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.

Immunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant.

Casitas B-lineage lymphoma (CBL) encodes an adaptor protein with E3-ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders. Here we report a novel CBL variant (c.1202G>T; p.Cys401Phe) occurring de novo in a subject with café-au-lait macules, feeding difficulties, mild dysmorphic features, psychomotor delay, autism spectrum disorder, thrombocytopenia, hepatosplenomegaly, and recurrent hypertransaminasemia. The identified variant affects an evolutionarily conserved residue located in the RING finger domain, a known mutational hot spot of both germline and somatic mutations. Functional studies documented enhanced EGF-induced ERK phosphorylation in transiently transfected COS1 cells. The present findings further support the association of pathogenic CBL variants with immunological and hematological manifestations in the context of a presentation with only minor findings reminiscent of NS or a clinically related RASopathy.

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.

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.

[Immunopsychiatry and SARS-CoV-2 pandemic: Links and possible consequences]. / Immuno-psychiatrie et pandémie de SARS-CoV-2 : liens et possibles conséquences.

OBJECTIVE: The SARS-CoV-2 (or COVID-19) pandemic has been propagating since December 2019, inducing a drastic increase in the prevalence of anxious and depressive disorders in the general population. Psychological trauma can partly explain these disorders. However, since psychiatric disorders also have an immuno-inflammatory component, the direct effects of the virus on the host's immune system, with a marked inflammatory response, but also the secondary inflammation to these psychosocial stressors, may cause the apparition or the worsening of psychiatric disorders. We describe here the probable immunopsychiatric consequences of the SARS-CoV-2 pandemic, to delineate possible screening actions and care that could be planned. METHOD: Data from previous pandemics, and existing data on the psychopathological consequences of the SARS-CoV-2 pandemic, allowed us to review the possible immunopsychiatric consequences of the SARS-CoV-2 pandemic, on the gestational environment, with the risk of consecutive neurodevelopmental disorders for the fetus on one hand, on the children and adults directly infected being at increased risks of psychiatric disorders on the other hand. RESULTS: As in previous pandemics, the activation of the immune system due to psychological stress and/or to infection during pregnancy, might lead to an increased risk of neurodevelopmental disorders for the fetus (schizophrenia and autism spectrum disorders). Furthermore, in individuals exposed to psychological trauma and/or infected by the virus, the risk of psychiatric disorders, especially mood disorders, is probably increased. CONCLUSION: In this context, preventive measures and specialized care are necessary. Thus, it is important to propose a close follow-up to the individuals who have been infected by the virus, in order to set up the earliest care possible. Likewise, in pregnant women, screening of mood disorders during the pregnancy or the postpartum period must be facilitated. The follow-up of the babies born during the pandemic must be strengthened to screen and care for possible neurodevelopmental disorders.

Immune Modulatory Treatments for Autism Spectrum Disorder.

Several lines of evidence from family history studies, immunogenetics, maternal immune activation, neuroinflammation, and systemic inflammation support an immune subtype of autism spectrum disorder (ASD). Current Food and Drug Administration-approved medications for ASD do not address the underlying pathophysiology of ASD, have not consistently been shown to address the core symptoms of ASD, and are currently only approved for treating irritability in children and adolescents. In this article, we review the immune modulatory effects of the 2 currently Food and Drug Administration-approved treatments for ASD. We then provide an overview of current data on emerging treatments for ASD from multiple fields of medicine with immune modulatory effects. Although further research is needed to more clearly establish the efficacy and safety of immune modulatory treatments, early data on repurposing medications used to treat systemic inflammation for ASD demonstrate potential benefit and further research is warranted.

Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that currently has no approved medical therapy to address core symptoms or underling pathophysiological processes. Several compounds are under development that address both underlying pathophysiological abnormalities and core ASD symptoms. This article reviews one of these treatments, d,l-leucovorin calcium (also known as folinic acid) for treatment of folate pathway abnormalities in children with ASD. Folate is a water-soluble B vitamin that is essential for normal neurodevelopment and abnormalities in the folate and related pathways have been identified in children with ASD. One of these abnormalities involves a partial blockage in the ability of folate to be transported into the brain utilizing the primary transport mechanism, the folate receptor alpha. Autoantibodies which interfere with the function of the folate receptor alpha called folate receptor alpha autoantibodies have been identified in 58%-76% of children with ASD and independent studies have demonstrated that blood titers of these autoantibodies correlate with folate levels in the cerebrospinal fluid. Most significantly, case-series, open-label, and single and double-blind placebo-controlled studies suggest that d,l-leucovorin, a reduced folate that can bypass the blockage at the folate receptor alpha by using the reduced folate carrier, an alternate pathway, can substantially improve particular symptoms in children with ASD, especially those positive for folate receptor alpha autoantibodies. This article reviews the current evidence for treating core and associated symptoms and underlying pathophysiological mechanisms in children with ASD with d,l-leucovorin.

Assessment of miR-181b-5p, miR-23a-3p, BCL-2, and IL-6 in Peripheral Blood Mononuclear Cells of Autistic Patients; Likelihood of Reliable Biomarkers.

Autism is a neurodevelopmental disorder that is recognized by stereotypic and repetitive behaviors after 2 years of old. Dysregulation of the immune system, especially inflammation which is mostly regulated by IL-6, imposes a deficit in CNS development. Along with this crucial biomarker, researchers have proposed BCL-2, micro RNA-23a-3p (miR-23a-3p), miR-181b-5p as other probable biomarkers involved in inflammation and apoptosis. The aim of the study was to evaluate the alteration in the expression of these biomarkers in a group of autism spectrum disorder (ASD) children. Peripheral blood mononuclear cells (PBMCs) were obtained from 37 autistic patients. After RNA extraction with precipitation method, the Syber green qReal-time Polymerase Chain Reaction (PCR) was performed in order to evaluate the possible alteration in the expression of IL-6, BCL-2, miR-181b-5p, and miR-23a-3p. The results were compared with healthy controls. IL-6 was significantly upregulated in ASD patients (p=0.003). On the other hand, miR-23a was upregulated and BCL-2 downregulated in ASD patients but the changes were not significant. In initial evaluations, expression changes of miR-181b-5p were not statistically significant. However, when Patients were divided into two groups of upregulated and downregulated, re-evaluation showed that both up- (p=0.005) and down-regulation (p=0.004) (i.e. changes regardless of the direction) of miR-181b were significant in autistic children. IL-6 and miR-181b-5p can have proper diagnostic values and are reliable biomarkers with high sensitivity and specificity. On the other hand, PBMC can be utilized for such studies and also evaluation of patients' condition instead of brain tissue as it is less accessible.

Involvement of CD45 cells in the development of autism spectrum disorder through dysregulation of granulocyte-macrophage colony-stimulating factor, key inflammatory cytokines, and transcription factors.

Autismspectrum disorder (ASD) is a complex and multifactorial heterogeneous disorder. Previous investigations have revealed the association between the immune system and ASD, which is characterized by impaired communication skills. Inflammatory response through CD45 cells plays a key role in the pathogenesis of several autoimmune disorders; however, the molecular mechanism of CD45 cells in ASD is not clearly defined.In this study, we investigated the role of CD45 signaling in children with ASD. In this study, we aimed to investigate the possible involvement of CD45 cells expressing granulocyte-macrophage colony-stimulating factor and inflammatory transcription factors in ASD. Flow cytometric analysis, using peripheral blood mononuclear cells (PBMC), revealed the numbers of GM-CSF-, IFN-γ-, IL-6-, IL-9-, IL-22-, T-bet-, pStat3-, Helios-, and Stat6-producing CD45+ cells in children with ASD and children in the control group. We further evaluated the mRNA and protein expression levels of GM-CSF in PBMC by RT-PCR and western blotting analysis. Our results revealed that the children with ASD exhibited significantly higher numbers of CD45+GM-CSF+, CD45+IFN-γ+, CD45+IL-6+, CD45+IL-9+, CD45+IL-22+, CD45+T-bet+, and CD45+pStat3+ cells compared with the control group. We also found that the children with ASD showed a lower number of CD45+Helios+ and CD45+Stat6+ cells compared with the control group. Furthermore, the children with ASD showed higher GM-CSF mRNA and protein expression levels compared with the control group. These results indicated that CD45 could play an essential role in the immune abnormalities of ASD. Further investigation of the role of CD45 in neurodevelopment in ASD is warranted.

Microbiota: a novel regulator of pain.

Among the various regulators of the nervous system, the gut microbiota has been recently described to have the potential to modulate neuronal cells activation. While bacteria-derived products can induce aversive responses and influence pain perception, recent work suggests that "abnormal" microbiota is associated with neurological diseases such as Alzheimer's, Parkinson's disease or autism spectrum disorder (ASD). Here we review how the gut microbiota modulates afferent sensory neurons function and pain, highlighting the role of the microbiota/gut/brain axis in the control of behaviors and neurological diseases. We outline the changes in gut microbiota, known as dysbiosis, and their influence on painful gastrointestinal disorders. Furthermore, both direct host/microbiota interaction that implicates activation of "pain-sensing" neurons by metabolites, or indirect communication via immune activation is discussed. Finally, treatment options targeting the gut microbiota, including pre- or probiotics, will be proposed. Further studies on microbiota/nervous system interaction should lead to the identification of novel microbial ligands and host receptor-targeted drugs, which could ultimately improve chronic pain management and well-being.

Dysregulation in IL-6 receptors is associated with upregulated IL-17A related signaling in CD4+ T cells of children with autism.

Autism spectrum disorder (ASD) is a heterogeneous syndrome characterized by dysregulations in speech and social interactions as well as repetitive and stereotypical behavioral patterns in which immune system plays a significant role. IL-6, an essential cytokine for polarization of Th0 cells into Th17 cells has been demonstrated to be crucial in the etiology of ASD in past studies both in humans and mice. Th17 cells are also believed to be central players in the pathogenesis of ASD through release of IL-17A. However, there is still insufficient data regarding identification of Th17 cells with respect to IL-6 signaling in ASD subjects. Therefore, this study explored IL-6 receptors (IL-6R/sIL-6R) and Th17 (p-STAT3/IL-17A/IL-23R) related markers comprehensively in the blood of typically-developing control (TDC, n = 35) and ASD children (n = 45). Our data show that there is enhanced sIL-6R levels in plasma and CD4+ T cells of ASD subjects as compared to TDC group. Increased sIL-6R signaling is associated with upregulated Th17 development in ASD subjects. Further, severe ASD subjects have higher inflammation in terms of IL-6/IL-17A related signaling as compared to moderate ASD patients. Furthermore, treatment of CD4 + T cells in vitro with IL-6 leads to much greater upregulation of p-STAT3, and IL-17A in ASD subjects than similarly treated CD4+ T cells in TDC group. Antagonism of IL-6 signaling by SC144 in vitro led to blockade of IL-6 mediated effects on CD4+ T cells. These data display unequivocally that IL-6 signaling components are dysregulated which play a crucial in enhancement of Th17 development in ASD subjects.

Maternal elevated salt consumption and the development of autism spectrum disorder in the offspring.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental condition with no known etiology or cure. Several possible contributing factors, both genetic and environmental, are being actively investigated. Amongst these, maternal immune dysregulation has been identified as potentially involved in promoting ASD in the offspring. Indeed, ASD-like behaviors have been observed in studies using the maternal immune activation mouse model. Furthermore, recent studies have shed light on maternal dietary habits and their impact on the gut microbiome as factors possibly facilitating ASD. However, most of these studies have been limited to the effects of high fat and/or high sugar. More recent data, however, have shown that elevated salt consumption has a significant effect on the immune system and gut microbiome, often resulting in gut dysbiosis and induction of pro-inflammatory pathways. Specifically, high salt alters the gut microbiome and induces the differentiation of T helper-17 cells that produce pro-inflammatory cytokines such as interleukin-17 and interleukin-23. Moreover, elevated salt can also reduce the differentiation of regulatory T cells that help maintaining a balanced immune system. While in the innate immune system, high salt can cause over activation of M1 pro-inflammatory macrophages and downregulation of M2 regulatory macrophages. These changes to the immune system are alarming because excessive consumption of salt is a documented worldwide problem. Thus, in this review, we discuss recent findings on high salt intake, gut microbiome, and immune system dysregulation while proposing a hypothesis to link maternal overconsumption of salt and children's ASD.

Children With Autism Spectrum Disorder and Their Mothers Share Abnormal Expression of Selected Endogenous Retroviruses Families and Cytokines.

The Autism Spectrum Disorder (ASD) is a heterogeneous group of neurodevelopmental disorders, only clinically diagnosed since the lack of reliable biomarkers. Autism etiology is probably attributable to the combination of genetic vulnerability and environmental factors, and recently, maternal immune activation has been linked to derailed neurodevelopment, resulting in ASD in the offspring. Human endogenous retroviruses (HERVs) are relics of ancestral infections, stably integrated in the human DNA. Given the HERV persistence in the genome, some of HERVs have been co-opted for physiological functions during evolution, while their reactivation has been associated with several pathological conditions, including cancer, autoimmune, and neurological and psychiatric disorders. Particularly, due to their intrinsic responsiveness to external stimuli, HERVs can modulate the host immune response and in turn HERVs can be activated by the immune effectors. In previous works we demonstrated high expression levels of HERV-H in blood of autistic patients, closely related with the severity of the disease. Moreover, in a preclinical ASD model we proved changes of expression of several ERV families and cytokines from the intrauterine life to the adulthood, and across generations via maternal lineage. Here we analyzed the expression of HEMO and of selected HERVs and cytokines in blood from ASD patients and their parents and corresponding healthy controls, to look for a common molecular trait within family members. ASD patients and their mothers share altered expression of HERV-H and HEMO and of cytokines such as TNF-α, IFN-γ, IL-10. The multivariate regression models showed a mother-child association by HEMO activity and demonstrated in children and mothers an association between HERV-H and HEMO expression and, only in mothers, between HEMO, and TNF-α expression. Furthermore, high diagnostic performance for HERV-H and HEMO was found, suggesting their potential application for the identification of ASD children and their mothers. The present data support the involvement of HERVs in ASD and suggest HERVs and cytokines as ASD-associated traits. Since ASD is a heterogeneous group of neurodevelopmental disorders, a single determinant alone could be not enough to account for the complexity, and HERV/cytokines expression could be considered in a set of biomarkers, easily detectable in blood, and potentially useful for an early diagnosis.

Activación inmune durante el embarazo y riesgo de Trastorno del Espectro Autista / Maternal immune activation and risk of Autism Spectrum Disorder

Resumen: En los últimos años se ha intentado comprender la etiología del Trastorno del Espectro Autista (TEA), evidenciandose que existe una compleja interacción entre factores genéticos y ambientales. Estudios epidemiológicos y en modelos animales sugieren que la activación inmune de la madre durante el embarazo puede asociarse un mayor riesgo de desarrollar TEA en los hijos, destacando el rol de las citoquinas proinflamatorias, los auto-anticuerpos y el rol de la microglia activada en la poda sináptica durante el desarrollo embrionario. Comprender mejor los factores asociados con los Trastornos del Neurodesarrollo permitirá en el futuro desarrollar estrategias de manejo y detección precoz en población de riesgo.

Abstract: Autism Spectrum Disorder (ASD) etiology has been related whit complex interaction between ge netic and environmental factors. In the last years, numerous studies have suggested that maternal immune activation during pregnancy could be related to ASD in the offspring. This relation could be explained by the effects of pro-inflammatory cytokines, autoantibodies and microglial synap tic pruning during early embryonic development. Better understanding of Neurodevelopmental Disorders risk factors will support appropriate strategies of screening and management of risk population.

Proband and Familial Autoimmune Diseases Are Associated With Proband Diagnosis of Autism Spectrum Disorders.

OBJECTIVE: There is evidence that parental autoimmune diseases (ADs) are associated with autism spectrum disorders (ASD) in offspring. The association between offspring ASD and ADs diagnosed in siblings and probands remains less clear. We examined whether proband and familial diagnoses of ADs were associated with increased odds of ASD in probands. METHOD: The study is based on a nested case-control design that used data from a large national birth cohort (N = 1.2 million) in Finland. There were 4,600 cases of ASD and controls matched 1:4 on date of birth, sex, and residence. Data were accessed from national medical, birth, and central registries. RESULTS: Probands had a statistically significant increase in odds of ASD when they (adjusted odds ratio [OR] = 1.2), their mother (adjusted OR = 1.1), or their sibling (adjusted OR = 1.2) were diagnosed with an AD. With regard to specific ADs, we found a statistically significant increase in odds of ASD in probands diagnosed with autoimmune thyroiditis (adjusted OR = 2.7). Further analyses considering ADs by body system yielded a statistically significant increase in odds of ASD in probands with ADs associated with the central/peripheral nervous (adjusted OR = 4.8) and skin/mucous membrane (adjusted OR = 1.3) systems. Probands of mothers diagnosed with ear/eye (adjusted OR = 1.6) or respiratory (adjusted OR = 1.4) ADs, or siblings diagnosed with skin/mucous membrane ADs (adjusted OR = 1.3) also had increased odds of ASD. CONCLUSION: The findings suggest that there may be common pathogenic, developmental mechanisms related to autoimmunity that are associated with the etiology of ASD.

HLA-G allelic distribution in Sardinian children with Autism spectrum disorders: A replication study.

Recent results show that in mainland Italian children with Autism spectrum disorder (ASD), HLA-G coding alleles distribution is skewed and an association between HLA-G*01:05N and ASD is present. Herein, in an independent cohort of Sardinian ASD (sASD) children and their relatives, we verify whether HLA-G allele association with ASD could be confirmed in this genetically peculiar insular population. One hundred children with a diagnosis of ASD, born in Sardinia and of Sardinian descent, 91 of their mothers, and 40 of their healthy siblings were enrolled. DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies. Alleles distribution was compared with that of continental ASD children and with a control group of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. Skewing of HLA-G allele distribution was replicated in sASD children; in particular, the HLA-G*01:03 allele, associated with reduced fetal tolerogenicity and development of myeloid leukemia, was more common in both ASD groups compared to controls (pc = 1 × 10-3; OR:3.5, 95%CI: 1.8-6.8). However, given the lack of data on HLA-G*01:03 allelic distribution among Sardinian healthy subjects, we cannot exclude a population effect. These data confirm an association of HLA-G locus with ASD development, particularly with those alleles linked to a lower expression of tolerogenic HLA-G protein, thus warranting further studies on HLA-G polymorphism distribution in different ASD populations.

Oxidative and inflammatory mediators are upregulated in neutrophils of autistic children: Role of IL-17A receptor signaling.

Autism spectrum disorder (ASD) is characterized by repetitive behaviors, impaired social communication and stereotyped interests, and often associated with dysregulations in innate/adaptive immune cells. IL-17A has been linked with abnormal behavioral patterns observed in autistic children and animal models of autism. However, it is yet to be investigated if IL-17A and its receptors are implicated in regulation of oxidative and inflammatory mediators in neutrophils of ASD patients. Therefore, we pursued to identify the effect of IL-17 receptor (IL-17R), and its inflammatory potential in neutrophils from ASD (n = 45) and typically developing control (TDC; n = 40) subjects. IL-17A, its receptor (IL-17R), associated signaling pathways [nuclear transcription factor nuclear factor-kappa B (NF-κB), IL-6 and oxidative stress parameters such as NADPH oxidase (NOX2), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), and nitrotyrosine] were determined in the neutrophils from TDC and ASD subjects. Our data show that IL-17A expression, and IL-17R are increased in neutrophils of ASD patients. Further, inflammatory signaling pathways such as such as phospho-NFκB, and ROS generating enzymes, i.e. NOX2/iNOS are increased in neutrophils of ASD patients as compared TDC subjects. Furthermore, activation of IL-17A/IL-17R signaling in neutrophils of ASD subjects leads to upregulation of phospho-NFκB, IL-6 and NOX2/ROS, thus suggesting a compelling role of IL-17A in modulation of inflammation. Our study displays for the first time that IL-17A/IL-17R signaling in neutrophils could play a pivotal role in autism through upregulation of oxidative and inflammatory mediators.

Immune aberrations in children with Autism Spectrum Disorder: a case-control study from a tertiary care neuropsychiatric hospital in India.

Multiple studies have identified the presence of peripheral immune aberrations in subjects with Autism Spectrum Disorder (ASD). However, comprehensive assessment of these peripheral immune aberrations, in the cellular and systemic compartments, in a single group of subjects with ASD is lacking. We assessed proportions of various subsets of immune cells in peripheral blood (T helper cells, T regulatory cells, B cells, monocytes, Natural Killer cells, dendritic cells) by multi-parametric flow cytometry in 50 children with ASD and compared it with thirty healthy controls matched for age, gender, socio-economic status and body mass index. There were no significant differences noted in the proportion of T regulatory cells, B cells, monocytes and Natural Killer cells, between ASD subjects and controls. On the contrary, the proportion of activated Th17 and myeloid dendritic cells were significantly higher in children with ASD. Based on these findings, group comparison of serum levels of Th17 cytokines (interleukin-6, interleukin-17A) was performed. Elevated serum levels of interleukin-6 and interleukin-17A in children with ASD corroborated our immunophenotyping findings. We did not find any significant differences among the pro-inflammatory (interleukin-1ß), Th1 (interferon-γ) and Th2 (interleukin-4) cytokines. This is the first evidence with concurrent findings from immunophenotyping and cytokine data demonstrating activation of the Th17 pathway in subjects with ASD. This finding assumes significance in the light of recent maternal immune activation mouse model study that has highlighted the role of Th17 pathway in the pathophysiology of ASD. Future longitudinal studies are needed to clarify the role of this dysregulated immune pathway in the development of ASD.

Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents.

Folate deficiency can affect fetal and neonatal brain development Considering the reported association of Folate receptor alpha (FRα) autoantibodies (Abs) with autism and developmental disorders, we sought to confirm this in families of 82 children with ASD, 53 unaffected siblings, 65 fathers, and 70 mothers, along with 52 unrelated normal controls. Overall, 76% of the affected children, 75% of the unaffected siblings, 69% of fathers and 59% of mothers were positive for either blocking or binding Ab, whereas the prevalence of this Ab in the normal controls was 29%. The Ab was highly prevalent in affected families including unaffected siblings. The appearance of these antibodies may have a familial origin but the risk of developing ASD is likely influenced by other mitigating factors since some siblings who had the antibodies were not affected. The antibody response appears heritable with the blocking autoantibody in the parents and affected child increasing the risk of ASD. Autism Res 2018, 11: 707-712. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Folate is an essential nutrient during fetal and infant development. Autoantibodies against the folate receptor alpha can block folate transport from the mother to the fetus and to the brain in infants. Children diagnosed with autism and their immediate family members were evaluated for the prevalence of folate receptor autoantibodies. The autoantibody was highly prevalent in affected families with similar distribution in parents, normal siblings and affected children. The presence of these antibodies appears to have a familial origin and may contribute to developmental deficits when combined with other factors.

Adenosine A2A receptor modulates neuroimmune function through Th17/retinoid-related orphan receptor gamma t (RORγt) signaling in a BTBR T+ Itpr3tf/J mouse model of autism.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by abnormal social interactions, repetitive behaviors that impair social communication, and circumscribed interests. BTBR T+tf/J (BTBR) inbred mice are generally used as a model for ASD, as they show repetitive behaviors and social deficits that resemble signs of ADS in humans. Adenosine A2A receptors (A2ARs) are considered as potential targets in the treatment of immune, inflammatory, and neurodegenerative diseases. In this study, we investigated the potential effects of the A2A adenosine receptor (A2AR) antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on behavior (self-grooming), hot plate test results, and expression levels of IL-17A+, RORγt+, Foxp3+, and IL-10+ in CD4+ T spleen cells in BTBR and C57BL/6 (B6) mice. We also assessed IL-17A, RORγt, Stat3, pStat3, Foxp3, and IL-10 mRNA and protein expression levels in the brain tissue. The CGS-treated mice showed a significantly altered self-grooming score and a reduced response to the hot plate test. The results further revealed that the SCH efficiently increased the IL-17A+ and RORγt+ expression levels and decreased the Foxp3+ and IL-10+ expression levels in CD4+ cells. However, the treatment with CGS significantly reversed these effects. In addition, CGS significantly decreased the IL-17A, RORγt, Stat3, and pStat3 levels and increased the Foxp3 and IL-10 mRNA and protein expression levels as compared with the BTBR control and SCH treatments. Our results clearly indicate that the CGS A2AR agonist may represent a unique target for future therapeutic strategies for neuroimmune dysfunction.