Immune dysfunction in autism: A pathway to treatment

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.     

Increased IgG4 levels in children with autism disorder

Accumulating evidence indicates that immune dysfunction is associated with autism disorders in a significant subset of children. Previous reports have shown abnormal immunoglobulin (Ig) levels, including an increased presence of autoreactive antibodies in the circulation of individuals with autism. As IgG is the predominant antibody isotype in circulation, we expected that an altered immune response could result in an abnormal IgG subclass profile in children with autism. We examined circulating plasma levels of IgG1, IgG2, IgG3, and IgG4 in 241 children from the CHARGE (Childhood Autism Risks from Genetics and the Environment) study, a large epidemiologic case-control investigation, including 114 children who meet full criteria for autism disorder (AU), 96 typically developing control children (TD) from a randomly selected sample of the general population, and 31 children with developmental delays (DD). We report significantly increased levels of the IgG4 subclass in children with AU compared with TD control children (p = 0.016) and compared with DD controls (p = 0.041). These results may suggest an underlying immunological abnormality in AU subjects resulting in elevated IgG4 production. Further investigation is necessary to elucidate the relationship between immunological findings and behavioral impairments in autism.     

Immunologic and neurodevelopmental susceptibilities of autism

Symposium 5 focused on research approaches that are aimed at understanding common patterns of immunological and neurological dysfunction contributing to neurodevelopmental disorders such as autism and ADHD. The session focused on genetic, epigenetic, and environmental factors that might act in concert to influence autism risk, severity and co-morbidities, and immunological and neurobiological targets as etiologic contributors. The immune system of children at risk of autism may be therefore especially susceptible to psychological stressors, exposure to chemical triggers, and infectious agents. Identifying early biomarkers of risk provides tangible approaches toward designing studies in animals and humans that yield a better understanding of environmental risk factors, and can help identify rational intervention strategies to mitigate these risks.     

孤独症与精神分裂症患者异常淋巴细胞的对照研究

目的了解孤独症患者免疫功能状况以及孤独症和精神分裂症在免疫指标上是否存在联系。方法采用随机、双盲法检测２４例孤独症和１５例精神分裂症患者外周血中的异常淋巴细胞。患者均未服过抗精神病药，精神分裂症为首次发作。结果孤独症和精神分裂症患者外周血中Ｐ型异常淋巴细胞分别为１２．７％±９．２％、１７．６％±８．７％，均较各自正常对照组（分别为３．２％±２．３％、５．１％±４．３％）显著增多（Ｐ＜０．０１），而孤独症组与精神分裂症组之间差异无显著性（Ｐ＞０．０５）。结论孤独症存在免疫功能异常，且在免疫指标上与精神分裂症存在某些相似的异常表现     

Plasma cytokine profiles in Fragile X subjects: Is there a role for cytokines in the pathogenesis?

BackgroundFragile X syndrome (FXS) is a single-gene disorder with a broad spectrum of involvement and a strong association with autism. Altered immune responses have been described in autism and there is potential that in children with FXS and autism, an abnormal immune response may play a role.ObjectivesTo delineate specific patterns of cytokine/chemokine profiles in individuals with FXS with and without autism and to compare them with typical developing controls.MethodsAge matched male subjects were recruited through the M.I.N.D. Institute and included: 19 typically developing controls, 64 subjects with FXS without autism and 40 subjects with FXS and autism. Autism diagnosis was confirmed with ADOS, ADI-R and DSM IV criteria. Plasma was isolated and cytokine and chemokine production was assessed by Luminex multiplex analysis.ResultsPreliminary observations indicate significant differences in plasma protein levels of a number of cytokines, including IL-1α, and the chemokines; RANTES and IP-10, between the FXS group and the typical developing controls (p < 0.01). In addition, significant differences were observed between the FXS group with autism and the FXS without autism for IL-6, eotaxin, MCP-1 (p < 0.04).ConclusionsIn this study, the first of its kind, we report a significantly altered cytokine profile in FXS. The characterization of an immunological profile in FXS with and without autism may help to elucidate if an abnormal immune response may play a role and help to identify mechanisms important in the etiology of autism both with and without FXS.     

Increased Serum Levels of Epidermal Growth Factor in Children with Autism

The etiology of autism is unclear, however autism is considered as a multifactorial disorder that is influenced by neurological, environmental, immunological and genetic factors. Growth factors, including epidermal growth factor (EGF), play an important role in the celluler proliferation and the differentiation of the central and peripheral nervous system. In this study we hypothesized that EGF may play a role in the pathophysiology of autism and examined serum EGF levels in children with autism. We measured serum levels of EGF in the 27 autistic children and 28 age- matched normal controls. The serum levels of EGF in the subjects with autism were significantly higher than those of normal control subjects. However, there were no correlations between serum EGF levels and clinical variables in the subjects with autism. This is the first report demonstrating the increased serum levels of EGF in children with autism. This study suggests that increased levels of EGF might have an importance in the pathophysiology of autism.     

The discrimination of and orienting to speech and non-speech sounds in children with autism

The present study aimed to find out how different stages of cortical auditory processing (sound encoding, discrimination, and orienting) are affected in children with autism. To this end, auditory event-related potentials (ERP) were studied in 15 children with autism and their controls. Their responses were recorded for pitch, duration, and vowel changes in speech stimuli, and for corresponding changes in the non-speech counterparts of the stimuli, while the children watched silent videos and ignored the stimuli. The responses to sound repetition were diminished in amplitude in the children with autism, reflecting impaired sound encoding. The mismatch negativity (MMN), an ERP indexing sound discrimination, was enhanced in the children with autism as far as pitch changes were concerned. This is consistent with earlier studies reporting auditory hypersensitivity and good pitch-processing abilities, as well as with theories proposing enhanced perception of local stimulus features in individuals with autism. The discrimination of duration changes was impaired in these children, however. Finally, involuntary orienting to sound changes, as reflected by the P3a ERP, was more impaired for speech than non-speech sounds in the children with autism, suggesting deficits particularly in social orienting. This has been proposed to be one of the earliest symptoms to emerge, with pervasive effects on later development.     

Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes

Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. There is evidence of both immune dysregulation and autoimmune phenomena in autism. We examined the regulatory cytokine transforming growth factor beta-1 (TGF beta 1) because of its role in controlling immune responses. Plasma levels of active TGF beta 1 were evaluated in 75 children with ASD compared with 68 controls. Children with ASD had significantly lower plasma TGF beta 1 levels compared with typically developing controls (p=0.0017) and compared with children with developmental disabilities other than ASD (p=0.0037), after adjusting for age and gender. In addition, there were significant correlations between psychological measures and TGF beta 1 levels, such that lower TGF beta 1 levels were associated with lower adaptive behaviors and worse behavioral symptoms. The data suggest that immune responses in autism may be inappropriately regulated due to reductions in TGF beta 1. Such immune dysregulation may predispose to the development of possible autoimmune responses and/or adverse neuroimmune interactions during critical windows in development.     

Brief report: immune factors in autism: a critical review

Pervasive developmental disorders represent a group of neurodevelopmental disorders that affect children early in their development. Autistic disorder is the best described of these disorders, yet even this term covers a broad group of clinical presentations. Various immune system abnormalities, including autoimmunity and defects in different subsets of immune cells, have been reported in children with autistic disorder, suggesting that immune factors may play a role in the development of autism. Based on anecdotal observation, vaccination was proposed to cause autism in some children, but several controlled studies have failed to support this claim. Intravenous immunoglobulin infusions has been tested as immunotherapy for autism, although the preliminary results are inconclusive and there is a risk of potentially fatal transmission of blood-borne pathogens. To examine this issue, intensive well-controlled epidemiological and bench studies need to be carried out in defined and carefully controlled study subjects to establish the cellular and molecular basis of autism, against which the effects of each proposed immune factor can be examined.     

Efficacy of sensory and motor interventions for children with autism

Idiosyncratic responses to sensory stimuli and unusual motor patterns have been reported clinically in young children with autism. The etiology of these behavioral features is the subject of much speculation. Myriad sensory- and motor-based interventions have evolved for use with children with autism to address such issues; however, much controversy exists about the efficacy of such therapies. This review paper summarizes the sensory and motor difficulties often manifested in autism, and evaluates the scientific basis of various sensory and motor interventions used with this population. Implications for education and further research are described.     

Etiology of infantile autism: a review of recent advances in genetic and neurobiological research

The etiology of autism is complex, and in most cases the underlying pathologic mechanisms are unknown. Autism is a hetereogeneous disorder, diagnosed subjectively on the basis of a large number of criteria. Recent research has investigated genetics, in utero insults and brain function as well as neurochemical and immunological factors. On the basis of family and twin studies, there appears to be a genetic basis for a wide "autistic syndrome." About a quarter of cases of autism are associated with genetic disorders such as fragile X syndrome or with infectious diseases such as congenital rubella. Genetic studies have shown an association between autism markers of brain development such as 3 markers of the c-Harvey-ros oncogene and the homeobox gene EN2. In some cases, autism is associated with insults early in gestation, including thalidomide embryopathy. Autism may arise from abnormal central nervous system functioning, since most autistic patients have indications of brain dysfunction, and about half of them have abnormal electroencephalograms. Similarly, the pattern of evoked response potentials and conduction time is altered in autistic children. There is substantial evidence from neuroimaging studies that dysfunctions in the cerebellum and possibly the temporal lobe and association cortex occur in autistic symptoms. Neurochemical studies have investigated the role of serotonin, epinephrine and norepinephrine, since levels of these neurotransmitters are altered in autism, although other hypotheses implicate overactive brain opioid systems and changes in oxytocin neurotransmission. Autoimmunity may also play a role; antibodies against myelin basic protein are often found in children with autism, who also have increased eosinophil and basophil response to IgE-mediated reactions. In summary, the prevailing view is that autism is caused by a pathophysiologic process arising from the interaction of an early environmental insult and a genetic predisposition.     

Cerebrospinal fluid and serum markers of inflammation in autism

Systemic immune abnormalities have no known relevance to brain dysfunction in autism. In order to find evidence for neuroinflammation, we compared levels of sensitive indicators of immune activation: quinolinic acid, neopterin, and biopterin, as well as multiple cytokines and cytokine receptors, in cerebrospinal fluid and serum from children with autism, to control subjects with other neurologic disorders. In cerebrospinal fluid from 12 children with autism, quinolinic acid (P = 0.037) and neopterin (P = 0.003) were decreased, and biopterin (P = 0.040) was elevated, compared with control subjects. In sera from 35 persons with autism, among cytokines, only tumor necrosis factor receptor II was elevated compared with controls (P < 0.02). Decreased quinolinic acid and neopterin in cerebrospinal fluid are paradoxical and suggest dysmaturation of metabolic pathways and absence of concurrent infection, respectively, in autism. Alternatively, they may be produced by microglia but remain localized and not expressed in cerebrospinal fluid.     

Skin Conductance Responses to Another Person’s Gaze in Children with Autism

The effects of another person’s gaze on physiological arousal were investigated by measuring skin conductance responses (SCR). Twelve able children with autism and 12 control children were shown face stimuli with straight gaze (eye contact) or averted gaze on a computer monitor. In children with autism, the responses to straight gaze were stronger than responses to averted gaze, whereas there was no difference in the responses to these gaze conditions in normally developing children. Thus, these results showed that eye gaze elicited differential pattern of SCR in normally developing children and in children with autism. It is possible that the enhanced arousal to eye contact may contribute to the abnormal gaze behaviour frequently reported in the context of autism.     

Identification of autoimmune gene signatures in autism

The role of the immune system in neuropsychiatric diseases, including autism spectrum disorder (ASD), has long been hypothesized. This hypothesis has mainly been supported by family cohort studies and the immunological abnormalities found in ASD patients, but had limited findings in genetic association testing. Two cross-disorder genetic association tests were performed on the genome-wide data sets of ASD and six autoimmune disorders. In the polygenic score test, we examined whether ASD risk alleles with low effect sizes work collectively in specific autoimmune disorders and show significant association statistics. In the genetic variation score test, we tested whether allele-specific associations between ASD and autoimmune disorders can be found using nominally significant single-nucleotide polymorphisms. In both tests, we found that ASD is probabilistically linked to ankylosing spondylitis (AS) and multiple sclerosis (MS). Association coefficients showed that ASD and AS were positively associated, meaning that autism susceptibility alleles may have a similar collective effect in AS. The association coefficients were negative between ASD and MS. Significant associations between ASD and two autoimmune disorders were identified. This genetic association supports the idea that specific immunological abnormalities may underlie the etiology of autism, at least in a number of cases.     

Emotional Responsivity in Children with Autism,Children with Other Developmental Disabilities,and Children with Typical Development

Twenty six children with autism, 24 children with developmental disabilities, and 15 typically developing children participated in tasks in which an adult displayed emotions. Child focus of attention, change in facial tone (i.e., hedonic tone), and latency to changes in tone were measured and summary scores of emotional contagion were created. Group differences existed in the ratio of episodes that resulted in emotional contagion. Correlations existed between measures of emotional contagion, measures of joint attention, and indices of severity of autism. Children with autism demonstrated muted changes in affect, but these responses occurred much less frequently than in comparison groups. The findings suggest directions for early identification and early treatment of autism.     

Immune therapy in autism: Historical experience and future directions with immunomodulatory therapy

Autism affects 1 in 110 new births, and it has no single etiology with uniform agreement. This has a significant impact on the quality of life for individuals who have been diagnosed with autism. Although autism has a spectrum quality with a shared diagnosis, it presents a uniquely different clinical appearance in each individual. Recent research of suspected immunological factors have provided more support for a probable immunological process or for processes that may play a role in the acquisition of an autistic condition. These factors include prenatal, genetic, and postnatal findings, as well as the discovery of a dysfunctional chronic pro-inflammatory state in brain tissue and cerebrospinal fluid in subsets of autistic patients. These findings offer new theories that may lead to the development of disease modification or preventative therapeutic options in the near future. This article reviews prenatal, genetic, and observed immune aspects of the autism condition that may be risk factors in the presentation of the autistic clinical phenotype. Historical immune interventions in autism are reviewed and potential new therapies and interventions are discussed.     

Winter day lengths enhance T lymphocyte phenotypes, inhibit cytokine responses, and attenuate behavioral symptoms of infection in laboratory rats

Annual variations in day length (photoperiod) trigger changes in the immune and reproductive system of seasonally-breeding animals. The purpose of this study was to determine whether photoperiodic changes in immunity depend on concurrent photoperiodic responses in the reproductive system, or whether immunological responses to photoperiod occur independent of reproductive responses. Here we report photoperiodic changes in enumerative, functional, and behavioral aspects of the immune system, and in immunomodulatory glucocorticoid secretion, in reproductively non-photoperiodic Wistar rats. T-cell numbers (CD3+, CD8+, CD8+CD25+, CD4+CD25+) were higher in the blood of rats housed in short as opposed to long-day lengths for 10 weeks. Following a simulated bacterial infection (Escherichia coli LPS; 125 microg/kg) the severity of several acute-phase sickness behaviors (anorexia, cachexia, neophobia, and social withdrawal) were attenuated in short days. LPS-stimulated IL-1beta and IL-6 production were comparable between photoperiods, but plasma TNFalpha was higher in long-day relative to short-day rats. In addition, corticosterone concentrations were higher in short-day relative to long-day rats. The data are consistent with the hypothesis that photoperiodic regulation of the immune system can occur entirely independently of photoperiodic regulation of the reproductive system. In the absence of concurrent reproductive responses, short days increase the numbers of leukocytes capable of immunosurveillance and inhibition of inflammatory responses, increase proinflammatory cytokine production, increase immunomodulatory glucocorticoid secretion, and ultimately attenuate behavioral responses to infection. Seasonal changes in the host immune system, endocrine system, and behavior may contribute to the seasonal variability in disease outcomes, even in reproductively non-photoperiodic mammals.     

Maternal antibrain antibodies in autism

Autism is a neurodevelopmental disorder of prenatal onset that is behaviorally defined. There is increasing evidence for systemic and neuroimmune mechanisms in children with autism. Although genetic factors are important, atypical prenatal maternal immune responses may also be linked to the pathogenesis of autism. We tested serum reactivity in 11 mothers and their autistic children, maternal controls, and several groups of control children, to prenatal, postnatal, and adult rat brain proteins, by immunoblotting. Similar patterns of reactivity to prenatal (gestational day 18), but not postnatal (day 8) or adult rat brain proteins were identified in autistic children, their mothers, and children with other neurodevelopmental disorders, and differed from mothers of normal children, normal siblings of children with autism and normal child controls. Specific patterns of antibody reactivity were present in sera from the autism mothers, from 2 to 18 years after the birth of their affected children and were unrelated to birth order. Immunoblotting using specific antigens for myelin basic protein (MBP) and glial acidic fibrillary protein (GFAP) suggests that these proteins were not targets of the maternal antibodies. The identification of specific serum antibodies in mothers of children with autism that recognize prenatally expressed brain antigens suggests that these autoantibodies could cross the placenta and alter fetal brain development.     

Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder

OBJECTIVES: Children with autism spectrum disorder (ASD) frequently reveal various gastrointestinal (GI) symptoms that may resolve with an elimination diet along with apparent improvement of some of the behavioral symptoms. Evidence suggests that ASD may be accompanied by aberrant (inflammatory) innate immune responses. This may predispose ASD children to sensitization to common dietary proteins (DP), leading to GI inflammation and aggravation of some behavioral symptoms. METHODS: We measured IFN-gamma, IL-5, and TNF-alpha production against representative DPs [gliadin, cow's milk protein (CMP), and soy] by peripheral blood mononuclear cells (PBMCs) from ASD and control children [those with DP intolerance (DPI), ASD siblings, and healthy unrelated children]. We evaluated the results in association with proinflammatory and counter-regulatory cytokine production with endotoxin (LPS), a microbial product of intestinal flora and a surrogate stimulant for innate immune responses. RESULTS: ASD PBMCs produced elevated IFN-gamma and TNF-alpha, but not IL-5 with common DPs at high frequency as observed in DPI PBMCs. ASD PBMCs revealed increased proinflammatory cytokine responses with LPS at high frequency with positive correlation between proinflammatory cytokine production with LPS and IFN-gamma and TNF-alpha production against DPs. Such correlation was less evident in DPI PBMCs. CONCLUSION: Immune reactivity to DPs may be associated with apparent DPI and GI inflammation in ASD children that may be partly associated with aberrant innate immune response against endotoxin, a product of the gut bacteria.     

Behavioral relationship between autism and fragile x syndrome

Previous researchers have reported autistic features in children with fragile X syndrome. We compared 21 children with pervasive developmental disorders (autism group) to 15 with fragile X syndrome on the Childhood Autism Rating Scale and the Reiss Scales for Children's Dual Diagnosis. The 7 children (47%) with fragile X who scored above the Childhood Autism Rating Scale cut-off (fragile X-autism group) were more impaired than the remaining children (fragile X-no autism) on Childhood Autism Rating Scale subscales related to emotion, visual and listening responses, and communication. The autism group's Reiss scores were higher than fragile X-no autism group, but not fragile X-autism group. Although the Childhood Autism Rating Scale identified almost 50% of children with fragile X as having autism, qualitative differences may exist in specific autistic-like behaviors between children with autism and children with fragile X.