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Increasing evidence points to a central role for immune dysregulation in autism spectrum disorder (ASD). Several ASD risk genes encode components of the immune system and many maternal immune system-related risk factors--including autoimmunity, infection and fetal reactive antibodies--are associated with ASD. In addition, there is evidence of ongoing immune dysregulation in individuals with ASD and in animal models of this disorder. Recently, several molecular signalling pathways--including pathways downstream of cytokines, the receptor MET, major histocompatibility complex class I molecules, microglia and complement factors--have been identified that link immune activation to ASD phenotypes. Together, these findings indicate that the immune system is a point of convergence for multiple ASD-related genetic and environmental risk factors.

Background: An emerging paradigm suggests children with autism display a unique pattern of environmental, genetic, and epigenetic triggers that make them susceptible to developing dysfunctional heavy metal and chemical detoxification systems. These abnormalities could be caused by alterations in the methylation, sulfation, and metalloprotein pathways. This study sought to evaluate the physiological and behavioral effects of children with autism sleeping in an International Organization for Standardization Class 5 cleanroom., Methods: Ten children with autism, ages 3-12, slept in a cleanroom for two weeks to evaluate changes in toxin levels, oxidative stress, immune dysregulation, and behavior. Before and after the children slept in the cleanroom, samples of blood and hair and rating scale scores were obtained to assess these changes., Results: Five children significantly lowered their concentration of oxidized glutathione, a biomarker of oxidative stress. The younger cohort, age 5 and under, showed significantly greater mean decreases in two markers of immune dysregulation, CD3% and CD4%, than the older cohort. Changes in serum magnesium, influencing neuronal regulation, correlated negatively while changes in serum iron, affecting oxygenation of tissues, correlated positively with age. Changes in serum benzene and PCB 28 concentrations showed significant negative correlations with age. The younger children demonstrated significant improvements on behavioral rating scales compared to the older children. In a younger pair of identical twins, one twin showed significantly greater improvements in 4 out of 5 markers of oxidative stress, which corresponded with better overall behavioral rating scale scores than the other twin., Conclusions: Younger children who slept in the cleanroom altered elemental levels, decreased immune dysregulation, and improved behavioral rating scales, suggesting that their detoxification metabolism was briefly enhanced. The older children displayed a worsening in behavioral rating scale performance, which may have been caused by the mobilization of toxins from their tissues. The interpretation of this exploratory study is limited by lack of a control group and small sample size. The changes in physiology and behavior noted suggest that performance of larger, prospective controlled studies of exposure to nighttime or 24 hour cleanroom conditions for longer time periods may be useful for understanding detoxification in children with autism., Trial Registration: Clinical Trial Registration Number NCT02195401 (Obtained July 18, 2014).

Animal models indicate that maternal infection during pregnancy can result in behavioral abnormalities and neuropathologies in offspring. We examined the association between maternal inpatient diagnosis with infection during pregnancy and risk of ASD in a Swedish nationwide register-based birth cohort born 1984-2007 with follow-up through 2011. In total, the sample consisted of 2,371,403 persons with 24,414 ASD cases. Infection during pregnancy was defined from ICD codes. In the sample, 903 mothers of ASD cases (3.7%) had an inpatient diagnosis of infection during pregnancy. Logistic regression models adjusted for a number of covariates yielded odds ratios indicating approximately a 30% increase in ASD risk associated with any inpatient diagnosis of infection. Timing of infection did not appear to influence risk in the total Swedish population, since elevated risk of ASD was associated with infection in all trimesters. In a subsample analysis, infections were associated with greater risk of ASD with intellectual disability than for ASD without intellectual disability. The present study adds to the growing body of evidence, encompassing both animal and human studies, that supports possible immune-mediated mechanisms underlying the etiology of ASD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Fragile X syndrome (FXS) is a single-gene disorder with a broad spectrum of involvement, including cognitive and behavioural impairments of varying degrees with specific physical features and a strong association with autism., Objectives: In this study, the frequency of serum anti-neural antibodies was investigated in FXS patients who did and those who did not manifest autism spectrum disorders (ASD) in comparison to typically developing controls., Methods: The study involved 23 males (mean age, 19.78 ± 6.56 years) who harboured a full mutation in the FMR1 gene. The control group comprised 19 healthy students (mean age 24.63 ± 1.89 years). Serum anti-neuronal antibodies were analyzed using Western blotting., Results: Serum anti-neuronal antibodies were present in 10/23 (43.48%) FXS males., Conclusion: Serum anti-neuronal antibodies were found in a subgroup of FXS patients. Autistic symptoms in FXS may, in part, be caused by auto-immune factors. Further studies in larger patient and control groups are necessary to elucidate the aetiopathogenic role of anti-neuronal antibodies in FXS patients., (© 2014 S. Karger AG, Basel.)

Autism spectrum disorders (ASD) are a group of disorders characterized by core behavioral features including stereotyped interests, repetitive behaviors and impairments in communication and social interaction. In addition, widespread changes in the immune systems of individuals with ASD have been identified, in particular increased evidence of inflammation in the periphery and central nervous system. While the etiology of these disorders remains unclear, it appears that multiple gene and environmental factors are involved. The need for animal models paralleling the behavioral and immunological features of ASD is paramount to better understand the link between immune system dysregulation and behavioral deficits observed in these disorders. As such, the asocial BTBR mouse strain displays both ASD relevant behaviors and persistent immune dysregulation, providing a model system that has and continues to be instructive in understanding the complex nature of ASD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A growing amount of research indicates that abnormalities in the gastrointestinal (GI) system during development might be a common factor in multiple neurological disorders and might be responsible for some of the shared comorbidities seen among these diseases. For example, many patients with Autism Spectrum Disorder (ASD) have symptoms associated with GI disorders. Maternal zinc status may be an important factor given the multifaceted effect of zinc on gut development and morphology in the offspring. Zinc status influences and is influenced by multiple factors and an interdependence of prenatal and early life stress, immune system abnormalities, impaired GI functions, and zinc deficiency can be hypothesized. In line with this, systemic inflammatory events and prenatal stress have been reported to increase the risk for ASD. Thus, here, we will review the current literature on the role of zinc in gut formation, a possible link between gut and brain development in ASD and other neurological disorders with shared comorbidities, and tie in possible effects on the immune system. Based on these data, we present a novel model outlining how alterations in the maternal zinc status might pathologically impact the offspring leading to impairments in brain functions later in life.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by deficits in social interactions, communication, and increased stereotypical repetitive behaviors. The immune system plays an important role in neurodevelopment, regulating neuronal proliferation, synapse formation and plasticity, as well as removing apoptotic neurons. Immune dysfunction in ASD has been repeatedly described by many research groups across the globe. Symptoms of immune dysfunction in ASD include neuroinflammation, presence of autoantibodies, increased T cell responses, and enhanced innate NK cell and monocyte immune responses. Moreover these responses are frequently associated with more impairment in core ASD features including impaired social interactions, repetitive behaviors and communication. In mouse models replacing immune components in animals that exhibit autistic relevant features leads to improvement in behavior in these animals. Taken together this research suggests that the immune dysfunction often seen in ASD directly affects aspects of neurodevelopment and neurological processes leading to changes in behavior. Discussion of immune abnormalities in ASD will be the focus of this review., (Copyright © 2014. Published by Elsevier B.V.)

Autism spectrum disorders (ASD) are a group of neuro-developmental disorders in early childhood which are defined by social difficulties, communication deficits and repetitive or restrictive interests and behaviours. The etiology of ASD remains poorly understood. Much research has shown that children with ASD suffer from immunological dysfunction. This article reviews the current research progress on immunological dysfunction in children with ASD, including abnormalities in immune cells, antibodies, complements, cytokines, major histocompatibility complex and their potential association with ASD, and explores the impacts of maternal immunological activation on the immune dysfunction of children with ASD.

Epidemiological studies have shown a clear association between maternal infection and schizophrenia or autism in the progeny. Animal models have revealed maternal immune activation (mIA) to be a profound risk factor for neurochemical and behavioural abnormalities in the offspring. Microglial priming has been proposed as a major consequence of mIA, and represents a critical link in a causal chain that leads to the wide spectrum of neuronal dysfunctions and behavioural phenotypes observed in the juvenile, adult or aged offspring. Such diversity of phenotypic outcomes in the mIA model are mirrored by recent clinical evidence suggesting that infectious exposure during pregnancy is also associated with epilepsy and, to a lesser extent, cerebral palsy in children. Preclinical research also suggests that mIA might precipitate the development of Alzheimer and Parkinson diseases. Here, we summarize and critically review the emerging evidence that mIA is a shared environmental risk factor across CNS disorders that varies as a function of interactions between genetic and additional environmental factors. We also review ongoing clinical trials targeting immune pathways affected by mIA that may play a part in disease manifestation. In addition, future directions and outstanding questions are discussed, including potential symptomatic, disease-modifying and preventive treatment strategies.

More than a century has passed since the first description of neuromyelitis optica (NMO) or Devic's disease. The relation between NMO and multiple sclerosis (MS) had long been debated, but the discovery of anti-aquaporin-4(AQP4) antibody, an NMO-specific autoantibody has accelerated clinical and experimental research of NMO, and contributed to estabilishing NMO spectrum disorder(NMOSD), a wider disease spectrum than a prototypic opticospinal phenotype and a new disease concept: autoimmune astrocytopathic disease. Clinical, MRI and laboratory findings and therapeutic response in NMOSD are different from those in MS. On the other hand, anti-AQP4 antibody-seronegative NMOSD has some distinct features from seropositive cases, and anti-myelin oligodendrocyte glycoprotein(MOG) antibody is detected in a fraction of cases of seronegative NMOSD. Unlike anti-AQP4 antibody-associated NMOSD, anti-MOG antibody-seropositive NMOSD may be a demyelinating desease. In this review, we provide an overview of how the concept of NMOSD has evolved in association with accumulated scientific evidences.

Background: Some children with autism spectrum disorders (ASD) are characterized by fluctuating behavioral symptoms following immune insults, persistent gastrointestinal (GI) symptoms, and a lack of response to the first-line intervention measures. These children have been categorized as the ASD-inflammatory subtype (ASD-IS) for this study. We reported a high prevalence of non-IgE mediated food allergy (NFA) in young ASD children before, but not all ASD/NFA children reveal such clinical features of ASD-IS. This study addressed whether behavioral changes of ASD-IS are associated with innate immune abnormalities manifested in isolated peripheral blood (PB) monocytes (Mo), major innate immune cells in the PB., Methods: This study includes three groups of ASD subjects (ASD-IS subjects (N = 24), ASD controls with a history of NFA (ASD/NFA (N = 20), and ASD/non-NFA controls (N = 20)) and three groups of non-ASD controls (non-ASD/NFA subjects (N = 16), those diagnosed with pediatric acute onset-neuropsychiatric syndrome (PANS, N = 18), and normal controls without NFA or PANS (N = 16)). Functions of purified PB Mo were assessed by measuring the production of inflammatory and counter-regulatory cytokines with or without stimuli of innate immunity (lipopolysaccharide (LPS), zymosan, CL097, and candida heat extracts as a source of β-lactam). In ASD-IS and PANS subjects, these assays were done in the state of behavioral exacerbation ('flare') and in the stable ('non-flare') condition. ASD-IS children in the 'flare' state revealed worsening irritability, lethargy and hyperactivity., Results: 'Flare' ASD-IS PB Mo produced higher amounts of inflammatory cytokines (IL-1β and IL-6) without stimuli than 'non-flare' ASD-IS cells. With zymosan, 'flare' ASD-IS cells produced more IL-1β than most control cells, despite spontaneous production of large amounts of IL-1ß. Moreover, 'flare' ASD-IS Mo produced less IL-10, a counterregulatory cytokine, in response to stimuli than 'non-flare' cells or other control cells. These changes were not observed in PANS cells., Conclusions: We observed an imbalance in the production of inflammatory (IL-1ß and IL-6) and counterregulatory (IL-10) cytokines by 'flare' ASD-IS monocytes, which may indicate an association between intrinsic abnormalities of PB Mo and changes in behavioral symptoms in the ASD-IS subjects.

Autism spectrum disorders are neurodevelopmental disorders characterized by two core symptoms; impaired social interactions and communication, and ritualistic or repetitive behaviors. Both epidemiological and biochemical evidence suggests that a subpopulation of autistics may be linked to immune perturbations that occurred during fetal development. These findings have given rise to an animal model, called the "maternal immune activation" model, whereby the offspring from female rodents who were subjected to an immune stimulus during early or mid-pregnancy are studied. Here, C57BL/6 mouse dams were treated mid-gestation with saline, lipopolysaccharide (LPS) to mimic a bacterial infection, or polyinosinic:polycytidylic acid (Poly IC) to mimic a viral infection. Autism-associated behaviors were examined in the adult offspring of the treated dams. Behavioral tests were conducted to assess motor activity, exploration in a novel environment, sociability, and repetitive behaviors, and data analyses were carried independently on male and female mice. We observed a main treatment effect whereby male offspring from Poly IC-treated dams showed reduced motor activity. In the marble burying test of repetitive behavior, male offspring but not female offspring from both LPS and Poly IC-treated mothers showed increased marble burying. Our findings indicate that offspring from mothers subjected to immune stimulation during gestation show a gender-specific increase in stereotyped repetitive behavior.

Autism spectrum disorders (ASD) comprise a group of neurodevelopmental abnormalities that begin in early childhood and are characterized by impairment of social communication and behavioral problems including restricted interests and repetitive behaviors. Several genes have been implicated in the pathogenesis of ASD, most of them are involved in neuronal synaptogenesis. A number of environmental factors and associated conditions such as gastrointestinal (GI) abnormalities and immune imbalance have been linked to the pathophysiology of ASD. According to the March 2012 report released by United States Centers for Disease Control and Prevention, the prevalence of ASD has sharply increased during the recent years and one out of 88 children suffers now from ASD symptoms. Although there is a strong genetic base for the disease, several associated factors could have a direct link to the pathogenesis of ASD or act as modifiers of the genes thus aggravating the initial problem. Many children suffering from ASD have GI problems such as abdominal pain, chronic diarrhea, constipation, vomiting, gastroesophageal reflux, and intestinal infections. A number of studies focusing on the intestinal mucosa, its permeability, abnormal gut development, leaky gut, and other GI problem raised many questions but studies were somehow inconclusive and an expert panel of American Academy of Pediatrics has strongly recommended further investigation in these areas. GI tract has a direct connection with the immune system and an imbalanced immune response is usually seen in ASD children. Maternal infection or autoimmune diseases have been suspected. Activation of the immune system during early development may have deleterious effect on various organs including the nervous system. In this review we revisited briefly the GI and immune system abnormalities and neuropeptide imbalance and their role in the pathophysiology of ASD and discussed some future research directions.

The maternal immune system may play a role in offspring neurodevelopment. We examined whether maternal autoimmune disease, asthma, and allergy were associated with child autism spectrum disorder (ASD) and developmental delay without autism (DD) using 560 ASD cases, 391 typically developing controls, and 168 DD cases from the CHildhood Autism Risk from Genetics and the Environment (CHARGE) study. Results from conditional logistic regression demonstrated few significant associations overall. Maternal autoimmune disease was significantly associated with a modest increase in odds of developmental disorders (combined ASD + DD; OR = 1.46, 95% CI 1.01, 2.09) but not of ASD alone. Associations with certain allergens and onset periods were also suggested. These findings suggest maternal autoimmune disease may modestly influence childhood developmental disorders (ASD + DD).

Background/aim: The etiology of autism spectrum disorder (ASD) is unknown, even though it is hypothesized that a viral infection could trigger this disorder. The aim of this study was to evaluate the seropositivity rate and antibody level of Herpes Simplex Virus 1 (HSV1) and Herpes Simplex Virus 2 (HSV2) in children with ASD compared to same-aged healthy controls., Patients and Methods: We compared seropositivity rate and levels of antibodies to HSV1/2 in 54 children with ASD (19 with autistic disorder and 35 with non-autistic ASD) and in 46 controls., Results: Seropositivity rate and levels of anti-HSV1/2 were not dissimilar between cases and controls. Exposure to HSV2 was minimal., Conclusion: Rate of contact with HSV1 and HSV2 assessed by the mean of detection of specific antibodies was similar between children with ASD and healthy controls., (Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: The etiology of autism spectrum disorders (ASD) is currently unknown. Few studies have explored the role of Cytomegalovirus (CMV) and Epstein Barr Virus (EBV) as potential etiological factors of ASD. The aim of the present study was to evaluate the seropositivity rate and antibody titre to CMV and EBV in children with ASD compared to same-aged healthy controls., Patients and Methods: We compared the seropositivity rate and titre of antibodies to CMV and EBV in 54 children with ASD (19 with autistic disorder and 35 with non-autistic disorder ASD) and in 46 controls., Results: Seropositivity rate and titre of the two antibodies were not dissimilar between cases and controls. However, considering only patients with ASD, those seropositive for CMV tended to test worse to the major severity scales than the seronegative ones., Conclusion: Titre and seropositivity rate of antibodies to CMV and EBV are similar between children with ASD and healthy controls., (Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: Autism spectrum disorder (ASD) is a group of central nervous system disorders lacking a definite etiology. The aim of the present study was to compare the exposure rate and titer of antibodies to Varicella Zoster Virus (VZV) in children with ASD and in healthy controls., Patients and Methods: We enrolled 54 children with ASD and 46 control individuals., Results: The exposure rate and titer of anti-VZV antibodies were significantly higher in children with ASD compared to controls (59% vs. 39% and 694 mIU/ml vs. 94 mIU/ml, respectively)., Conclusion: In the present case-control study, exposure to VZV was found to be independently associated with ASD., (Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Despite the emerging role of mitochondria in immunity, a link between bioenergetics and the immune response in autism has not been explored. Mitochondrial outcomes and phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst were evaluated in granulocytes from age-, race-, and gender-matched children with autism with severity scores of ≥7 (n = 10) and in typically developing (TD) children (n = 10). The oxidative phosphorylation capacity of granulocytes was 3-fold lower in children with autism than in TD children, with multiple deficits encompassing ≥1 Complexes. Higher oxidative stress in cells of children with autism was evidenced by higher rates of mitochondrial reactive oxygen species production (1.6-fold), higher mitochondrial DNA copy number per cell (1.5-fold), and increased deletions. Mitochondrial dysfunction in children with autism was accompanied by a lower (26% of TD children) oxidative burst by PMA-stimulated reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and by a lower gene expression (45% of TD children's mean values) of the nuclear factor erythroid 2-related factor 2 transcription factor involved in the antioxidant response. Given that the majority of granulocytes of children with autism exhibited defects in oxidative phosphorylation, immune response, and antioxidant defense, our results support the concept that immunity and response to oxidative stress may be regulated by basic mitochondrial functions as part of an integrated metabolic network., (Copyright © 2014 by the American Academy of Pediatrics.)

Circulating 45 and 62kDa antibodies targeting the cerebellum were previously associated with Autism Spectrum Disorder (ASD), lower adaptive/cognitive function and aberrant behaviors. Moreover, 37, 39 and 73kDa maternal antibodies (mAb) targeting the fetal brain were previously correlated with broad autism spectrum, irritability, abnormal brain enlargement and impaired expressive language. The present study aims towards clinically characterizing individuals with brain-targeted IgG and/or exposed to maternal antibrain antibodies in a large sample of Italian autistic children (N=355), their unaffected siblings (N=142) and mothers (N=333). The presence of patient- and mother-produced anti-brain antibodies does not confer increased risk of autism within the same sibship. However, the 45 and 62kDa antibodies are correlated with autism severity: the 45kDa Ab is associated with cognitive impairment and lower scores at the Vineland Adaptive Behavior Scales, the 62kDa Ab with motor stereotypies, while both correlate with larger head circumference (all P<0.05). On the other hand, maternal 37, 39 and 73kDa antibrain antibodies, either alone or in combination, are correlated with impaired verbal and non-verbal language development, neurodevelopmental delay and sleep/wake cycle disturbances in their autistic children (P<0.05). Presence of the 62kDa autoAb in the child is significantly associated with presence of the 39 and/or 73kDa antibodies in his/her mother. Our results confirm and extend previous observations in an ethnically distinct sample, providing further evidence of a pathomorphic role for anti-brain antibodies in autism while demonstrating their familial clustering., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Autism is a vexed problem today. Overall, there is a high frequency of birth children (1:80 - 1:150) with late diagnosed autism spectrum disorders (ASD) and this trend is getting progressively stronger. The causes for the currently increased frequency of ASD and the pathogenesis of ASD are not fully understood yet. One of the most likely mechanisms inducing ASD may be a maternal immune imprinting. This phenomenon is based on transplacental translocation of maternal antibodies of IgG class and, as a consequence, on the epigenetic "tuning" of immune system of the fetus and child. This mechanism provides development of child's anti-infection resistance before meeting with microorganisms, but it can be also a cause of inborn pathology including the ASD appearance. The quantitative changes in maternal blood serum autoantibodies depend on a specific microbial population, or are induced by environmental chemical pollutants in association with some individual features of the maternal metabolism. These immune changes are adaptive in most cases for the maternal organism, but can be pathogenic for the fetus in some cases. We discuss in the present paper the possibilities to predict the risk from abnormal development of nervous system in fetus and early diagnosis of ASD in high-risk group of children.

Increasing clinical and experimental evidence links immune and inflammatory alterations with the pathogenesis of autism spectrum disorders (ASD). Autistic individuals show signs of neuroinflammation, altered inflammatory responses, and immune abnormalities throughout life. Mice injected subcutaneously with 600 mg/kg valproic acid (VPA600) at gestational day 12.5 show reduced social interaction in adulthood (at 8 weeks of age), and they have been proposed as a mouse model of autism. Here, we show that these adult animals present signs of chronic glial activation in the hippocampus and the cerebellum. Moreover, when they are challenged with a peripheral inflammatory stimulus (intraperitoneal lipopolysaccharides, LPS), VPA600 animals show an exacerbated inflammatory response. Two hours after LPS injection, VPA600 animals secrete more corticosterone to the blood than control mice, and show an increase in the levels of expression of proinflammatory cytokines in the spleen. After LPS challenge, VPA600 mice also show signs of increased neuroinflammation compared with control mice: they have more microglial cells in the hippocampus, and they show higher levels of proinflammatory cytokines in the cerebellum. Our results provide evidence of basal neuroinflammation and an altered inflammatory response in the VPA model of autism. We propose that this model can be used to evaluate the contribution of inflammatory reactivity to autism-related behaviors. These studies will contribute to elucidate the role of the inflammatory alterations observed in ASD individuals., (© 2013 International Society for Autism Research, Wiley Periodicals, Inc.)

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by impairments in three core behavioral areas. As prevalence rates for ASD continue to rise there is also increasing interest in finding biomarkers associated with ASD. The use of biomarkers could help identify those at risk for ASD or ASD-associated comorbid conditions and help to predict the developmental course of these children. Due to the heterogeneity of ASD, biomarkers may help to identify subpopulations within ASD that share similar traits or profiles. Such work could lead to specialized therapy and help to develop biomarkers whereby the benefits of treatments/therapies for individuals could be monitored over time and through clinical trials. Over the last 10 years, the evidence of immune involvement in ASD has been steadily growing and many investigators have begun to look at possible immune biomarkers, such as immune cytokine profiles, in children with ASD.

Autism spectrum disorders (ASDs) are heterogeneous complex neurodevelopmental pathologies defined by behavioral symptoms, but which have well-characterized genetic, immunological, and physiological comorbidities. Despite extensive research efforts, there are presently no agreed upon therapeutic approaches for either the core behaviors or the associated comorbidities. In particular, the known autoimmune disorders associated with autism are appealing targets for potential stem cell therapeutics. Of the various stem cell populations, fetal stem cells (FSCs) offer the potent immunoregulatory functions found in primordial mesenchymal stem cells, while exhibiting rapid expansion capacity and recognized plasticity. These properties enhance their potential for clinical use. Furthermore, FSCs are potent and implantable "biopharmacies" capable of delivering trophic signals to the host, which could influence brain development. This study investigated the safety and efficacy of FSC transplantations in treating children diagnosed with ASDs. Subjects were monitored at pre, and then 6 and 12 months following the transplantations, which consisted of two doses of intravenously and subcutaneously administered FSCs. The Autism Treatment Evaluation Checklist (ATEC) test and Aberrant Behavior Checklist (ABC) scores were performed. Laboratory examinations and clinical assessment of adverse effects were performed in order to evaluate treatment safety. No adverse events of significance were observed in ASD children treated with FSCs, including no transmitted infections or immunological complications. Statistically significant differences (p < 0.05) were shown on ATEC/ABC scores for the domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores when compared to pretreatment values. We recognize that the use of FSCs remains controversial for the present. The results of this study, however, warrant additional investigations into the mechanisms of cell therapies for ASDs, while prompting the exploration of FSCs as "biopharmacies" capable of manufacturing the full array of cell-signaling chemistry. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

Unlabelled: Autism spectrum disorder (ASD) is a common and severe neuro-developmental disorder in early childhood which is defined by social and communication deficits and repetitive and stereotypic behaviours. The aetiology of ASD remains poorly understood. Susceptibility to development of ASD has significant environmental components, in addition to the profound genetic heritability. Few genes have been associated to the risk for ASD development. There is substantial evidence implicating chronic neurological inflammation and immune dysregulation leading to upregulation of inflammatory cytokines in the ASD brain, probably due to altered blood-brain barrier function. The immune system is characterized by excessive and skewed cytokine responses, modulated T cell reactivity, decreased regulation and production of immunosuppressive cytokines, modified NK function and increased autoantibody production., Conclusion: The perinatal environment generates vulnerability to chronic neuro-inflammation in the brain associated with profound modulation and dysregulation in the immune system leading to the rapid development of ASD in genetically susceptible children.

It is believed that in utero environmental factors contribute to autism spectrum disorder (ASD). The goal of this study was to demonstrate, using the largest cohort reported so far, that mothers of an ASD child have an elevated frequency of anti-brain antibodies and to assess whether brain reactivity is associated with an autoimmune diathesis of the mother. We screened plasma of 2431 mothers of an ASD child from Simon Simplex Collection and plasma of 653 unselected women of child-bearing age for anti-brain antibodies using immunohistology on mouse brain. Positive and negative plasma from mothers with an ASD child were analyzed for anti-nuclear antibodies and for autoimmune disorders. Mothers of an ASD child were four times more likely to harbor anti-brain antibodies than unselected women of child-bearing age (10.5 vs 2.6%). A second cohort from The Autism Genetic Resource Exchange with multiplex families displayed an 8.8% prevalence of anti-brain antibodies in the mothers of these families. Fifty-three percent of these mothers with anti-brain antibodies also exhibited anti-nuclear autoantibodies compared with 13.4% of mothers of an ASD child without anti-brain antibodies and 15% of control women of child-bearing age. The analysis of ASD mothers with brain-reactive antibodies also revealed an increased prevalence of autoimmune diseases, especially rheumatoid arthritis and systemic lupus erythematosus. This study provides robust evidence that brain-reactive antibodies are increased in mothers of an ASD child and may be associated with autoimmunity. The current study serves as a benchmark and justification for studying the potential pathogenicity of these antibodies on the developing brain. The detailed characterization of the specificity of these antibodies will provide practical benefits for the management and prevention of this disorder.

The contribution of neuroimmune functioning and brain-derived neurotrophic factor (BDNF) to functional dysregulation in autism spectrum disorder was assessed in 29 patients under treatment in two specialized centers of Basilicata (Chiaromonte and Matera), Southern Italy, through analysis of serum levels of cytokines and BDNF. Elevated levels of the pro-inflammatory cytokine, including interleukin-1, interleukin-6, interleukin-12, interleukin-23, tumor necrosis factor-α and BDNF were observed, regardless of age and gender. Comparisons were made with age- and gender-related healthy controls. The present findings reinforce current notions regarding immunoexcitotoxic mechanisms contributing to the pathophysiology of autistic disorder.

Objectives: The aim of the study was to analyze cytokine profiles in amniotic fluid (AF) samples of children developing autism spectrum disorders (ASD) and controls, adjusting for maternal autoimmune disorders and maternal infections during pregnancy., Methods: AF samples of 331 ASD cases and 698 controls were analyzed for inflammatory cytokines using Luminex xMAP technology utilizing a historic birth cohort. Clinical data were retrieved from nationwide registers, and case-control differences in AF cytokine levels were assessed using chi-square tests, logistic and tobit regression models., Results: Overall, individuals with ASD had significantly elevated AF levels of TNF-α and TNF-β compared to controls. Analyzing individuals diagnosed only with ICD-10 codes yielded significantly elevated levels of IL-4, IL-10, TNF-α and TNF-β in ASD patients. Restricting analysis to infantile autism cases showed significantly elevated levels of IL-4, TNF-α and TNF-β compared to controls with no psychiatric comorbidities. Elevated levels of IL-6 and IL-5 were found in individuals with other childhood psychiatric disorders (OCPD) when compared to controls with no psychiatric comorbidities., Conclusions: AF samples of individuals with ASD or OCPD showed differential cytokine profiles compared to frequency-matched controls. Further studies to examine the specificity of the reported cytokine profiles in ASD and OCPD are required.

Autism Spectrum Disorders (ASD) are a group of heterogeneous neurodevelopmental conditions presenting in early childhood with a prevalence ranging from 0.7% to 2.64%. Social interaction and communication skills are impaired and children often present with unusual repetitive behavior. The condition persists for life with major implications for the individual, the family and the entire health care system. While the etiology of ASD remains unknown, various clues suggest a possible association with altered immune responses and ASD. Inflammation in the brain and CNS has been reported by several groups with notable microglia activation and increased cytokine production in postmortem brain specimens of young and old individuals with ASD. Moreover several laboratories have isolated distinctive brain and CNS reactive antibodies from individuals with ASD. Large population based epidemiological studies have established a correlation between ASD and a family history of autoimmune diseases, associations with MHC complex haplotypes, and abnormal levels of various inflammatory cytokines and immunological markers in the blood. In addition, there is evidence that antibodies that are only present in some mothers of children with ASD bind to fetal brain proteins and may be a marker or risk factor for ASD. Studies involving the injection of these ASD specific maternal serum antibodies into pregnant mice during gestation, or gestational exposure of Rhesus monkeys to IgG subclass of these antibodies, have consistently elicited behavioral changes in offspring that have relevance to ASD. We will summarize the various types of studies associating ASD with the immune system, critically evaluate the quality of these studies, and attempt to integrate them in a way that clarifies the areas of immune and autoimmune phenomena in ASD research that will be important indicators for future research., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The pathophysiology of autism spectrum disorder (ASD) is not yet known; however, studies suggest that dysfunction of the immune system affects many children with ASD. Increasing evidence points to dysfunction of the innate immune system including activation of microglia and perivascular macrophages, increases in inflammatory cytokines/chemokines in brain tissue and CSF, and abnormal peripheral monocyte cell function. Dendritic cells are major players in innate immunity and have important functions in the phagocytosis of pathogens or debris, antigen presentation, activation of naïve T cells, induction of tolerance and cytokine/chemokine production. In this study, we assessed circulating frequencies of myeloid dendritic cells (defined as Lin-1(-)BDCA1(+)CD11c(+) and Lin-1(-)BDCA3(+)CD123(-)) and plasmacytoid dendritic cells (Lin-1(-)BDCA2(+)CD123(+) or Lin-1(-)BDCA4(+) CD11c(-)) in 57 children with ASD, and 29 typically developing controls of the same age, all of who were enrolled as part of the Autism Phenome Project (APP). The frequencies of dendritic cells and associations with behavioral assessment and MRI measurements of amygdala volume were compared in the same participants. The frequencies of myeloid dendritic cells were significantly increased in children with ASD compared to typically developing controls (p<0.03). Elevated frequencies of myeloid dendritic cells were positively associated with abnormal right and left amygdala enlargement, severity of gastrointestinal symptoms and increased repetitive behaviors. The frequencies of plasmacytoid dendritic cells were also associated with amygdala volumes as well as developmental regression in children with ASD. Dendritic cells play key roles in modulating immune responses and differences in frequencies or functions of these cells may result in immune dysfunction in children with ASD. These data further implicate innate immune cells in the complex pathophysiology of ASD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Autism spectrum disorders (ASDs) are characterized by deficits in social communication and language and the presence of repetitive behaviors that affect as many as 1 in 50 US children. Perinatal stress and environmental factors appear to play a significant role in increasing the risk for ASDs. There is no definitive pathogenesis, which therefore significantly hinders the development of a cure., Objective: We aimed to identify publications using basic or clinical data that suggest a possible association between atopic symptoms and ASDs, as well as evidence of how such an association could lead to brain disease, that may explain the pathogenesis of ASD., Methods: PubMed was searched for articles published since 1995 that reported any association between autism and/or ASDs and any one of the following terms: allergy, atopy, brain, corticotropin-releasing hormone, cytokines, eczema, food allergy, food intolerance, gene mutation, inflammation, mast cells, mitochondria, neurotensin, phenotype, stress, subtype, or treatment., Results: Children with ASD respond disproportionally to stress and also present with food and skin allergies that involve mast cells. Brain mast cells are found primarily in the hypothalamus, which participates in the regulation of behavior and language. Corticotropin-releasing hormone is secreted from the hypothalamus under stress and, together with neurotensin, stimulates brain mast cells that could result in focal brain allergy and neurotoxicity. Neurotensin is significantly increased in serum of children with ASD and stimulates mast cell secretion of mitochondrial adenosine triphosphate and DNA, which is increased in these children; these mitochondrial components are misconstrued as innate pathogens, triggering an autoallergic response in the brain. Gene mutations associated with higher risk of ASD have been linked to reduction of the phosphatase and tensin homolog, which inhibits the mammalian target of rapamycin (mTOR). These same mutations also lead to mast cell activation and proliferation. Corticotropin-releasing hormone, neurotensin, and environmental toxins could further trigger the already activated mTOR, leading to superstimulation of brain mast cells in those areas responsible for ASD symptoms. Preliminary evidence indicates that the flavonoid luteolin is a stronger inhibitor of mTOR than rapamycin and is a potent mast cell blocker., Conclusion: Activation of brain mast cells by allergic, environmental, immune, neurohormonal, stress, and toxic triggers, especially in those areas associated with behavior and language, lead to focal brain allergies and subsequent focal encephalitis. This possibility is more likely in the subgroup of patients with ASD susceptibility genes that also involve mast cell activation., (Copyright © 2013 Elsevier HS Journals, Inc. All rights reserved.)

Background/aim: The etiology of autism spectrum disorders (ASD) is unknown. The measles-mumps-rubella (MMR) vaccination has been in the past implicated in ASD pathogenesis. The aim of our study was to evaluate the rate of seropositivity and the levels of antibodies against MMR antigens in a cohort of children with ASD compared to control children., Patients and Methods: In a cohort of children with ASD and same-age healthy controls, we measured levels and seropositivity of antibodies against MMR., Results: A total of 60 children, 31 with ASD and 29 controls were enrolled. The seropositivity rate and levels of all the three antibodies were similar in cases and controls., Conclusion: Children with ASD have a similar level and seropositivity rate of antibodies against the MMR vaccine to same-age controls. As persistent infections are typically associated with high antibody levels, our results support the arguments against a role of MMR vaccination as a causal factor or co-factor in development of ASD.

Autism spectrum disorder (ASD) is very heterogeneous and multiple subtypes and etiologies likely exist. The maternal immune system has been implicated in the pathogenesis of some forms of ASD. Previous studies have identified the presence of specific maternal IgG autoantibodies with reactivity to fetal brain proteins at 37 and 73kDa in up to 12% of mothers of children with ASD. The current study evaluates the presence of these autoantibodies in an independent cohort of mothers of 181 preschool-aged male children (131 ASD, 50 typically developing (TD) controls). We also investigated whether ASD children born to mothers with these autism-specific maternal IgG autoantibodies exhibit a distinct neural phenotype by evaluating total brain volume using structural magnetic resonance imaging (MRI). Of the 131 ASD children, 10 (7.6%) were born to mothers with the 37/73kDa IgG autoantibodies (ASD-IgG). The mothers of the remaining ASD children and all TD controls were negative for these paired autoantibodies. While both ASD groups exhibited abnormal brain enlargement that is commonly observed in this age range, the ASD-IgG group exhibited a more extreme 12.1% abnormal brain enlargement relative to the TD controls. In contrast, the remaining ASD children exhibited a smaller 4.4% abnormal brain enlargement relative to TD controls. Lobar and tissue type analyses revealed that the frontal lobe is selectively enlarged in the ASD-IgG group and that both gray and white matter are similarly affected. These results suggest that maternal autoantibodies associated with autism spectrum disorder may impact brain development leading to abnormal enlargement., (Copyright © 2013 Elsevier Inc. All rights reserved.)

It is becoming increasingly apparent that the causes of autism spectrum disorders (ASD) are due to both genetic and environmental factors. Animal studies provide important translational models for elucidating specific genetic or environmental factors that contribute to ASD-related behavioral deficits. For example, mouse research has demonstrated a link between maternal immune activation and the expression of ASD-like behaviors. Although these studies have provided insights into the potential causes of ASD, they are limited in their ability to model the important interactions between genetic variability and environmental insults. This is of particular concern given the broad spectrum of severity observed in the human population, suggesting that subpopulations may be more susceptible to the adverse effects of particular environmental insults. It is hypothesized that the severity of effects of maternal immune activation on ASD-like phenotypes is influenced by the genetic background in mice. To test this, pregnant dams of two inbred strains (that is, C57BL/6J and BTBR T(+)tf/J) were exposed to the viral mimic polyinosinic-polycytidylic acid (polyI:C), and their offspring were tested for the presence and severity of ASD-like behaviors. To identify differences in immune system regulation, spleens were processed and measured for alterations in induced cytokine responses. Strain-treatment interactions were observed in social approach, ultrasonic vocalization, repetitive grooming and marble burying behaviors. Interestingly, persistent dysregulation of adaptive immune system function was only observed in BTBR mice. Data suggest that behavioral and immunological effects of maternal immune activation are strain-dependent in mice.

Folate supplementation reduces the risk of neural tube defect (NTD) pregnancy, and folinic acid has been used to correct cerebral folate deficiency (CFD) in children with developmental disorders. In the absence of systemic folate deficiency, the discovery of autoantibodies (AuAbs) to folate receptor α (FRα) that block the uptake of folate offers one mechanism to explain the response to folate in these disorders. The association of FRα AuAbs with pregnancy-related complications, CFD syndrome, and autism spectrum disorders and response to folate therapy is highly suggestive of the involvement of these AuAbs in the disruption of brain development and function via folate pathways. The two types of antibodies identified in the serum of patients are blocking antibody and binding antibody. The two antibodies can be measured by the specific assays described and exert their pathological effects either by functional blocking of folate transport as previously shown or hypothetically by disrupting the FR by an antigen-antibody-mediated inflammatory response. We have identified both IgG and IgM AuAbs in these conditions. The predominant antibodies in women with NTD pregnancy belong to the IgG1 and IgG2 isotype and in CFD children, the IgG1 and IgG4 isotype. This review describes the methods used to measure these AuAbs, their binding characteristics, affinity, cross-reactivity, and potential mechanisms by which folate therapy could work. Because these AuAbs are associated with various pathologies during fetal and neonatal development, early detection and intervention could prevent or reverse the consequences of exposure to these AuAbs.

Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.

Recent reports have given a central role to environmental factors in the etiology of autism spectrum disorders (ASD). However, most proposed perinatal factors seem to converge into the activation of the immune system, suggesting that an early inflammatory response could be a unifying factor in the etiology ASD. Here I review the evidence of early immune activation in individuals with ASD, and the chronic peripheral and central alterations observed in the inflammatory response in ASD. This evidence shows that ASD is associated with altered neuroinflammatory processes and abnormal immune responses in adulthood. How these immune alterations can affect developmental programming of adult behavior or directly affect behavior later in life is discussed in the context of both clinical and animal models of research. Recent studies in rodents clearly support a role of elevated cytokines in the behavioral symptoms of ASD, both during development and in adulthood. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Autism spectrum disorders (ASD) are neurodevelopmental diseases that affect an alarming number of individuals. The etiological basis of ASD is unclear, and evidence suggests it involves both genetic and environmental factors. There are many reports of cytokine imbalances in ASD. These imbalances could have a pathogenic role, or they may be markers of underlying genetic and environmental influences. Cytokines act primarily as mediators of immunological activity but they also have significant interactions with the nervous system. They participate in normal neural development and function, and inappropriate activity can have a variety of neurological implications. It is therefore possible that cytokine dysregulation contributes directly to neural dysfunction in ASD. Further, cytokine profiles change dramatically in the face of infection, disease, and toxic exposures. Imbalances in cytokines may represent an immune response to environmental contributors to ASD. The following review is presented in two main parts. First, we discuss select cytokines implicated in ASD, including IL-1Β, IL-6, IL-4, IFN-γ, and TGF-Β, and focus on their role in the nervous system. Second, we explore several neurotoxic environmental factors that may be involved in the disorders, and focus on their immunological impacts. This review represents an emerging model that recognizes the importance of both genetic and environmental factors in ASD etiology. We propose that the immune system provides critical clues regarding the nature of the gene by environment interactions that underlie ASD pathophysiology., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Immune system of some autistic patients could be abnormally triggered by gluten/casein assumption. The prevalence of antibodies to gliadin and milk proteins in autistic children with paired/impaired intestinal permeability and under dietary regimen either regular or restricted is reported., Methods: 162 ASDs and 44 healthy children were investigated for intestinal permeability, tissue-transglutaminase (tTG), anti-endomysium antibodies (EMA)-IgA, and total mucosal IgA to exclude celiac disease; HLA-DQ2/-DQ8 haplotypes; total systemic antibodies (IgA, IgG, and IgE); specific systemic antibodies: α-gliadin (AGA-IgA and IgG), deamidated-gliadin-peptide (DGP-IgA and IgG), total specific gliadin IgG (all fractions: α, β, γ, and ω), β-lactoglobulin IgG, α-lactalbumin IgG, casein IgG; and milk IgE, casein IgE, gluten IgE,-lactoglobulin IgE, and α-lactalbumin IgE., Results: AGA-IgG and DPG-IgG titers resulted to be higher in ASDs compared to controls and are only partially influenced by diet regimen. Casein IgG titers resulted to be more frequently and significantly higher in ASDs than in controls. Intestinal permeability was increased in 25.6% of ASDs compared to 2.3% of healthy children. Systemic antibodies production was not influenced by paired/impaired intestinal permeability., Conclusions: Immune system of a subgroup of ASDs is triggered by gluten and casein; this could be related either to AGA, DPG, and Casein IgG elevated production or to impaired intestinal barrier function.

Autism spectrum disorder (ASD) is a highly heterogeneous disorder diagnosed based on the presence and severity of core abnormalities in social communication and repetitive behavior, yet several studies converge on immune dysregulation as a feature of ASD. Widespread alterations in immune molecules and responses are seen in the brains and periphery of ASD individuals, and early life immune disruptions are associated with ASD. This chapter discusses immune-related environmental and genetic risk factors for ASD, emphasizing population-wide studies and animal research that reveal potential mechanistic pathways involved in the development of ASD-related symptoms. It further reviews immunologic pathologies seen in ASD individuals and how such abnormalities can impact neurodevelopment and behavior. Finally, it evaluates emerging evidence for an immune contribution to the pathogenesis of ASD and a potential role for immunomodulatory effects in current treatments for ASD., (© 2013 Elsevier Inc. All rights reserved.)

Autism spectrum disorders (ASD) encompass a range of neurodevelopmental conditions that are clinically and etiologically very heterogeneous. ASD is currently diagnosed entirely on behavioral criteria, but intensive research efforts are focused on identifying biological markers for disease risk and early diagnosis. Here, we discuss recent progress toward identifying biological markers for ASD and highlight specific challenges as well as ethical aspects of translating ASD biomarker research into the clinic.

Autism spectrum disorders (ASD) are characterized by impairments in communication, social interactions, and repetitive behaviors. While the etiology of ASD is complex and likely involves the interplay of genetic and environmental factors, growing evidence suggests that immune dysfunction and the presence of autoimmune responses including autoantibodies may play a role in ASD. Anti-phospholipid antibodies are believed to occur from both genetic and environmental factors and have been linked to a number of neuropsychiatric symptoms such as cognitive impairments, anxiety, and repetitive behaviors. In the current study, we investigated whether there were elevated levels of anti-phospholipid antibodies in a cross-sectional analysis of plasma of young children with ASD compared to age-matched typically developing (TD) controls and children with developmental delays (DD) other than ASD. We found that levels of anti-cardiolipin, β 2-glycoprotein 1, and anti-phosphoserine antibodies were elevated in children with ASD compared with age-matched TD and DD controls. Further, the increase in antibody levels was associated with more impaired behaviors reported by parents. This study provides the first evidence for elevated production of anti-phospholipid antibodies in young children with ASD and provides a unique avenue for future research into determining possible pathogenic mechanisms that may underlie some cases of ASD.

Objectives: Results of animal studies suggest that maternal immune activation during pregnancy causes deficiencies in fetal neurodevelopment. Infectious disease is the most common path to maternal immune activation during pregnancy. The goal of this study was to determine the occurrence of common infections, febrile episodes, and use of antibiotics reported by the mother during pregnancy and the risk for autism spectrum disorder (ASD) and infantile autism in the offspring., Methods: We used a population-based cohort consisting of 96 736 children aged 8 to 14 years and born from 1997 to 2003 in Denmark. Information on infection, febrile episodes, and use of antibiotics was self-reported through telephone interviews during pregnancy and early postpartum. Diagnoses of ASD and infantile autism were retrieved from the Danish Psychiatric Central Register; 976 children (1%) from the cohort were diagnosed with ASD., Results: Overall, we found little evidence that various types of mild common infectious diseases or febrile episodes during pregnancy were associated with ASD/infantile autism. However, our data suggest that maternal influenza infection was associated with a twofold increased risk of infantile autism, prolonged episodes of fever caused a threefold increased risk of infantile autism, and use of various antibiotics during pregnancy were potential risk factors for ASD/infantile autism., Conclusions: Our results do not suggest that mild infections, febrile episodes, or use of antibiotics during pregnancy are strong risk factors for ASD/infantile autism. The results may be due to multiple testing; the few positive findings are potential chance findings.

The aim of the study was to analyze cytokine profiles in neonatal dried blood samples (n-DBSS) retrieved from The Danish Newborn Screening Biobank of children developing Autism Spectrum Disorders (ASD) later in life and controls. Samples of 359 ASD cases and 741 controls were analyzed using Luminex xMAP technology and clinical data were retrieved from nationwide registers. Findings showed that children developing ASD were more likely to have decreased levels of both T helper-1(Th-1)-like cytokines (i.e. IFN-γ) and Th-2like cytokines (i.e. IL-4, IL-10) which may suggest a depressed or hypoactive immune cell activity during neonatal period in ASD., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Many neuropsychiatric conditions are primed or triggered by different types of stressors. The mechanisms through which stress induces neuropsychiatric disease are complex and incompletely understood. A 'double hit' hypothesis of neuropsychiatric disease postulates that stress induces maladaptive behavior in two phases separated by a dormant period. Recent research shows that the pleiotropic cytokine IL-6 is released centrally and peripherally following physical and psychological stress. In this article, we analyze evidence from clinics and animal models suggesting that stress-induced elevation in the levels of IL-6 may play a key role in the etiology of a heterogeneous family of hyperexcitable central conditions including epilepsy, schizophrenic psychoses, anxiety and disorders of the autistic spectrum. The cellular mechanism leading to hyperexcitable conditions might be a decrease in inhibitory/excitatory synaptic balance in either or both temporal phases of the conditions. Following these observations, we discuss how they may have important implications for optimal prophylactic and therapeutic pharmacological treatment.

Autism spectrum disorder (ASD) is a complex disorder that appears to be caused by interactions between genetic changes and environmental insults during early development. A wide range of factors have been linked to the onset of ASD, but recently both genetic associations and environmental factors point to a central role for immune-related genes and immune responses to environmental stimuli. Specifically, many of the proteins encoded by the major histocompatibility complex (MHC) play a vital role in the formation, refinement, maintenance, and plasticity of the brain. Manipulations of levels of MHC molecules have illustrated how disrupted MHC signaling can significantly alter brain connectivity and function. Thus, an emerging hypothesis in our field is that disruptions in MHC expression in the developing brain caused by mutations and/or immune dysregulation may contribute to the altered brain connectivity and function characteristic of ASD. This review provides an overview of the structure and function of the three classes of MHC molecules in the immune system, healthy brain, and their possible involvement in ASD., (Copyright © 2012 Wiley Periodicals, Inc.)

Autism spectrum disorders (ASDs) affect approximately 1 in 110 children in the United States. This report profiles fetal-brain reactive autoantibodies of a large cohort of mothers of children with autism and controls, yielding significant associations between the presence of IgG reactivity to fetal brain proteins at 37 and 73 kDa and a childhood diagnosis of full autism (p = 0.0005), which also correlated with lower expressive language scores (p = 0.005). Additionally, we report on reactivity to proteins at 39 and 73 kDa, which correlated with the broader diagnosis of ASD (p = 0.0007) and increased irritability on the Aberrant Behavioral Checklist (p = 0.05). This study provides evidence of multiple patterns of reactivity to fetal brain proteins by maternal antibodies associated with ASD and specific childhood behavioral outcomes.

We are exploring the mechanisms underlying how maternal infection increases the risk for schizophrenia and autism in the offspring. Several mouse models of maternal immune activation (MIA) were used to examine the immediate effects of MIA induced by influenza virus, poly(I:C) and interleukin IL-6 on the fetal brain transcriptome. Our results indicate that all three MIA treatments lead to strong and common gene expression changes in the embryonic brain. Most notably, there is an acute and transient upregulation of the α, β and γ crystallin gene family. Furthermore, levels of crystallin gene expression are correlated with the severity of MIA as assessed by placental weight. The overall gene expression changes suggest that the response to MIA is a neuroprotective attempt by the developing brain to counteract environmental stress, but at a cost of disrupting typical neuronal differentiation and axonal growth. We propose that this cascade of events might parallel the mechanisms by which environmental insults contribute to the risk of neurodevelopmental disorders such as schizophrenia and autism.

Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures ('four major areas'). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics ('four comparison areas'). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006-2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders.