules related to the ASD and immune. We also choose the best combination and screen out the core genes from Consensus Machine Learning Driven Signatures (CMLS). Subsequently, we evaluated the genetic correlation between immune cells and ASD used GNOVA. And pleiotropic regions identified by PLACO and CPASSOC between ASD and immune cells. FUMA was used to identify pleiotropic regions, and expression trait loci (EQTL) analysis was used to determine their expression in different tissues and cells. Finally, we use qPCR to detect the gene expression level of the core gene. Results: We found a close relationship between neutrophils and ASD, and subsequently, CMLS identified a total of 47 potential candidate genes. Secondly, GNOVA showed a significant genetic correlation between neutrophils and ASD, and PLACO and CPASSOC identified a total of 14 pleiotropic regions. We annotated the 14 regions mentioned above and identified a total of 6 potential candidate genes. Through EQTL, we found that the CFLAR gene has a specific expression pattern in neutrophils, suggesting that it may serve as a potential biomarker for ASD and is closely related to its pathogenesis. Conclusions: In conclusion, our study yields unprecedented insights into the molecular and genetic heterogeneity of ASD through a comprehensive bioinformatics analysis. These valuable findings hold significant implications for tailoring personalized ASD therapies.

NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways.

BACKGROUND: Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology. METHODS: Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene. RESULTS: We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type tNASP, tNASP(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the tNASP mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in Caenorhabditis elegans. Two additional patients with ASD were found carrying deletion or deleterious mutation in the NASP gene. CONCLUSION: We identified novel epigenetic mechanisms mediated by tNASP which may contribute to the pathogenesis of ASD and its immune comorbidity.

Maternal immune activation increases excitability via downregulation of A-type potassium channels and reduces dendritic complexity of hippocampal neurons of the offspring.

The epidemiological association between bacterial or viral maternal infections during pregnancy and increased risk for developing psychiatric disorders in offspring is well documented. Numerous rodent and non-human primate studies of viral- or, to a lesser extent, bacterial-induced maternal immune activation (MIA) have documented a series of neurological alterations that may contribute to understanding the pathophysiology of schizophrenia and autism spectrum disorders. Long-term neuronal and behavioral alterations are now ascribed to the effect of maternal proinflammatory cytokines rather than the infection itself. However, detailed electrophysiological alterations in brain areas relevant to psychiatric disorders, such as the dorsal hippocampus, are lacking in response to bacterial-induced MIA. This study determined if electrophysiological and morphological alterations converge in CA1 pyramidal cells (CA1 PC) from the dorsal hippocampus in bacterial-induced MIA offspring. A series of changes in the functional expression of K+ and Na+ ion channels altered the passive and active membrane properties and triggered hyperexcitability of CA1 PC. Contributing to the hyperexcitability, the somatic A-type potassium current (IA) was decreased in MIA CA1 PC. Likewise, the spontaneous glutamatergic and GABAergic inputs were dysregulated and biased toward increased excitation, thereby reshaping the excitation-inhibition balance. Consistent with these findings, the dendritic branching complexity of MIA CA1 PC was reduced. Together, these morphophysiological alterations modify CA1 PC computational capabilities and contribute to explaining cellular alterations that may underlie the cognitive symptoms of MIA-associated psychiatric disorders.

Animal Model of Neonatal Immune Challenge by Lipopolysaccharide: A Study of Sex Influence in Behavioral and Immune/Neurotrophic Alterations in Juvenile Mice.

INTRODUCTION: The prenatal/perinatal exposure to infections may trigger neurodevelopmental alterations that lead to neuropsychiatric disorders such as autism spectrum disorder (ASD). Previous evidence points to long-term behavioral consequences, such as autistic-like behaviors in rodents induced by lipopolysaccharide (LPS) pre- and postnatal (PN) exposure during critical neurodevelopmental periods. Additionally, sex influences the prevalence and symptoms of ASD. Despite this, the mechanisms underlying this influence are poorly understood. We aim to study sex influences in behavioral and neurotrophic/inflammatory alterations triggered by LPS neonatal exposure in juvenile mice at an approximate age of ASD diagnosis in humans. METHODS: Swiss male and female mice on PN days 5 and 7 received a single daily injection of 500 µg/kg LPS from Escherichia coli or sterile saline (control group). We conducted behavioral determinations of locomotor activity, repetitive behavior, anxiety-like behavior, social interaction, and working memory in animals on PN25 (equivalent to 3-5 years old of the human). To determine BDNF levels in the prefrontal cortex and hippocampus, we used animals on PN8 (equivalent to a human term infant) and PN25. In addition, we evaluated iba-1 (microglia marker), TNFα, and parvalbumin expression on PN25. RESULTS: Male juvenile mice presented repetitive behavior, anxiety, and working memory deficits. Females showed social impairment and working memory deficits. In the neurochemical analysis, we detected lower BDNF levels in brain areas of female mice that were more evident in juvenile mice. Only LPS-challenged females presented a marked hippocampal expression of the microglial activation marker, iba-1, and increased TNFα levels, accompanied by a lower parvalbumin expression. DISCUSSION/CONCLUSION: Male and female mice presented distinct behavioral alterations. However, LPS-challenged juvenile females showed the most prominent neurobiological alterations related to autism, such as increased microglial activation and parvalbumin impairment. Since these sex-sensitive alterations seem to be age-dependent, a better understanding of changes induced by the exposure to specific risk factors throughout life represents essential targets for developing strategies for autism prevention and precision therapy.

Abnormal mTOR Activity in Pediatric Autoimmune Neuropsychiatric and MIA-Associated Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by the early onset of communication and behavioral problems. ASD is highly heritable; however, environmental factors also play a considerable role in this disorder. A significant part of both syndromic and idiopathic autism cases could be attributed to disorders caused by mammalian target of rapamycin (mTOR)-dependent translation deregulation. This narrative review analyzes both bioinformatic and experimental evidence that connects mTOR signaling to the maternal autoantibody-related (MAR) autism spectrum and autoimmune neuropsychiatric disorders simultaneously. In addition, we reconstruct a network presenting the interactions between the mTOR signaling and eight MAR ASD genes coding for ASD-specific maternal autoantibody target proteins. The research discussed in this review demonstrates novel perspectives and validates the need for a subtyping of ASD on the grounds of pathogenic mechanisms. The utter necessity of designing ELISA-based test panels to identify all antibodies related to autism-like behavior is also considered.

Imbalance in pro-inflammatory and anti-inflammatory cytokines milieu in B cells of children with autism.

B cells play multiple roles in preservation of healthy immune system including management of immune responses by expression of pro- and anti-inflammatory cytokines. Several earlier studies have documented that B cells express both pro-inflammatory cytokines such as IL-6, TNF-α as well as anti-inflammatory cytokines such as IL-10. However, it is yet to be examined whether these pro-/anti-inflammatory cytokines are expressed in B cells of children with autism spectrum disorder (ASD). Pathophysiology of ASD begins in early childhood and is characterized by repetitive/restricted behavioral patterns, and dysfunction in communal/communication skills. ASD pathophysiology also has a strong component of immune dysfunction which has been highlighted in numerous earlier publications. In this study, we specifically explored pro-/anti-inflammatory cytokines (IL-6, IL-17A, IFN-γ, TNF-α, IL-10) in B cells of ASD subjects and compared them typically developing control (TDC) children. Present study shows that inflammatory cytokines such as IL-6 and TNF-α are elevated in B cells of ASD subjects, while anti-inflammatory cytokine, IL-10 is decreased in ASD group when compared to TDC group. Further, TLR4 activation by its ligand, lipopolysaccharide (LPS) further upregulates inflammatory potential of B cells from ASD group by increasing IL-6 expression, whereas LPS has no significant effect on IL-10 expression in ASD group. Furthermore, LPS-induced inflammatory signaling of IL-6 in B cells of ASD subjects was partially mitigated by the pretreatment with NF-kB inhibitor. Present study propounds the idea that B cells could be crucial players in causing immune dysfunction in ASD subjects through an imbalance in expression of pro-/anti-inflammatory cytokines.

Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4+ T cells.

Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4+ T cells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders.

The Role of Maternal Immune Activation in the Pathogenesis of Autism: A Review of the Evidence, Proposed Mechanisms and Implications for Treatment.

Autism spectrum disorder (ASD) is a neurodevelopmental disease that is characterized by a deficit in social interactions and communication, as well as repetitive and restrictive behaviors. Increasing lines of evidence suggest an important role for immune dysregulation and/or inflammation in the development of ASD. Recently, a relationship between inflammation, oxidative stress, and mitochondrial dysfunction has been reported in the brain tissue of individuals with ASD. Some recent studies have also reported oxidative stress and mitochondrial abnormalities in animal models of maternal immune activation (MIA). This review is focused on the hypothesis that MIA induces microglial activation, oxidative stress, and mitochondrial dysfunction, a deleterious trio in the brain that can lead to neuroinflammation and neurodevelopmental pathologies in offspring. Infection during pregnancy activates the mother's immune system to release proinflammatory cytokines, such as IL-6, TNF-α, and others. Furthermore, these cytokines can directly cross the placenta and enter the fetal circulation, or activate resident immune cells, resulting in an increased production of proinflammatory cytokines, including IL-6. Proinflammatory cytokines that cross the blood-brain barrier (BBB) may initiate a neuroinflammation cascade, starting with the activation of the microglia. Inflammatory processes induce oxidative stress and mitochondrial dysfunction that, in turn, may exacerbate oxidative stress in a self-perpetuating vicious cycle that can lead to downstream abnormalities in brain development and behavior.

MGEnrichment: A web application for microglia gene list enrichment analysis.

Gene expression analysis is becoming increasingly utilized in neuro-immunology research, and there is a growing need for non-programming scientists to be able to analyze their own genomic data. MGEnrichment is a web application developed both to disseminate to the community our curated database of microglia-relevant gene lists, and to allow non-programming scientists to easily conduct statistical enrichment analysis on their gene expression data. Users can upload their own gene IDs to assess the relevance of their expression data against gene lists from other studies. We include example datasets of differentially expressed genes (DEGs) from human postmortem brain samples from Autism Spectrum Disorder (ASD) and matched controls. We demonstrate how MGEnrichment can be used to expand the interpretations of these DEG lists in terms of regulation of microglial gene expression and provide novel insights into how ASD DEGs may be implicated specifically in microglial development, microbiome responses and relationships to other neuropsychiatric disorders. This tool will be particularly useful for those working in microglia, autism spectrum disorders, and neuro-immune activation research. MGEnrichment is available at https://ciernialab.shinyapps.io/MGEnrichmentApp/ and further online documentation and datasets can be found at https://github.com/ciernialab/MGEnrichmentApp. The app is released under the GNU GPLv3 open source license.

SARS-CoV-2-associated cytokine storm during pregnancy as a possible risk factor for neuropsychiatric disorder development in post-pandemic infants.

A strong association between perinatal viral infections and neurodevelopmental disorders has been established. Both the direct contact of the virus with the developing brain and the strong maternal immune response originated by viral infections can impair proper neurodevelopment. Coronavirus disease 2019 (COVID-19), caused by the highly-infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a large global outbreak and is a major public health issue. While initial studies focused on the viral impact on the respiratory system, increasing evidence suggest that SARS-CoV-2 infects other organs and tissues including the mature brain. While studies continue to determine the neuropathology associated to COVID-19, the consequences of SARS-CoV-2 infection to the developing brain remain largely unexplored. The present review discusses evidence suggesting that SARS-CoV-2 infection may have persistent effects on the course of pregnancy and on brain development. Studies have shown that several proinflammatory mediators which are increased in the SARS-CoV-2-associated cytokine storm, are also modified in other viral infections known to increase the risk of neurodevelopmental disorders. In this sense, further studies should assess the genuine effects of SARS-CoV-2 infection during pregnancy and delivery along with an extended follow-up of the offspring, including neurocognitive, neuroimaging, and electrophysiological examination. It also remains to be determined whether and by which mechanisms SARS-CoV-2 intrauterine and early life infection could lead to an increased risk of developing neuropsychiatric disorders, such as autism (ASD) and schizophrenia (SZ), in the offspring.

IFNγ-Producing γ/δ T Cells Accumulate in the Fetal Brain Following Intrauterine Inflammation.

Intrauterine inflammation impacts prenatal neurodevelopment and is linked to adverse neurobehavioral outcomes ranging from cerebral palsy to autism spectrum disorder. However, the mechanism by which a prenatal exposure to intrauterine inflammation contributes to life-long neurobehavioral consequences is unknown. To address this gap in knowledge, this study investigates how inflammation transverses across multiple anatomic compartments from the maternal reproductive tract to the fetal brain and what specific cell types in the fetal brain may cause long-term neuronal injury. Utilizing a well-established mouse model, we found that mid-gestation intrauterine inflammation resulted in a lasting neutrophil influx to the decidua in the absence of maternal systemic inflammation. Fetal immunologic changes were observed at 72-hours post-intrauterine inflammation, including elevated neutrophils and macrophages in the fetal liver, and increased granulocytes and activated microglia in the fetal brain. Through unbiased clustering, a population of Gr-1+ γ/δ T cells was identified as the earliest immune cell shift in the fetal brain of fetuses exposed to intrauterine inflammation and determined to be producing high levels of IFNγ when compared to γ/δ T cells in other compartments. In a case-control study of term infants, IFNγ was found to be elevated in the cord blood of term infants exposed to intrauterine inflammation compared to those without this exposure. Collectively, these data identify a novel cellular immune mechanism for fetal brain injury in the setting of intrauterine inflammation.

Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS.

Almost 60 years have passed since the initial discovery by Hubel and Wiesel that changes in neuronal activity can elicit developmental rewiring of the central nervous system (CNS). Over this period, we have gained a more comprehensive picture of how both spontaneous neural activity and sensory experience-induced changes in neuronal activity guide CNS circuit development. Here we review activity-dependent synaptic pruning in the mammalian CNS, which we define as the removal of a subset of synapses, while others are maintained, in response to changes in neural activity in the developing nervous system. We discuss the mounting evidence that immune and cell-death molecules are important mechanistic links by which changes in neural activity guide the pruning of specific synapses, emphasizing the role of glial cells in this process. Finally, we discuss how these developmental pruning programmes may go awry in neurodevelopmental disorders of the human CNS, focusing on autism spectrum disorder and schizophrenia. Together, our aim is to give an overview of how the field of activity-dependent pruning research has evolved, led to exciting new questions and guided the identification of new, therapeutically relevant mechanisms that result in aberrant circuit development in neurodevelopmental disorders.

Correlation analysis of expression of CC and CXC chemokines in children with autism spectrum disorder.

ABSTRACT: To investigate the relationship between the expression of CC and CXC chemokines and autism spectrum disorder (ASD).A total of 62 children with ASD (ASD group) and 60 gender- and age-matched normal children (control group) admitted to our hospital from January 2019 to January 2020 were included in the study. Monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1ß (MIP-1ß), regulated upon activation, normal T-cell expressed and secreted (RANTES), interleukin-8 (IL-8), monokine induced by interferon (IFN)-γ (MIG), and purified human interferon-γ-induced protein-10 (IP-10) were detected in the ASD group. The correlation between the above indexes and the severity of the ASD group was analyzed.Significantly increased MCP-1 levels (P < .01) along with the markedly decreased MIP-1α and MIP-1ß levels (P < .01) were detected in the venous blood of the ASD group compared with the control group. In addition, they exhibited no significant difference (yet a downward trend) in the level of RANTES (P > .05). Children in the ASD group showed significantly decreased IP-10 levels (P < .01); however, they had no noticeable change (yet a decreasing trend) in the levels of IL-8 and MIG (P > .05). MCP-1 level was positively related to the Module 1 scores of Autism Diagnostic Observation Schedule-second edition (ADOS-2), whereas the levels of Childhood Autism Rating Scale MIP-1α, MIP-1ß, IL-8, IP-10, and MIG were negatively correlated with the ADOS-2 Module 1 scores (P < .01). However, no significant correlation was found between RANTES and the ADOS-2 Module 1 scores (P > .05).The levels of CC chemokines (MCP-1, MIP-1α, MIP-1ß, and RANTES) and CXC chemokines (IL-8, IP-10, and MIG) are positively correlated with the pathogenesis of ASD. Inflammation is an important contributing factor to ASD.

Microbiota and Microglia Interactions in ASD.

Autism spectrum disorders (ASD) are serious, highly variable neurodevelopmental disorders, commonly characterized by the manifestation of specific behavioral abnormalities, such as stereotypic behaviors and deficits in social skills, including communication. Although the neurobiological basis for ASD has attracted attention in recent decades, the role of microglial cells, which are the main resident myeloid cell population in the brain, is still controversial and underexplored. Microglia play several fundamental roles in orchestrating brain development and homeostasis. As such, alterations in the intrinsic functions of these cells could be one of the driving forces responsible for the development of various neurodevelopmental disorders, including ASD. Microglia are highly sensitive to environmental cues. Amongst the environmental factors known to influence their intrinsic functions, the gut microbiota has emerged as a central player, controlling both microglial maturation and activation. Strikingly, there is now compelling data suggesting that the intestinal microbiota can play a causative role in driving the behavioural changes associated with ASD. Not only is intestinal dysbiosis commonly reported in ASD patients, but therapies targeting the microbiome can markedly alleviate behavioral symptoms. Here we explore the emerging mechanisms by which altered microglial functions could contribute to several major etiological factors of ASD. We then demonstrate how pre- and postnatal environmental stimuli can modulate microglial cell phenotype and function, underpinning the notion that reciprocal interactions between microglia and intestinal microbes could play a crucial role in ASD aetiology.

Intestinal permeability correlates with behavioural severity in very young children with ASD: A preliminary study.

Systemic inflammation is known to alter behaviour, and since it has been reported that individuals with autism spectrum disorder (ASD) have higher levels of circulating cytokines, it has been hypothesized that systemic inflammation may exacerbate behaviours characteristic of ASD. The acute phase proteins α-2-macroglobulin, C-reactive protein, haptoglobin, serum amyloid P, serum amyloid A, ferritin and tissue plasminogen activator, as well as markers of intestinal permeability (intestinal fatty acid binding protein and lipopolysaccharide) were quantitated in the plasma of very young children with ASD. Behaviour severity was measured using the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS) and the Vineland Adaptive Behaviour Scale (VABS). An increase in circulating I-FABP correlated with more severe deficits in communication, communication + social interaction as well as maladaptive behaviour. The acute phase protein haptoglobin was associated with more severe social interaction and communication + social interaction. In summary, I-FABP, a marker of intestinal epithelial damage, was associated with more severe behavioural phenotypes in very young children with ASD. In addition, the acute phase protein, haptoglobin, was associated with behaviour.

Identification of aberrant innate and adaptive immunity based on changes in global gene expression in the blood of adults with autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is characterized as a neurodevelopmental disorder, and one of the main hypotheses regarding its cause is genetic factors. A previous meta-analysis of seven microarray studies and one RNA sequencing (RNA-seq) study using the blood of children with ASD identified dysregulation of gene expressions relevant to the immune system. In this study, we explored changes in global gene expression as the phenotype of ASD in the blood of adults with ASD. METHODS: We recruited an RNA-seq cohort (ASD vs. control; n = 6 each) and a replication cohort (ASD vs. control; n = 19 each) and conducted RNA-seq to explore changes in global gene expression. We then subjected the significantly up- and downregulated genes to gene ontology (GO) and core analyses. Weighted gene correlation network analysis (WGCNA) was performed with all 11,617 genes detected in RNA-seq to identify the ASD-specific gene network. RESULTS: In total, 117 significantly up- and 83 significantly downregulated genes were detected in the ASD compared with the control group, respectively (p < 0.05 and q < 0.05). GO analysis revealed that the aberrant innate and adaptive immunity were more obvious in the 117 upregulated than in the 83 downregulated genes. WGCNA with core analysis revealed that one module including many immune-related genes was associated with the natural killer cell signaling pathway. In the results for the replication cohort, significant changes with same trend found in RNA-seq data were confirmed for MAFB (p = 0.046), RPSAP58 (p = 0.030), and G2MK (p = 0.004). LIMITATIONS: The sample size was relatively small in both the RNA-seq and replication cohorts. This study examined the mRNA expression level, so the interaction between mRNA and protein remains unclear. The expression changes between children and adults with ASD were not compared because only adults with ASD were targeted. CONCLUSIONS: The dysregulated gene expressions confirmed in the blood of adults with ASD were relevant to the dysfunction of innate and adaptive immunity. These findings may aid in understanding the pathogenesis of ASD.

Reviewing the association between aluminum adjuvants in the vaccines and autism spectrum disorder.

The manuscript reviews the association between aluminum adjuvants (AlAd) in vaccines and autism spectrum disorder (ASD). Aluminum (Al) is neurotoxic. Infants who have received AlAd in vaccines show a higher rate of ASD. The behavior of mice changes with Al injection. Patients suffering from ASD have higher concentrations of Al in their brains. Thus, AlAd is an etiologic factor in ASD. Immune efficacy led to the use of the AlAd in vaccines; however, the safety of those who are vaccinated with such vaccines has not been considered. The mechanisms of action of AlAd and the pharmacodynamics of injected AlAd used in vaccines are not well-characterized. The association between aluminum adjuvants in the vaccines and autism spectrum disorder is suggested by multiple lines of evidence.

In utero immune programming of autism spectrum disorder (ASD).

Maladaptation of immune tolerance at the maternal-fetal interface affects balanced maternal-fetal cross-talk and placental health and is associated with adverse pregnancy outcomes. The concept of in utero programming of childhood and adulthood diseases has revolutionized the research on the role of pregnancy in maternal, neonatal, and adult health. However, it is not yet well understood whether dysregulation of uterine immunity contributes to any health consequences during childhood or later in life. Recent observations in mice and humans have strongly supported the notion that uterine immunity during pregnancy determines the health trajectory of the offspring and significantly impacts cognitive function and mental health. Importantly, IL-17a producing Th17 T cells have been projected as the main contributors to heterogeneous pathological and behavioral phenotypes associated with autism spectrum disorder (ASD). However, since normal pregnancy is associated with little or no Th17 cells at the maternal-fetal interface, it is not clear how and when the Th17 T cells are generated and which interventions can ameliorate the ASD-like features in newborns. We propose that infection-associated uterine immune activation within a critical window of development may propel trans-differentiation of Th17 T cells that eventually affect fetal brain development and induce ASD-like behavioral phenotype in the offspring.