Immune mediators in the brain and peripheral tissues in autism spectrum disorder.

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.

A cleanroom sleeping environment's impact on markers of oxidative stress, immune dysregulation, and behavior in children with autism spectrum disorders.

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).

Zinc in gut-brain interaction in autism and neurological disorders.

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.

Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders.

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.

Evidence supporting an altered immune response in ASD.

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.

Inflammatory profiles in the BTBR mouse: how relevant are they to autism spectrum disorders?

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.

Anti-neuronal antibodies in patients with fragile X syndrome: is there a role of autoimmunity in its pathogenesis?

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.

[Research advances in immunological dysfunction in children with autism spectrum disorders].

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.

[Clinical concept, etiology and pathology of neuromyelitis optica].

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.

Potential cytokine biomarkers in autism spectrum disorders.

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.

Maternal immune activation and abnormal brain development across CNS disorders.

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.

Cytokine profiles by peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype?

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 ß-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-1ß and IL-6) without stimuli than 'non-flare' ASD-IS cells. With zymosan, 'flare' ASD-IS cells produced more IL-1ß 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.

Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study.

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.

Adaptive maternal immune deviations as a ground for autism spectrum disorders development in children.

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.

Pathophysiology of autism spectrum disorders: revisiting gastrointestinal involvement and immune imbalance.

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.

Gender-dependent effects of maternal immune activation on the behavior of mouse offspring.

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.

Prevalence and titre of antibodies to cytomegalovirus and epstein-barr virus in patients with autism spectrum disorder.

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.

Exposure to Varicella Zoster Virus is higher in children with autism spectrum disorder than in healthy controls. Results from a case-control study.

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.

Prevalence of herpes simplex virus 1 and 2 antibodies in patients with autism spectrum disorders.

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.