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1.  Myeloid dendritic cells frequencies are increased in children with autism spectrum disorder and associated with amygdala volume and repetitive behaviors 
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.
doi:10.1016/j.bbi.2012.10.006
PMCID: PMC4229011  PMID: 23063420
Autism; dendritic cells; repetitive behaviors; amygdala volume; innate immunity
2.  Maternal Immune-Mediated Conditions, Autism Spectrum Disorders, and Developmental Delay 
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).
doi:10.1007/s10803-013-2017-2
PMCID: PMC4104679  PMID: 24337796
Autoimmune disease; Asthma; Allergy; Autism; Developmental delay; Maternal risk factors
3.  Immune-mediated Disorders among Women Carrier of Fragile X Premutation Alleles 
The relative risk of immune-mediated disorders (IMDs) among women carrier of premutation alleles is estimated by a survey for IMDs among 344 carrier women (age 19 to 81 years; mean 46.35 and SD 12.60) and 72 controls (age 18 to 87 years; mean 52.40 and SD 15.40). One hundred fifty four (44.77%) women carrier had at least one IMD, as did 20 controls (27.78%). Among women carrier, autoimmune thyroid disorder was the most common (24.4%), then fibromyalgia (10.2%), irritable bowel syndrome (IBS; 9.9%), Raynaud’s phenomenon (7.6%), rheumatoid arthritis (RA; 3.8%), Sjögren syndrome (2.6%), systemic lupus erythematosus (SLE; 2.03%), multiple sclerosis (1.74%). Of 55 carriers age 40 or older with FXTAS, 72.73% had at least one IMD, compared to 46.54% of those without FXTAS (n=159), and 31.58% of controls (n=57). The estimated odds ratio (OR) for IMD is 2.6 (95% CI 1.2–5.6, p = 0.015) for women with FXTAS relative to those without FXTAS; the likelihood of IMD in carriers without or with FXTAS was also significantly higher than for controls (OR 2.1, 95% CI 1.1–4.2, p = 0.034; OR 5.5, 95% CI 2.4–12.5, p < 0.001 respectively). Similarly, the odds of having an IMD among carriers with FXPOI is about 2.4 times higher when compared to carriers without FXPOI (95% CI 1.1–5.0; p = 0.021). The likelihood of IMD in carriers with or without FXPOI is greater (OR 2.4, 95% CI 1.1–5.0; p = 0.021) compared to that of controls.
doi:10.1002/ajmg.a.35569
PMCID: PMC4105154  PMID: 22903889
Autoimmune; FXTAS; RNA toxicity; ovarian insufficiency
4.  Maternal autism-associated IgG antibodies delay development and produce anxiety in a mouse gestational transfer model 
Journal of neuroimmunology  2012;252(0):56-65.
A murine passive transfer model system was employed to ascertain the effects of gestational exposure to a single, intravenous dose of purified, brain-reactive IgG antibodies from individual mothers of children with autism (MAU) or mothers with typically developing children (MTD). Growth and behavioral outcomes in offspring were measured from postnatal days 8 – 65 in each group. Comparisons revealed alterations in early growth trajectories, significantly impaired motor and sensory development, and increased anxiety. This report demonstrates for the first time the effects of a single, low dose gestational exposure of IgG derived from individual MAU on their offspring’s physical and social development.
doi:10.1016/j.jneuroim.2012.08.002
PMCID: PMC4096980  PMID: 22951357
Autism; maternal antibodies; passive transfer; immune; mouse behavior
5.  Neonatal cytokines and chemokines and risk of Autism Spectrum Disorder: the Early Markers for Autism (EMA) study: a case-control study 
Background
Biologic markers of infection and inflammation have been associated with Autism Spectrum Disorders (ASD) but prior studies have largely relied on specimens taken after clinical diagnosis. Research on potential biologic markers early in neurodevelopment is required to evaluate possible causal pathways and screening profiles.
Objective
To investigate levels of cytokines and chemokines in newborn blood specimens as possible early biologic markers for autism.
Methods
We conducted a population-based case-control study nested within the cohort of infants born from July 2000 to September 2001 to women who participated in the prenatal screening program in Orange County, California, USA. The study population included children ascertained from the California Department of Developmental Services with Autism Spectrum Disorder (ASD, n = 84), or developmental delay but not ASD (DD, n = 49), and general population controls randomly sampled from the birth certificate files and frequency matched to ASD cases on sex, birth month and birth year (GP, n = 159). Cytokine and chemokine concentrations were measured in archived neonatal blood specimens collected for routine newborn screening.
Results
Cytokines were not detected in the vast majority of newborn samples regardless of case or control status. However, the chemokine monocyte chemotactic protein-1 (MCP-1) was elevated and the chemokine Regulated upon Activation Normal T-Cell Expressed and Secreted (RANTES) was decreased in ASD cases compared to GP controls. The chemokines macrophage inflammatory protein-1alpha (MIP-1α) and RANTES were decreased in children with DD compared to GP controls.
Conclusion
Measurement of immune system function in the first few days of life may aid in the early identification of abnormal neurodevelopment and shed light on the biologic mechanisms underlying normal neurodevelopment.
doi:10.1186/1742-2094-11-113
PMCID: PMC4080514  PMID: 24951035
Newborn; Cytokines; Chemokines; Autism spectrum disorders
6.  Group I metabotropic glutamate receptor mediated dynamic immune dysfunction in children with fragile X syndrome 
Background
Fragile X syndrome (FXS) is the leading cause of inheritable intellectual disability in male children, and is predominantly caused by a single gene mutation resulting in expanded trinucleotide CGG-repeats within the 5’ untranslated region of the fragile X mental retardation (FMR1) gene. Reports have suggested the presence of immune dysregulation in FXS with evidence of altered plasma cytokine levels; however, no studies have directly assessed functional cellular immune responses in children with FXS. In order to ascertain if immune dysregulation is present in children with FXS, dynamic cellular responses to immune stimulation were examined.
Methods
Peripheral blood mononuclear cells (PBMC) were from male children with FXS (n = 27) and from male aged-matched typically developing (TD) controls (n = 8). PBMC were cultured for 48 hours in media alone or with lipopolysaccharides (LPS; 1 μg/mL) to stimulate the innate immune response or with phytohemagglutinin (PHA; 8 μg/mL) to stimulate the adaptive T-cell response. Additionally, the group I mGluR agonist, DHPG, was added to cultures to ascertain the role of mGluR signaling in the immune response in subject with FXS. Supernatants were harvested and cytokine levels were assessed using Luminex multiplexing technology.
Results
Children with FXS displayed similar innate immune response following challenge with LPS alone when compared with TD controls; however, when LPS was added in the presence of a group I mGluR agonist, DHPG, increased immune response were observed in children with FXS for a number of pro-inflammatory cytokines including IL-6 (P = 0.02), and IL-12p40 (P < 0.01). Following PHA stimulation, with or without DHPG, no significant differences between subjects with FXS and TD were seen.
Conclusions
In unstimulated cultures, subjects with FXS did not display altered dynamic immune response to LPS or PHA alone; however, subjects with FXS showed an altered response to co-current stimulation of LPS and DHPG, such that subjects with FXS failed to inhibit production of pro-inflammatory cytokines, suggesting a role of group I mGluR signaling in innate immune responses in FXS.
doi:10.1186/1742-2094-11-110
PMCID: PMC4107617  PMID: 24942544
Fragile x syndrome; Immune; Cytokine; Metabotropic glutamate receptor
7.  Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder 
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.
doi:10.1016/j.bbi.2013.01.084
PMCID: PMC3641177  PMID: 23395715
Autism spectrum disorder; MRI; structural neuroimaging; maternal antibody; autoantibody
8.  Levels of Soluble Adhesion Molecules PECAM-1 and P-Selectin are Decreased in Children with Autism Spectrum Disorder 
Biological psychiatry  2012;72(12):1020-1025.
Background
Although the etiopathology of Autism Spectrum Disorder (ASD) is not clear there is increasing evidence that dysfunction in the immune system affects many children with ASD. Findings of immune dysfunction in ASD include increases in inflammatory cytokines, chemokines and microglial activity in brain tissue and CSF, as well as abnormal peripheral immune cell function.
Methods
Adhesion molecules, such as platelet endothelial adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), P-Selectin, and L-Selectin, function to facilitate leukocyte transendothelial migration. We assessed concentrations of soluble adhesion molecules, sPECAM-1, sICAM-1, sVCAM-1, sP-Selectin, and sL-Selectin in the plasma of 49 participants with ASD, and 31 typically developing controls of the same age, all of whom were enrolled as part of the Autism Phenome Project (APP). Behavioral assessment, the levels of soluble adhesion molecules, head circumference and MRI measurements of brain volume were compared in the same subjects.
Results
Levels of sPECAM-1 and sP-Selectin were significantly reduced in the ASD group compared to typically developing controls (p < 0.02). Soluble PECAM-1 levels were negatively associated with repetitive behavior and abnormal brain growth in children with ASD (p=0.03).
Conclusions
As adhesion molecules modulate the permeability and signaling at the blood brain barrier as well as leukocyte infiltration into the CNS, current data suggests a role for these molecules in the complex pathophysiology of ASD.
doi:10.1016/j.biopsych.2012.05.004
PMCID: PMC3496806  PMID: 22717029
Autism; PECAM-1; P-Selectin; CD31; CD62-P; Adhesion
9.  Decreased Levels of Total Immunoglobulin in Children with Autism is not a Result of B Cell Dysfunction 
Journal of neuroimmunology  2012;251(1-2):94-102.
Autism spectrum disorders are a heterogeneous group of behaviorally defined disorders having complex etiologies. We previously reported a direct correlation between lower plasma levels of the immunoglobulins (Ig) IgG and IgM and increased severity of behavioral symptoms in children with autism. Our current objective was to determine if these reduced plasma levels of IgG and IgM are the result of defective B cell development, activation, or function. Results suggest no differences in the B cell parameters measured, indicating that decreased Ig in autism is not a result of B cell dysfunction and other immune cells might be involved.
doi:10.1016/j.jneuroim.2012.07.001
PMCID: PMC3432686  PMID: 22854260
Autism; B cell; Immunoglobulin; Immune system
10.  Maternal and Fetal Anti-brain Antibodies in Development and Disease 
Developmental neurobiology  2012;72(10):1327-1334.
Recent evidence has emerged indicating that the maternal immune response can have a substantial deleterious impact on prenatal development (Croen et al., 2008). The maternal immune response is largely sequestered from the fetus. Maternal antibodies, specifically immunoglobulin G (IgG), are passed to the fetus to provide passive immunity throughout much of pregnancy. However, both protective and pathogenic autoantibodies have equal access to the fetus (Goines and Van de Water, 2010). If the mother has an underlying autoimmune disease or has reactivity to fetal antigens, autoantibodies produced before or during pregnancy can target tissues in the developing fetus. One such tissue is the fetal brain. The blood brain barrier (BBB) is developing during the fetal period allowing maternal antibodies to have direct access to the brain during gestation (Diamond et al., 2009; Braunschweig et al., 2011). It has been proposed that brain injury by circulating brain–specific maternal autoantibodies might underlie multiple congenital, developmental disorders (Lee et al., 2009). In this review, we will discuss the current state of research in the area of maternal autoantibodies and the development of autism.
doi:10.1002/dneu.22052
PMCID: PMC3478666  PMID: 22911883
11.  Increased Anti-Phospholipid Antibodies in Autism Spectrum Disorders 
Mediators of Inflammation  2013;2013:935608.
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, β2-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.
doi:10.1155/2013/935608
PMCID: PMC3794552  PMID: 24174712
12.  Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism☆ 
Brain, behavior, and immunity  2008;22(6):806-816.
Autism together with Asperger syndrome and pervasive developmental disorder not otherwise specified form a spectrum of conditions (autism spectrum disorders or ASD) that is characterized by disturbances in social behavior, impaired communication and the presence of stereotyped behaviors or circumscribed interests. Recent estimates indicate a prevalence of ASD of 1 per 150 (Kuehn, 2007). The cause(s) of most cases of ASD are unknown but there is an emerging consensus that ASD have multiple etiologies. One proposed cause of ASD is exposure of the fetal brain to maternal autoantibodies during pregnancy [Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533–537]. To provide evidence for this hypothesis, four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Monkeys were observed in a variety of behavioral paradigms involving unique social situations. Behaviors were scored by trained observers and overall activity was monitored with actimeters. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Treatment with IgG purified from mothers of typically developing children did not induce stereotypical or hyperactive behaviors. These findings support the potential for an autoimmune etiology in a subgroup of patients with neurodevelopmental disorders. This research raises the prospect of prenatal evaluation for neurodevelopmental risk factors and the potential for preventative therapeutics.
doi:10.1016/j.bbi.2007.12.007
PMCID: PMC3779644  PMID: 18262386
Repetitive; Primate; Macaque; Macaca mulatta; Activity; Asperger syndrome
13.  Ultra Low Density and Highly Crosslinked Biocompatible Shape Memory Polyurethane Foams 
We report the development of highly chemically crosslinked, ultra low density (~0.015 g/cc) polyurethane shape memory foams synthesized from symmetrical, low molecular weight and branched hydroxyl monomers. Sharp single glass transitions (Tg) customizable in the functional range of 45–70 °C were achieved. Thermomechanical testing confirmed shape memory behavior with 97–98% shape recovery over repeated cycles, a glassy storage modulus of 200–300 kPa and recovery stresses of 5–15 kPa. Shape holding tests under constrained storage above the Tg showed stable shape memory. A high volume expansion of up to 70 times was seen on actuation of these foams from a fully compressed state. Low in-vitro cell activation induced by the foam compared to controls demonstrates low acute bio-reactivity. We believe these porous polymeric scaffolds constitute an important class of novel smart biomaterials with multiple potential applications.
doi:10.1002/polb.23056
PMCID: PMC3345164  PMID: 22570509
Shape Memory Polymer; Low Density Foams; Polyurethane; Aneurysm; Secondary - shape forming
14.  Autism: Where Genetics Meets the Immune System 
Autism Research and Treatment  2012;2012:486359.
doi:10.1155/2012/486359
PMCID: PMC3440848  PMID: 22988503
15.  DETECTION OF PLASMA AUTOANTIBODIES TO BRAIN TISSUE IN YOUNG CHILDREN WITH AND WITHOUT AUTISM SPECTRUM DISORDERS 
Brain, Behavior, and Immunity  2011;25(6):1123-1135.
Autism spectrum disorders (ASDs) are characterized by impaired language and social skills, often with restricted interests and stereotyped behaviors. A previous investigation of blood plasma from children with ASDs (mean age = 5½ years) demonstrated that 21% of samples contained autoantibodies that reacted intensely with GABAergic Golgi neurons of the cerebellum while no samples from non-sibling, typically developing children showed similar staining (Wills et al., 2009). In order to characterize the clinical features of children positive for these autoantibodies, we analyzed plasma samples from children enrolled in the Autism Phenome Project, a multidisciplinary project aimed at identifying subtypes of ASD. Plasma from male and female children (mean age = 3.2 years) was analyzed immunohistochemically for the presence of autoantibodies using histological sections of macaque monkey brain. Immunoreactivity to cerebellar Golgi neurons and other presumed interneurons was observed for some samples but there was no difference in the rate of occurrence of these autoantibodies between children with ASD and their typically developing peers. Staining of neurons, punctate profiles in the molecular layer of the dentate gyrus, and neuronal nuclei were also observed. Taken together, 42% of controls and subjects with ASD demonstrated immunoreactivity to some neural element. Interestingly, children whose plasma reacted to brain tissue had scores on the Child Behavior Checklist (CBCL) that indicated increased behavioral and emotional problems. Children whose plasma was immunoreactive with neuronal cell bodies scored higher on multiple CBCL scales. These studies indicate that additional research into the genesis and prevalence of brain-directed autoantibodies is warranted.
doi:10.1016/j.bbi.2011.02.011
PMCID: PMC3313674  PMID: 21420487
Autism; autoantibody; interneurons; immunohistochemistry; Child Behavior Checklist
16.  Altered T cell responses in children with autism 
Brain, behavior, and immunity  2010;25(5):840-849.
Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential etiologic role for immune dysfunction in ASD has been suggested. Dynamic adaptive cellular immune function was investigated in 66 children with a confirmed diagnosis of ASD and 73 confirmed typically developing (TD) controls 2–5 years-of-age. In vitro stimulation of peripheral blood mononuclear cells with PHA and tetanus was used to compare group-associated cellular responses. The production of GM-CSF, TNFα, and IL-13 were significantly increased whereas IL-12p40 was decreased following PHA stimulation in ASD relative to TD controls. Induced cytokine production was associated with altered behaviors in ASD children such that increased pro-inflammatory or TH1 cytokines were associated with greater impairments in core features of ASD as well as aberrant behaviors. In contrast, production of GM-CSF and TH2 cytokines were associated with better cognitive and adaptive function. Following stimulation, the frequency of CD3+, CD4+ and CD8+ T cells expressing activation markers CD134 and CD25 but not CD69, HLA-DR or CD137 were significantly reduced in ASD, and suggests an altered activation profile for T cells in ASD. Overall these data indicate significantly altered adaptive cellular immune function in children with ASD that may reflect dysfunctional immune activation, along with evidence that these perturbations may be linked to disturbances in behavior and developmental functioning. Further longitudinal analyzes of cellular immunity profiles would delineate the relationship between immune dysfunction and the progression of behavioral and developmental changes throughout the course of this disorder.
doi:10.1016/j.bbi.2010.09.002
PMCID: PMC3039713  PMID: 20833247
17.  Decreased Levels of EGF in Plasma of Children with Autism Spectrum Disorder 
Autism Research and Treatment  2012;2012:205362.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder estimated to affect 1 in 110 children in the U.S., yet the pathology of this disorder is not fully understood. Abnormal levels of several growth factors have been demonstrated in adults with ASD, including epidermal growth factor (EGF) and hepatocyte growth factor (HGF). Both of these growth factors serve important roles in neurodevelopment and immune function. In this study, concentrations of EGF and HGF were assessed in the plasma of 49 children with ASD aged 2–4 years old and 31 typically developing controls of a similar age as part of the Autism Phenome Project (APP). Levels of EGF were significantly reduced in the ASD group compared to typically developing controls (P = 0.003). There were no significant differences in HGF levels in young children with ASD and typically developing controls. EGF plays an important role in regulating neural growth, proliferation, differentiation and migration, and reduced levels of this molecule may negatively impact neurodevelopment in young children with ASD.
doi:10.1155/2012/205362
PMCID: PMC3420731  PMID: 22937258
18.  Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders 
Journal of neuroimmunology  2010;232(1-2):196-199.
A role for immune dysfunction has been suggested in autism spectrum disorders (ASD). Elevated levels of chemokines have been detected in the brain and CSF of individuals with ASD but, to date, no study has examined chemokine levels in the plasma of children with this disorder. In the current study, we determined whether there were differential profiles of chemokines in the plasma of children with ASD compared to age-matched typically developing controls and children with developmental disabilities other than ASD. Increased MCP-1, RANTES and eotaxin levels were observed in ASD children compared with both control groups (p<0.03), and increased chemokine production was associated with higher aberrant behavior scores and more impaired developmental and adaptive function.. Elevated MCP-1, RANTES and eotaxin in some ASD children and their association with more impaired behaviors may have etiological significance. Chemokines and their receptors might provide unique targets for future therapies in ASD.
doi:10.1016/j.jneuroim.2010.10.025
PMCID: PMC3053074  PMID: 21095018
19.  AUTOANTIBODIES TO CEREBELLUM IN CHILDREN WITH AUTISM ASSOCIATE WITH BEHAVIOR 
Brain, behavior, and immunity  2010;25(3):514-523.
Autism is a heterogeneous disorder with a poorly understood biological basis. Some children with autism harbor plasma autoantibodies that target brain proteins. Similarly, some mothers of children with autism produce antibodies specific to autism that target pairs of fetal brain proteins at 37/73 kDa and 39/73kDa. We explored the relationship between the presence of brain-specific autoantibodies and several behavioral characteristics of autism in 277 children with an autism spectrum disorder and 189 typically developing age-matched controls. Further, we used maternal autoantibody data to investigate potential familial relationships for the production of brain-directed autoantibodies. We demonstrated by western blot that autoantibodies specific for a 45kDa cerebellar protein in children were associated with a diagnosis of autism (p=0.017) while autoantibodies directed towards a 62kDa protein were associated with the broader diagnosis of autism spectrum disorder (ASD) (p=0.043). Children with such autoantibodies had lower adaptive (p=0.0008) and cognitive function (p=0.005), as well as increased aberrant behaviors (p<0.05) compared to children without these antibodies. No correlation was noted for those mothers with the most specific pattern of anti-fetal brain autoantibodies and children with the autoantibodies to either the 45 or 62 kDa bands. Collectively, these data suggest that antibodies towards brain proteins in children are associated with lower adaptive and cognitive function as well as core behaviors associated with autism. It is unclear whether these antibodies have direct pathologic significance, or if they are merely a response to previous injury. Future studies are needed to determine the identities of the protein targets and explore their significance in autism.
doi:10.1016/j.bbi.2010.11.017
PMCID: PMC3039058  PMID: 21134442
Autism spectrum disorders; immune system; immunoglobulin; autoantibody; brain; cerebellum; neurodevelopment; behavior
20.  Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome 
Brain, behavior, and immunity  2010;25(1):40-45.
Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential role for immune dysfunction has been suggested in ASD. To test this hypothesis, we investigated evidence of differential cytokine release in plasma samples obtained from 2-5 year-old children with ASD compared with age-matched typically developing (TD) children and children with developmental disabilities other than autism (DD). Participants were recruited as part of the population based case-control CHARGE (Childhood Autism Risks from Genetics and Environment) study and included: 97 participants with a confirmed diagnosis of ASD using standard assessments (DSM IV criteria and ADOS, ADI-R), 87 confirmed TD controls, and 39 confirmed DD controls. Plasma was isolated and cytokine production was assessed by multiplex Luminex™ analysis. Observations indicate significant increases in plasma levels of a number of cytokines, including IL-1β, IL-6, IL-8 and IL-12p40 in the ASD group compared with TD controls (p < 0.04). Moreover, when the ASD group was separated based on the onset of symptoms, it was noted that the increased cytokine levels were predominantly in ASD children who had a regressive form of ASD. In addition, increasing cytokine levels were associated with more impaired communication and aberrant behaviors. In conclusion, using larger number of participants than previous studies, we report significantly shifted cytokine profiles in ASD. These findings suggest that ongoing inflammatory responses may be linked to disturbances in behavior and require confirmation in larger replication studies. The characterization of immunological parameters in ASD has important implications for diagnosis, and should be considered when designing therapeutic strategies to treat core symptoms and behavioral impairments of ASD.
doi:10.1016/j.bbi.2010.08.003
PMCID: PMC2991432  PMID: 20705131
21.  Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis 
Hepatology (Baltimore, Md.)  2010;52(3):987-998.
Our understanding of primary biliary cirrhosis (PBC) has been significantly enhanced by the rigorous dissection of the multilineage T and B cell response against the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2). PDC-E2 is a ubiquitous protein present in mitochondria of nucleated cells. However, the damage in PBC is confined to small biliary epithelial cells (BEC). We have previously demonstrated that BEC translocate immunologically intact PDC-E2 to apoptotic bodies, creating an apotope. To define the significance of this observation, we studied the ability of biliary or control epithelial apotopes to induce cytokine secretion from mature monocyte derived macrophages (MDMΦ) from either patients with PBC or controls in the presence or absence of anti-mitochondrial antibodies (AMA). We demonstrate that there is intense inflammatory cytokine production in the presence of the unique triad of BEC apotopes, macrophages from patients with PBC and AMA. The cytokine secretion is inhibited by anti-CD16 and not due to differences in apotope uptake. Moreover, MDMΦ from PBC patients cultured with BEC apoptotic bodies in the presence of AMA markedly increased TNF-related apoptosis-inducing ligand expression.
Conclusion
These results provide a mechanism for the biliary specificity of PBC, the recurrence of disease following liver transplantation and the success of ursodiol in treatment. They further emphasize a critical role of the innate immune system in the perpetuation of this autoimmune disease.
doi:10.1002/hep.23783
PMCID: PMC2932809  PMID: 20568301
autoimmunity; biliary epithelial cell; macrophages; cytokines; Fc receptor
22.  Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: A case-control study 
Molecular Autism  2011;2:13.
Background
Immune anomalies have been documented in individuals with autism spectrum disorders (ASDs) and their family members. It is unknown whether the maternal immune profile during pregnancy is associated with the risk of bearing a child with ASD or other neurodevelopmental disorders.
Methods
Using Luminex technology, levels of 17 cytokines and chemokines were measured in banked serum collected from women at 15 to 19 weeks of gestation who gave birth to a child ultimately diagnosed with (1) ASD (n = 84), (2) a developmental delay (DD) but not autism (n = 49) or (3) no known developmental disability (general population (GP); n = 159). ASD and DD risk associated with maternal cytokine and chemokine levels was estimated by using multivariable logistic regression analysis.
Results
Elevated concentrations of IFN-γ, IL-4 and IL-5 in midgestation maternal serum were significantly associated with a 50% increased risk of ASD, regardless of ASD onset type and the presence of intellectual disability. By contrast, elevated concentrations of IL-2, IL-4 and IL-6 were significantly associated with an increased risk of DD without autism.
Conclusion
The profile of elevated serum IFN-γ, IL-4 and IL-5 was more common in women who gave birth to a child subsequently diagnosed with ASD. An alternative profile of increased IL-2, IL-4 and IL-6 was more common for women who gave birth to a child subsequently diagnosed with DD without autism. Further investigation is needed to characterize the relationship between these divergent maternal immunological phenotypes and to evaluate their effect on neurodevelopment.
doi:10.1186/2040-2392-2-13
PMCID: PMC3170586  PMID: 21810230
23.  In Search of Cellular Immunophenotypes in the Blood of Children with Autism 
PLoS ONE  2011;6(5):e19299.
Background
Autism is a neurodevelopmental disorder characterized by impairments in social behavior, communication difficulties and the occurrence of repetitive or stereotyped behaviors. There has been substantial evidence for dysregulation of the immune system in autism.
Methods
We evaluated differences in the number and phenotype of circulating blood cells in young children with autism (n = 70) compared with age-matched controls (n = 35). Children with a confirmed diagnosis of autism (4–6 years of age) were further subdivided into low (IQ<68, n = 35) or high functioning (IQ≥68, n = 35) groups. Age- and gender-matched typically developing children constituted the control group. Six hundred and forty four primary and secondary variables, including cell counts and the abundance of cell surface antigens, were assessed using microvolume laser scanning cytometry.
Results
There were multiple differences in immune cell populations between the autism and control groups. The absolute number of B cells per volume of blood was over 20% higher for children with autism and the absolute number of NK cells was about 40% higher. Neither of these variables showed significant difference between the low and high functioning autism groups. While the absolute number of T cells was not different across groups, a number of cellular activation markers, including HLA-DR and CD26 on T cells, and CD38 on B cells, were significantly higher in the autism group compared to controls.
Conclusions
These results support previous findings that immune dysfunction may occur in some children with autism. Further evaluation of the nature of the dysfunction and how it may play a role in the etiology of autism or in facets of autism neuropathology and/or behavior are needed.
doi:10.1371/journal.pone.0019299
PMCID: PMC3087757  PMID: 21573236
24.  Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism 
Molecular Autism  2011;2:5.
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 reacted with plasma from each of seven individuals with autism who had previously demonstrated positive Golgi cell staining, as well as six negative controls. In addition, brain sections from adult male mice were similarly examined.
Results
In each case, specific staining was observed for neurons that had the morphological appearance of interneurons. By double-labeling sections with plasma and with antibodies directed against γ-aminobutyric acid (GABA), we determined that all autoantibody-positive neurons were GABAergic. However, not all GABAergic neurons were autoantibody-positive. Calbindin was colabeled in several of the autoantibody-labeled cells, while parvalbumin colabeling was less frequently observed. Autoantibody-positive cells rarely expressed calretinin. Sections from the mouse brain processed similarly to the primate sections also demonstrated immunoreactivity to interneurons distributed throughout the neocortex and many subcortical regions. Some cell populations stained in the primate (such as the Golgi neurons in the cerebellum) were not as robustly immunoreactive in the mouse brain.
Conclusions
These results suggest that the earlier report of autoantibody immunoreactivity to specific cells in the cerebellum extend to other regions of the brain. Further, these findings confirm the autoantibody-targeted cells to be a subpopulation of GABAergic interneurons. The potential impact of these autoantibodies on GABAergic disruption with respect to the etiology of autism is discussed herein.
doi:10.1186/2040-2392-2-5
PMCID: PMC3108923  PMID: 21521495
25.  The Immune System’s Role in the Biology of Autism 
Current opinion in neurology  2010;23(2):111-117.
PURPOSE OF REVIEW
The following is a review of the most recent research concerning the potential role of immune system dysfunction in autism. This body of literature has expanded dramatically over the past few years as researchers continue to identify immune anomalies in individuals with autism.
RECENT FINDINGS
The most exciting of these recent findings is the discovery of autoantibodies targeting brain proteins in both children with autism and their mothers. In particular, circulating maternal autoantibodies directed towards fetal brain proteins are highly specific for autism. This finding has great potential as a biomarker for disease risk, and may provide an avenue for future therapeutics and prevention. Additionally, data concerning the cellular immune system in children with autism suggest there may be a defect in signaling pathways that are shared by the immune and central nervous systems. While studies to explore this hypothesis are ongoing, there is great interest in the commonalities between the neural and immune systems and their extensive interactions.
SUMMARY
In summary, there is exciting research regarding the role of the immune system in autism spectrum disorders that may have profound implications for diagnosis and treatment of this devastating disease.
doi:10.1097/WCO.0b013e3283373514
PMCID: PMC2898160  PMID: 20160651
Immune system; autoantibodies; immunoglobulin; cytokines; autism

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