Background-Autism Spectrum Disorder (ASD) is characterized by social communication deficits and r... more Background-Autism Spectrum Disorder (ASD) is characterized by social communication deficits and restricted, repetitive patterns of behavior. Varied immunological findings have been reported in children with ASD. To address the question of heterogeneity in immune responses, we sought to examine the diversity of immune profiles within a representative cohort of boys with ASD. Methods-Peripheral blood mononuclear cells (PBMC) from male children with ASD (n=50) and from typically developing (TD) age-matched male controls (n=16) were stimulated with either lipopolysaccharide (LPS) or phytohaemagglutinin (PHA). Cytokine production was assessed after stimulation. The ASD study population was clustered into subgroups based on immune responses and assessed for behavioral outcomes. Results-Children with ASD who had a pro-inflammatory profile based on LPS stimulation were more developmentally impaired as assessed by the Mullen's Scale of Early Learning (MSEL). They also had greater impairments in social affect as measured by the Autism Diagnostic Observation Schedule (ADOS). These children also displayed more frequent sleep disturbances and episodes of aggression. Similarly, children with ASD and a more activated T cell cytokine profile after PHA stimulation were more developmentally impaired as measured by the MSEL. Conclusions-Children with ASD may be phenotypically characterized based upon their immune profile. Those showing either a pro-inflammatory response or increased T cell activation/
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
The prevalence of autism spectrum disorder (ASD) has starkly increased, instigating research into... more The prevalence of autism spectrum disorder (ASD) has starkly increased, instigating research into risk factors for ASD. This research has identified immune risk factors for ASD, along with evidence of immune dysfunction and excess inflammation frequently experienced by autistic individuals. Increased innate inflammatory cytokines, including interleukin (IL)-6, are seen repeatedly in ASD; however, the origin of excess IL-6 in ASD has not been identified. Here we explore specific responses of circulating monocytes from autistic children. We isolated CD14+ monocytes from whole blood and stimulated them for 24 h under three conditions: media alone, lipoteichoic acid to activate TLR2, and lipopolysaccharide to activate TLR4. We then measured secreted cytokine concentrations in cellular supernatant using a human multiplex bead immunoassay. We found that after TLR4 activation, CD14+ monocytes from autistic children produce increased IL-6 compared to monocytes from children with typical dev...
The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Gene ... more The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Gene expression in blood was correlated with mercury levels in blood of 2- to 5-year-old boys with autism (AU) compared to age-matched typically develop-ing (TD) control boys. This was done to address the pos-sibility that the two groups might metabolize toxicants, such as mercury, differently. RNA was isolated from blood and gene expression assessed on whole genome Affymetrix Human U133 expression microarrays. Mercury levels were measured using an inductively coupled plasma mass spectrometer. Analysis of covariance (ANCOVA) was performed and partial correlations between gene expres-sion and mercury levels were calculated, after correcting for age and batch effects. To reduce false positives, only genes shared by the ANCOVA models were analyzed. Of
In autism spectrum disorders (ASD) many individuals have co-morbid immune dysregulation that can ... more In autism spectrum disorders (ASD) many individuals have co-morbid immune dysregulation that can lead to inflammation in the brain and periphery. The novel cytokine interleukin (IL)-35 has described anti-inflammatory properties; however, the plasma levels of IL-35 in children with ASD have never been investigated. The plasma levels of IL-35 were measured by an enzyme-linked immunosorbent assay in 30 children with ASD and 39 typically developing (TD) controls. In the current study, we found that plasma IL-35 levels were significantly decreased in children with ASD compared with TD children. Furthermore, lower IL-35 levels were associated with worse behaviors as assessed using the aberrant behavior checklist. These findings are in line with other observations of decreased regulatory cytokines such as transforming growth factor beta and IL-10 in ASD, and associations with severity of behaviors. In conclusion, regulating the expression of IL-35 may provide a new possible target for the ...
Autism spectrum disorders (ASD) are a group of heterogeneous neurological disorders that are high... more Autism spectrum disorders (ASD) are a group of heterogeneous neurological disorders that are highly variable and are clinically characterized by deficits in social interactions, communication, and stereotypical behaviors. Prevalence has risen from 1 in 10,000 in 1972 to 1 in 59 children in the United States in 2014. This rise in prevalence could be due in part to better diagnoses and awareness, however, these together cannot solely account for such a significant rise. While causative connections have not been proven in the majority of cases, many current studies focus on the combined effects of genetics and environment. Strikingly, a distinct picture of immune dysfunction has emerged and been supported by many independent studies over the past decade. Many players in the immune-ASD puzzle may be mechanistically contributing to pathogenesis of these disorders, including skewed cytokine responses, differences in total numbers and frequencies of immune cells and their subsets, neuroinflammation, and adaptive and innate immune dysfunction, as well as altered levels of immunoglobulin and the presence of autoantibodies which have been found in a substantial number of individuals with ASD. This review summarizes the latest research linking ASD, autoimmunity and immune dysfunction, and discusses evidence of a potential autoimmune component of ASD.
Dysregulation in immune responses during pregnancy increase the risk of a having a child with an ... more Dysregulation in immune responses during pregnancy increase the risk of a having a child with an autism spectrum disorder (ASD). Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. We recently developed a mouse model of maternal allergic asthma (MAA) that induces changes in sociability, repetitive and perseverative behaviors in the offspring. Since epigenetic changes help a static genome adapt to the maternal environment, activation of the immune system may epigenetically alter fetal microglia, the brain's resident immune cells. We therefore tested the hypothesis that epigenomic alterations to microglia may be involved in behavioral abnormalities observed in MAA offspring. We used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation and RNA sequencing to examine gene expression in microglia from juvenile MAA offspring. Differentially methylated regions (DMRs) were enriched for i...
Infection during pregnancy can lead to activation of the maternal immune system and has been asso... more Infection during pregnancy can lead to activation of the maternal immune system and has been associated with an increased risk of having an offspring later diagnosed with a neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) or schizophrenia (SZ). Most maternal immune activation (MIA) studies to date have been in rodents and usually involve the use of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C). However, since NDD are based on behavioral changes, a model of MIA in non-human primates could potentially provide data that helps illuminate complex behavioral and immune outputs in human NDD. In this study twenty-one pregnant rhesus macaques were either given three injections over 72 hours of poly I:C-LC, a double stranded RNA analog (viral mimic), or saline as a control. Injections were given near the end of the first trimester or near the end of the second trimester to determine if there were differences in immune output due to the timing ...
Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs... more Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothe...
Background: Many phenotypes are being described for children with autism, including onset type. C... more Background: Many phenotypes are being described for children with autism, including onset type. Comparison of children with autism (AU) and pervasive developmental disorders not otherwise specified (PDDNOS) to GP yielded 12 genes expressed in Natural Killer (NK) cells or CD8+ cytotoxic lymphocytes. Approximately 70% of AU subjects had high expression of these NK/CD8+ genes. Objectives: Identify RNA expression biomarkers associated with AU subgroups. Methods: 35 children ages 2-5 with autism (AU) and 14 PDDNOS children were compared to 12 typically developing children (GP). Total RNA from blood was processed on human Affymetrix microarrays. Results: Using the 12 genes expressed in NK cells, AU children were separated into high NK and normal NK expression. Comparison of AU children with high NK to normal NK yielded hundreds of genes. Unsupervised cluster analyses revealed 3-4 subgroups. Of 10 children with early onset AU, 9 had high NK gene expression profiles. Specific comparisons of...
Background: Polybrominated diphenyl ethers (PBDEs) are flame retardants used widely, with a rapid... more Background: Polybrominated diphenyl ethers (PBDEs) are flame retardants used widely, with a rapid increase in body burdens in the U.S. over the last few decades. PBDEs and their metabolites cross the placenta and studies in rodents show neurodevelopmental toxicity from prenatal exposures. Objectives: To review PBDEs and the development of 100 children from CHARGE (Childhood Autism Risk from Genetics and the Environment), a case-control epidemiologic study of autism/autism spectrum (AU/ASD), developmental delays (DD) and typically developing (TD) population-based controls. Methods: Developmental diagnoses were confirmed by the ADOS, ADI-R, Mullen's Scales of Early Learning, and Vineland Adaptive Behavior Scales. Eleven PBDE congeners were measured by GC/MS from serum specimens collected after children were assessed. Immunoglobulins and cytokines were measured by LuminexTM multiplex platform. Multiple logistic and linear regression models were used to control confounding factors i...
Autism spectrum disorders (ASD) are neurodevelopmental diseases that affect an alarming number of... more 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. Therefore, imbalances 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.
Background Autism is a neurodevelopmental disorder characterized by impairments in social interac... more Background Autism is a neurodevelopmental disorder characterized by impairments in social interaction and deficits in verbal and nonverbal communication, together with the presence of repetitive behaviors or a limited repertoire of activities and interests. The causes of autism are currently unclear. In a previous study, we determined that 21% of children with autism have plasma autoantibodies that are immunoreactive with a population of neurons in the cerebellum that appear to be Golgi cells, which are GABAergic interneurons. Methods We have extended this analysis by examining plasma immunoreactivity in the remainder of the brain. To determine cell specificity, double-labeling studies that included one of the calcium-binding proteins that are commonly colocalized in GABAergic neurons (calbindin, parvalbumin or calretinin) were also carried out to determine which GABAergic neurons are immunoreactive. Coronal sections through the rostrocaudal extent of the macaque monkey brain were r...
The contribution of peripheral immunity to autism spectrum disorders (ASDs) risk is debated and p... more The contribution of peripheral immunity to autism spectrum disorders (ASDs) risk is debated and poorly understood. Some mothers of children with ASD have autoantibodies that react to fetal brain proteins, raising the possibility that a subset of ASD cases may be associated with a maternal antibody response during gestation. The mechanism by which the maternal immune system breaks tolerance has not been addressed. We hypothesized that the mechanism may involve decreased expression of the MET receptor tyrosine kinase, an ASD risk gene that also serves as a key negative regulator of immune responsiveness. In a sample of 365 mothers, including 202 mothers of children with ASD, the functional MET promoter variant rs1858830 C allele was strongly associated with the presence of an ASD-specific 37 þ 73-kDa band pattern of maternal autoantibodies to fetal brain proteins (P ¼ 0.003). To determine the mechanism of this genetic association, we measured MET protein and cytokine production in freshly prepared peripheral blood mononuclear cells from 76 mothers of ASD and typically developing children. The MET rs1858830 C allele was significantly associated with MET protein expression (P ¼ 0.025). Moreover, decreased expression of the regulatory cytokine IL-10 was associated with both the MET gene C allele (P ¼ 0.001) and reduced MET protein levels (P ¼ 0.002). These results indicate genetic distinction among mothers who produce ASD-associated antibodies to fetal brain proteins, and suggest a potential mechanism for how a genetically determined decrease in MET protein production may lead to a reduction in immune regulation.
ABSTRACT Autistic spectrum disorders (ASD) are a broad spectrum of heterogeneous neurodevelopment... more ABSTRACT Autistic spectrum disorders (ASD) are a broad spectrum of heterogeneous neurodevelopmental disorders, most with unknown etiology. Although the development of autism is suspected to be the result of a complex combination of genetic, environmental, neurobiological, and immunological factors, the role of each of these factors is still under investigation. In this chapter, we review current concepts regarding the immunological aspects of autism as they pertain to areas of our own research. Three specific areas are covered including autoantibodies in children with ASD, maternal antibodies directed against fetal brain, and immune dysfunction in children with ASD. KeywordsAutism–immunology–maternal–autoantibodies–fetus
Autism is a complex and clinically heterogeneous disorder with a spectrum of symptoms. Clinicians... more Autism is a complex and clinically heterogeneous disorder with a spectrum of symptoms. Clinicians, schools, and service agencies worldwide have reported a dramatic increase in the number of children identified with autism. Despite expanding research, the etiology and underlying biological processes of autism remain poorly understood, and the relative contribution from genetic, epigenetic, and environmental factors remains unclear. Although autism affects primarily brain function (especially affect, social functioning, and cognition), it is unknown to what extent other organs and systems are disrupted. Published findings have identified widespread changes in the immune systems of children with autism, at both systemic and cellular levels. Brain specimens from autism subjects exhibit signs of active, ongoing inflammation, as well as alterations in gene pathways associated with immune signaling and immune function. Moreover, many genetic studies have indicated a link between autism and genes that are relevant to both the nervous system and the immune system. Alterations in these pathways can affect function in both systems. Together, these reports suggest that autism may in fact be a systemic disorder with connections to abnormal immune responses. Such immune system dysfunction may represent novel targets for treatment. A better understanding of the involvement of the immune response in autism, and of how early brain development is altered, may have important therapeutic implications.
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2006
We compared the compositions of fatty acids including n-3, n-6 polyunsaturated fatty acids, trans... more We compared the compositions of fatty acids including n-3, n-6 polyunsaturated fatty acids, trans-and cis-monounsaturated fatty acids, and saturated fatty acids in the red blood cell membranes of 40 children with autism (20 with early onset autism and 20 with developmental regression) and age-matched, 20 typically developing controls and 20 subjects with non-autistic developmental disabilities. The main findings include increased levels of eicosenoic acid (20:1n9) and erucic acid (22:1n9) in autistic subjects with developmental regression when compared with typically developing controls. In addition, an increase in 20:2n6 and a decrease in 16:1n7t were observed in children with clinical regression compared to those with early onset autism. Our results do not provide strong evidence for the hypothesis that abnormal fatty acid metabolism plays a role in the pathogenesis of autism spectrum disorder, although they suggest some metabolic or dietary abnormalities in the regressive form of autism.
Objective: Autism is a syndrome with a number of etiologies with differing mechanisms that lead t... more Objective: Autism is a syndrome with a number of etiologies with differing mechanisms that lead to abnormal development. This review highlights the need to identify autism subgroups as they each might require unique approaches for prevention or treatment. Methods: Targeting treatments to specific mechanisms and utilizing biomarkers can more rapidly advance our understanding of how to classify and treat autism subgroups based on translational mechanisms. We illustrate this approach using mechanisms that may influence the course of autism and provide rationale for selected biomarkers that could guide treatments targeted anywhere from DNA to symptom expression. Conclusions: The use of potential biomarkers that point to specific mechanisms of disordered neurodevelopment will help identify meaningful subtypes of autism and will help tailor treatment or prevention strategies for each mechanism rather than solely to a symptom category.
Background-Autism Spectrum Disorder (ASD) is characterized by social communication deficits and r... more Background-Autism Spectrum Disorder (ASD) is characterized by social communication deficits and restricted, repetitive patterns of behavior. Varied immunological findings have been reported in children with ASD. To address the question of heterogeneity in immune responses, we sought to examine the diversity of immune profiles within a representative cohort of boys with ASD. Methods-Peripheral blood mononuclear cells (PBMC) from male children with ASD (n=50) and from typically developing (TD) age-matched male controls (n=16) were stimulated with either lipopolysaccharide (LPS) or phytohaemagglutinin (PHA). Cytokine production was assessed after stimulation. The ASD study population was clustered into subgroups based on immune responses and assessed for behavioral outcomes. Results-Children with ASD who had a pro-inflammatory profile based on LPS stimulation were more developmentally impaired as assessed by the Mullen's Scale of Early Learning (MSEL). They also had greater impairments in social affect as measured by the Autism Diagnostic Observation Schedule (ADOS). These children also displayed more frequent sleep disturbances and episodes of aggression. Similarly, children with ASD and a more activated T cell cytokine profile after PHA stimulation were more developmentally impaired as measured by the MSEL. Conclusions-Children with ASD may be phenotypically characterized based upon their immune profile. Those showing either a pro-inflammatory response or increased T cell activation/
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
The prevalence of autism spectrum disorder (ASD) has starkly increased, instigating research into... more The prevalence of autism spectrum disorder (ASD) has starkly increased, instigating research into risk factors for ASD. This research has identified immune risk factors for ASD, along with evidence of immune dysfunction and excess inflammation frequently experienced by autistic individuals. Increased innate inflammatory cytokines, including interleukin (IL)-6, are seen repeatedly in ASD; however, the origin of excess IL-6 in ASD has not been identified. Here we explore specific responses of circulating monocytes from autistic children. We isolated CD14+ monocytes from whole blood and stimulated them for 24 h under three conditions: media alone, lipoteichoic acid to activate TLR2, and lipopolysaccharide to activate TLR4. We then measured secreted cytokine concentrations in cellular supernatant using a human multiplex bead immunoassay. We found that after TLR4 activation, CD14+ monocytes from autistic children produce increased IL-6 compared to monocytes from children with typical dev...
The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Gene ... more The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Gene expression in blood was correlated with mercury levels in blood of 2- to 5-year-old boys with autism (AU) compared to age-matched typically develop-ing (TD) control boys. This was done to address the pos-sibility that the two groups might metabolize toxicants, such as mercury, differently. RNA was isolated from blood and gene expression assessed on whole genome Affymetrix Human U133 expression microarrays. Mercury levels were measured using an inductively coupled plasma mass spectrometer. Analysis of covariance (ANCOVA) was performed and partial correlations between gene expres-sion and mercury levels were calculated, after correcting for age and batch effects. To reduce false positives, only genes shared by the ANCOVA models were analyzed. Of
In autism spectrum disorders (ASD) many individuals have co-morbid immune dysregulation that can ... more In autism spectrum disorders (ASD) many individuals have co-morbid immune dysregulation that can lead to inflammation in the brain and periphery. The novel cytokine interleukin (IL)-35 has described anti-inflammatory properties; however, the plasma levels of IL-35 in children with ASD have never been investigated. The plasma levels of IL-35 were measured by an enzyme-linked immunosorbent assay in 30 children with ASD and 39 typically developing (TD) controls. In the current study, we found that plasma IL-35 levels were significantly decreased in children with ASD compared with TD children. Furthermore, lower IL-35 levels were associated with worse behaviors as assessed using the aberrant behavior checklist. These findings are in line with other observations of decreased regulatory cytokines such as transforming growth factor beta and IL-10 in ASD, and associations with severity of behaviors. In conclusion, regulating the expression of IL-35 may provide a new possible target for the ...
Autism spectrum disorders (ASD) are a group of heterogeneous neurological disorders that are high... more Autism spectrum disorders (ASD) are a group of heterogeneous neurological disorders that are highly variable and are clinically characterized by deficits in social interactions, communication, and stereotypical behaviors. Prevalence has risen from 1 in 10,000 in 1972 to 1 in 59 children in the United States in 2014. This rise in prevalence could be due in part to better diagnoses and awareness, however, these together cannot solely account for such a significant rise. While causative connections have not been proven in the majority of cases, many current studies focus on the combined effects of genetics and environment. Strikingly, a distinct picture of immune dysfunction has emerged and been supported by many independent studies over the past decade. Many players in the immune-ASD puzzle may be mechanistically contributing to pathogenesis of these disorders, including skewed cytokine responses, differences in total numbers and frequencies of immune cells and their subsets, neuroinflammation, and adaptive and innate immune dysfunction, as well as altered levels of immunoglobulin and the presence of autoantibodies which have been found in a substantial number of individuals with ASD. This review summarizes the latest research linking ASD, autoimmunity and immune dysfunction, and discusses evidence of a potential autoimmune component of ASD.
Dysregulation in immune responses during pregnancy increase the risk of a having a child with an ... more Dysregulation in immune responses during pregnancy increase the risk of a having a child with an autism spectrum disorder (ASD). Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. We recently developed a mouse model of maternal allergic asthma (MAA) that induces changes in sociability, repetitive and perseverative behaviors in the offspring. Since epigenetic changes help a static genome adapt to the maternal environment, activation of the immune system may epigenetically alter fetal microglia, the brain's resident immune cells. We therefore tested the hypothesis that epigenomic alterations to microglia may be involved in behavioral abnormalities observed in MAA offspring. We used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation and RNA sequencing to examine gene expression in microglia from juvenile MAA offspring. Differentially methylated regions (DMRs) were enriched for i...
Infection during pregnancy can lead to activation of the maternal immune system and has been asso... more Infection during pregnancy can lead to activation of the maternal immune system and has been associated with an increased risk of having an offspring later diagnosed with a neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) or schizophrenia (SZ). Most maternal immune activation (MIA) studies to date have been in rodents and usually involve the use of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C). However, since NDD are based on behavioral changes, a model of MIA in non-human primates could potentially provide data that helps illuminate complex behavioral and immune outputs in human NDD. In this study twenty-one pregnant rhesus macaques were either given three injections over 72 hours of poly I:C-LC, a double stranded RNA analog (viral mimic), or saline as a control. Injections were given near the end of the first trimester or near the end of the second trimester to determine if there were differences in immune output due to the timing ...
Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs... more Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothe...
Background: Many phenotypes are being described for children with autism, including onset type. C... more Background: Many phenotypes are being described for children with autism, including onset type. Comparison of children with autism (AU) and pervasive developmental disorders not otherwise specified (PDDNOS) to GP yielded 12 genes expressed in Natural Killer (NK) cells or CD8+ cytotoxic lymphocytes. Approximately 70% of AU subjects had high expression of these NK/CD8+ genes. Objectives: Identify RNA expression biomarkers associated with AU subgroups. Methods: 35 children ages 2-5 with autism (AU) and 14 PDDNOS children were compared to 12 typically developing children (GP). Total RNA from blood was processed on human Affymetrix microarrays. Results: Using the 12 genes expressed in NK cells, AU children were separated into high NK and normal NK expression. Comparison of AU children with high NK to normal NK yielded hundreds of genes. Unsupervised cluster analyses revealed 3-4 subgroups. Of 10 children with early onset AU, 9 had high NK gene expression profiles. Specific comparisons of...
Background: Polybrominated diphenyl ethers (PBDEs) are flame retardants used widely, with a rapid... more Background: Polybrominated diphenyl ethers (PBDEs) are flame retardants used widely, with a rapid increase in body burdens in the U.S. over the last few decades. PBDEs and their metabolites cross the placenta and studies in rodents show neurodevelopmental toxicity from prenatal exposures. Objectives: To review PBDEs and the development of 100 children from CHARGE (Childhood Autism Risk from Genetics and the Environment), a case-control epidemiologic study of autism/autism spectrum (AU/ASD), developmental delays (DD) and typically developing (TD) population-based controls. Methods: Developmental diagnoses were confirmed by the ADOS, ADI-R, Mullen's Scales of Early Learning, and Vineland Adaptive Behavior Scales. Eleven PBDE congeners were measured by GC/MS from serum specimens collected after children were assessed. Immunoglobulins and cytokines were measured by LuminexTM multiplex platform. Multiple logistic and linear regression models were used to control confounding factors i...
Autism spectrum disorders (ASD) are neurodevelopmental diseases that affect an alarming number of... more 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. Therefore, imbalances 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.
Background Autism is a neurodevelopmental disorder characterized by impairments in social interac... more Background Autism is a neurodevelopmental disorder characterized by impairments in social interaction and deficits in verbal and nonverbal communication, together with the presence of repetitive behaviors or a limited repertoire of activities and interests. The causes of autism are currently unclear. In a previous study, we determined that 21% of children with autism have plasma autoantibodies that are immunoreactive with a population of neurons in the cerebellum that appear to be Golgi cells, which are GABAergic interneurons. Methods We have extended this analysis by examining plasma immunoreactivity in the remainder of the brain. To determine cell specificity, double-labeling studies that included one of the calcium-binding proteins that are commonly colocalized in GABAergic neurons (calbindin, parvalbumin or calretinin) were also carried out to determine which GABAergic neurons are immunoreactive. Coronal sections through the rostrocaudal extent of the macaque monkey brain were r...
The contribution of peripheral immunity to autism spectrum disorders (ASDs) risk is debated and p... more The contribution of peripheral immunity to autism spectrum disorders (ASDs) risk is debated and poorly understood. Some mothers of children with ASD have autoantibodies that react to fetal brain proteins, raising the possibility that a subset of ASD cases may be associated with a maternal antibody response during gestation. The mechanism by which the maternal immune system breaks tolerance has not been addressed. We hypothesized that the mechanism may involve decreased expression of the MET receptor tyrosine kinase, an ASD risk gene that also serves as a key negative regulator of immune responsiveness. In a sample of 365 mothers, including 202 mothers of children with ASD, the functional MET promoter variant rs1858830 C allele was strongly associated with the presence of an ASD-specific 37 þ 73-kDa band pattern of maternal autoantibodies to fetal brain proteins (P ¼ 0.003). To determine the mechanism of this genetic association, we measured MET protein and cytokine production in freshly prepared peripheral blood mononuclear cells from 76 mothers of ASD and typically developing children. The MET rs1858830 C allele was significantly associated with MET protein expression (P ¼ 0.025). Moreover, decreased expression of the regulatory cytokine IL-10 was associated with both the MET gene C allele (P ¼ 0.001) and reduced MET protein levels (P ¼ 0.002). These results indicate genetic distinction among mothers who produce ASD-associated antibodies to fetal brain proteins, and suggest a potential mechanism for how a genetically determined decrease in MET protein production may lead to a reduction in immune regulation.
ABSTRACT Autistic spectrum disorders (ASD) are a broad spectrum of heterogeneous neurodevelopment... more ABSTRACT Autistic spectrum disorders (ASD) are a broad spectrum of heterogeneous neurodevelopmental disorders, most with unknown etiology. Although the development of autism is suspected to be the result of a complex combination of genetic, environmental, neurobiological, and immunological factors, the role of each of these factors is still under investigation. In this chapter, we review current concepts regarding the immunological aspects of autism as they pertain to areas of our own research. Three specific areas are covered including autoantibodies in children with ASD, maternal antibodies directed against fetal brain, and immune dysfunction in children with ASD. KeywordsAutism–immunology–maternal–autoantibodies–fetus
Autism is a complex and clinically heterogeneous disorder with a spectrum of symptoms. Clinicians... more Autism is a complex and clinically heterogeneous disorder with a spectrum of symptoms. Clinicians, schools, and service agencies worldwide have reported a dramatic increase in the number of children identified with autism. Despite expanding research, the etiology and underlying biological processes of autism remain poorly understood, and the relative contribution from genetic, epigenetic, and environmental factors remains unclear. Although autism affects primarily brain function (especially affect, social functioning, and cognition), it is unknown to what extent other organs and systems are disrupted. Published findings have identified widespread changes in the immune systems of children with autism, at both systemic and cellular levels. Brain specimens from autism subjects exhibit signs of active, ongoing inflammation, as well as alterations in gene pathways associated with immune signaling and immune function. Moreover, many genetic studies have indicated a link between autism and genes that are relevant to both the nervous system and the immune system. Alterations in these pathways can affect function in both systems. Together, these reports suggest that autism may in fact be a systemic disorder with connections to abnormal immune responses. Such immune system dysfunction may represent novel targets for treatment. A better understanding of the involvement of the immune response in autism, and of how early brain development is altered, may have important therapeutic implications.
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2006
We compared the compositions of fatty acids including n-3, n-6 polyunsaturated fatty acids, trans... more We compared the compositions of fatty acids including n-3, n-6 polyunsaturated fatty acids, trans-and cis-monounsaturated fatty acids, and saturated fatty acids in the red blood cell membranes of 40 children with autism (20 with early onset autism and 20 with developmental regression) and age-matched, 20 typically developing controls and 20 subjects with non-autistic developmental disabilities. The main findings include increased levels of eicosenoic acid (20:1n9) and erucic acid (22:1n9) in autistic subjects with developmental regression when compared with typically developing controls. In addition, an increase in 20:2n6 and a decrease in 16:1n7t were observed in children with clinical regression compared to those with early onset autism. Our results do not provide strong evidence for the hypothesis that abnormal fatty acid metabolism plays a role in the pathogenesis of autism spectrum disorder, although they suggest some metabolic or dietary abnormalities in the regressive form of autism.
Objective: Autism is a syndrome with a number of etiologies with differing mechanisms that lead t... more Objective: Autism is a syndrome with a number of etiologies with differing mechanisms that lead to abnormal development. This review highlights the need to identify autism subgroups as they each might require unique approaches for prevention or treatment. Methods: Targeting treatments to specific mechanisms and utilizing biomarkers can more rapidly advance our understanding of how to classify and treat autism subgroups based on translational mechanisms. We illustrate this approach using mechanisms that may influence the course of autism and provide rationale for selected biomarkers that could guide treatments targeted anywhere from DNA to symptom expression. Conclusions: The use of potential biomarkers that point to specific mechanisms of disordered neurodevelopment will help identify meaningful subtypes of autism and will help tailor treatment or prevention strategies for each mechanism rather than solely to a symptom category.
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Papers by Paul Ashwood