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Immunological Findings in Autism
Abstract
This chapter discusses the immunopathogenesis of autism. Two main immune dysfunctions in autism are immune regulation involving pro-inflammatory cytokines and autoimmunity. Mercury and an infectious agent like the measles virus are currently two main candidate environmental-triggers for immune dysfunction in autism. Genetically immune dysfunction in autism involves the major histocompatibility complex (MHC) region, as this is an immunologic gene cluster whose gene products are class I, II, and III molecules. Class I and II molecules are associated with antigen presentation. The antigen in virus infection initiated by the virus particle itself, while the cytokine production and inflammatory mediators are due to the response to the putative antigen in question. Environmental exposure to mercury is believed to harm human health, possibly through modulation of immune homeostasis. A mercury link with the immune system has been postulated due to the involvement of postnatal exposure to thimerosal, a preservative added in the measles, mumps and rubella (MMR) vaccines.
... Autism spectrum disorder (ASD), a group of complex mu neurodevelopmental disorders occurring in the first 3 years of life, is characte wide and variable set of neuropsychiatric symptoms, including deficits communication, narrow and restricted interests, and repetitive behavior [7][8][9] adaptive immune response plays a major role in autism development is demon various early reports from authors in this field [10][11][12]. As early as 1982, is w that the immune system impacts cerebral function in autism, so immune dysreg this pathology is not a recent theory [10], as has been shown by several met immune mechanisms impacting cerebral function and the behavioral impairm in neuropsychiatry disorders [11,12]. ...
... Autism spectrum disorder (ASD), a group of complex mu neurodevelopmental disorders occurring in the first 3 years of life, is characte wide and variable set of neuropsychiatric symptoms, including deficits communication, narrow and restricted interests, and repetitive behavior [7][8][9] adaptive immune response plays a major role in autism development is demon various early reports from authors in this field [10][11][12]. As early as 1982, is w that the immune system impacts cerebral function in autism, so immune dysreg this pathology is not a recent theory [10], as has been shown by several met immune mechanisms impacting cerebral function and the behavioral impairm in neuropsychiatry disorders [11,12]. This review summarizes current state insights into immune dysfunction in ASD, with particular reference to the related immunological factors, including maternal influence regarding the risk development as well as comorbidities influencing the autism disease course. ...
... A relevant insight into ASD pathogenesis was achieved through cytokine studies on autistic brains, as well as several immune phenotypes derived from the studies of peripheral blood soluble factors that correlate with increased or/and severe behavioral impairments of the disorder [10]. In this context, it has been concluded that ASD may be linked to a disturbed immune balance involving both of the main dysregulations focused on pro-inflammatory mediators, as well as anti-inflammatory cytokines and autoimmunity [11]. ...
Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental disorders characterized by a wide and variable set of neuropsychiatric symptoms, including deficits in social communication, narrow and restricted interests, and repetitive behavior. The immune hypothesis is considered to be a major factor contributing to autism pathogenesis, as well as a way to explain the differences of the clinical phenotypes and comorbidities influencing disease course and severity. Evidence highlights a link between immune dysfunction and behavioral traits in autism from several types of evidence found in both cerebrospinal fluid and peripheral blood and their utility to identify autistic subgroups with specific immunophenotypes; underlying behavioral symptoms are also shown. This review summarizes current insights into immune dysfunction in ASD, with particular reference to the impact of immunological factors related to the maternal influence of autism development; comorbidities influencing autism disease course and severity; and others factors with particular relevance, including obesity. Finally, we described main elements of similarities between immunopathology overlapping neurodevelopmental and neurodegenerative disorders, taking as examples autism and Parkinson Disease, respectively.
... Also, the increased incidence of autoimmune illness in some autistic families is another indication of the autoimmune pathogenesis of autism [3,4]. Moreover, some autistic children may have increased lymphocytes with an imbalance in T-helper (Th) cell subsets, which could damage astrocytes and disrupt the blood-brain barrier (BBB) [5]. Th17 cells, a unique subset of effector CD4 + Th cells, can be protective in immunosurveillance and are harmful in autoimmune illness. ...
... Forty-eight pediatric subjects participated in the current study, they were divided into 24 pediatric patients with ASD and 24 age-and gender-matched controls. The median (IQR) age of the ASD patient group was 5.25 (5)(6)(7)(8) years and ranged from 3.5 to 14 years, while the median (IQR) age of the control group was 6 (5-9) years and ranged from 4 to 13 (p-value = 0.476). There was a male predominance in both ASD patient and control groups, with no significant difference between both groups (18 (75.0%) vs. 15 (62.5%); p-value = 0.350). ...
Background
Many neurodevelopmental abnormalities are connected to autism spectrum disorder (ASD), which can result in inflammation and elevated cytokine levels due to immune system dysregulation. Interleukin (IL)-17 A and IL-22 have been linked to the regulation of host defense against pathogens at the barrier surface, the regeneration of injured tissue, and the integration of the neurological, endocrine, and immune systems. Several studies have investigated the possible connection between IL-17 A and ASD as well as the severity of behavioral symptoms, but few of them included IL-22.
Objectives
To measure serum levels of interleukin (IL)-17 A and IL-22 in children with ASD and to investigate their association with disease severity.
Methods
This pilot study was performed on 24 children with ASD and 24 matched controls. Childhood Autism Rating Scale (CARS) assessed ASD severity, and serum levels of IL-17 A and IL-22 were assessed by enzyme-linked immunosorbent assay (ELISA).
Results
In ASD patients, serum levels of IL-17 A and IL-22 showed a significant increase compared to controls (p-values < 0.001). We compared serum levels of IL-17 A and IL-22 according to the severity categories by CARS and could not find any significant differences (p-values > 0.05). Only IL-22 had a significant positive correlation with ASD severity by CARS scores.
Conclusions
Raised serum levels of IL-17 A and IL-22 are associated with ASD; only IL-22, not IL-17 A, is correlated with ASD severity. This finding proposes IL-22 as a possible future effective target for ASD treatment. To fully comprehend the significance of these cytokines in ASD and their possible effects on ASD diagnosis and treatment, more research on a wider scale is required.
... The Mean (SD) values of total SRS scores of all the ASD, severe and mild-to-moderate ASD categories were found to be 119 (44), 134 (43) and 102 (39), respectively, which are considered severe and are strongly linked with a clinical diagnosis of ASD. Also, the SSP measured sensory processing dysfunction and showed a mean (SD) score of 153 (29) in children with ASD ( Figure 1). ...
... [36][37][38] These results advised immune system alterations, which may involve neuroinflammation and possible neurotransmitter imbalances in ASD. 39 Despite extensive research, the pathogenic mechanism of ASD has not been explained yet. It was assumed that mitochondrial dysfunction, oxidative stress, abnormal protein folding and apoptotic mechanisms might be reasons for neurodegeneration in relationship with neuroinflammatory mechanisms, which could stimulate the cascade of incidents leading to ASD. 15 Moreover, the link between neuroinflammation, mast cell activation and seizures through the secretion of pro-inflammatory mediators and regulation of the blood-brain barrier (BBB) permeability was also proposed. ...
Background
Converging lines of evidence confirmed neuroinflammation’s role in autism spectrum disorder (ASD) etiological pathway. A disintegrin and metalloproteinase 8 (ADAM8) play major roles in inflammatory and allergic processes in various diseases.
Aim
This study aimed to investigate ADAM8 plasma levels in autistic children compared to healthy controls. Also, to discover the association between ADAM8, disease severity, and neuroinflammation in ASD.
Methodology
This case–control study included children with ASD (n=40) and aged-matched healthy controls (n=40). The plasma levels of the ADAM 8 were determined using enzyme-linked immunosorbent assay (ELISA). The assessment of ASD severity and social and sensory behaviors were categorized as mild, moderate and severe. Correlations among ADAM8 plasma levels and ASD severity scores [Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS) and Short Sensory Profile (SSP)] were obtained by Spearman correlation coefficient (r).
Results
ASD children (n=40), including severe autism (n=21) and mild-to-moderate autism (n=19), showed significantly (p ≤ 0.05) lower plasma levels of ADAM8 [4683 (2885–5229); 4663 (4060–5000); 4632 (2885–5229)], respectively, than those of healthy controls [5000 (4047–5000)] [median (IQR) pg/mL]. However, there was no significant difference between the ADAM8 levels of children with severe and mild-to-moderate autism (p = 0.71). Moreover, ADAM8 plasma levels were not significantly correlated with the severity of ASD measured by behavioral scales [CARS (r= −0.11, p=0.55), SRS (r=0.11, p= 0.95), SSP (r=−0.23, p=0.23)].
Conclusion
The low ADAM8 plasma levels in children with ASD possibly indicated that ADAM8 might be implicated in the pathogenesis of ASD but not in the severity of the disease. These results should be interpreted with caution until additional studies are carried out with larger populations to decide whether the reduction in plasma ADAM8 levels is a mere consequence of ASD or if it plays a pathogenic role in the disease.
... This function is vital for providing energy to carry out various cellular processes that may be relevant to ASD. Because ASD is a severe neurodegenerative syndrome [42,68], we performed a KEGG pathway enrichment analysis, which revealed enrichment in the neurodegeneration pathways. In addition, our gene list showed enrichment in the Huntington's disease pathway, suggesting a potential connection between this neurodegenerative disease and ASD [67]. ...
... Additionally, we conducted a pathway enrichment analysis on Reactome [42] and identified enrichment in 'MHC Class II Antigen Presentation' (R-HSA-2132295). This pathway is a part of 'Adaptive Immune System (Homo sapiens)' (R-HSA-1280218) pathway, and previous research has highlighted the significant role of the adaptive immune response in the development of autism [18,68]. Our comprehensive enrichment analysis revealed that our candidate genes exhibit significant associations with mitochondrial function, the negative regulation of macromolecule biosynthesis, cell-matrix adhesion, protein kinase binding, neurodegeneration pathways, and immune system involvement, emphasizing their potential relevance to ASD. ...
Identifying genes associated with autism spectrum disorder (ASD) is crucial for understanding the underlying mechanisms of the disorder. However, ASD is a complex condition involving multiple mechanisms, and this has resulted in an unclear understanding of the disease and a lack of precise knowledge concerning the genes associated with ASD. To address these challenges, we conducted a systematic analysis that integrated multiple data sources, including associations among ASD-associated genes and gene expression data from ASD studies. With these data, we generated both a gene embedding profile that captured the complex relationships between genes and a differential gene expression profile (built from the gene expression data). We utilized the XGBoost classifier and leveraged these profiles to identify novel ASD associations. This approach revealed 10,848 potential gene–gene associations and inferred 125 candidate genes, with DNA Topoisomerase I, ATP Synthase F1 Subunit Gamma, and Neuronal Calcium Sensor 1 being the top three candidates. We conducted a statistical analysis to assess the relevance of candidate genes to specific functions and pathways. Additionally, we identified sub-networks within the candidate network to uncover sub-groups of associations that could facilitate the identification of potential ASD-related genes. Overall, our systematic analysis, which integrated multiple data sources, represents a significant step towards unraveling the complexities of ASD. By combining network-based gene associations, gene expression data, and machine learning, we contribute to ASD research and facilitate the discovery of new targets for molecularly targeted therapies.
... Different autoimmune 13 disorders were reported in ASD patients such as T reg-14 ulatory cell defects [4][5][6], IgA deficiency, suppressed 15 cellular immune system through reduction in induced 16 lymphocytes and decreased activity of natural killer 17 cells [6,7]. In this regards, one of the suggested en- 18 vironmental causes of ASD is viral infection during 19 pregnancy or early infancy [8,9]. Since the central ner-20 Rubella infection and ASD [10]. ...
... The development of brain is strongly influenced by 160 immune system and it is showed that dysregulation of 161 neuroendocrine pathways due to immune defects may 162 lead to behavioral disorders [17]. In particular, recently 163 increasing amount of evidence indicate that aberrant 164 immune functions in ASD patients such as reduced 165 number of lymphocytes and natural killer cells [7], ab-166 normal cytokine profiles, imbalance level of serum im-167 munoglobulins [18] and also, the association between 168 autism and immune-related genes include complement 169 C4 alleles and human leukocyte antigen (HLA) [19] 170 may cause neurological manifestations of ASD espe-171 cially if they occurred during critical neurodevelop-172 mental periods of pregnancy and early infancy [20]. ...
Autism is a neurodevelopmental disease that manifested by a wide range of behavioral disorders. Although the etiology of autism is remained unknown but it is suggested that ASD have a complex etiology, including genetic and environmental factors, which may explain the observed different behavioral disorders in these patients. One of the proposed reasons for autism is viral infection in the early stages of development. The mechanism by which viral infection could lead to autism is still unclear.Previous studiesemphasized on the role of family membersof Herpesviruses in autism susceptibility. In this study, anti-Cytomegalovirus (CMV) and anti-Epstein-Barr virus (EBV) antibodies in the serum of 45 children with autism and 45 healthy individuals were evaluated. Serum samples were isolated from 5 ml blood of the patients and controls. Sandwich ELISA was used to quantitatively measure antibodies against the mentioned viruses. Results analyzed by SPSS software showed an increased amount of anti-CMV IgG and IgM antibodies in the blood of patients with Autism but not statistically significant (P< 0.05). The anti-EBV IgM antibody in the blood of patients with Autism was not only increased but also statistically significant (P< 0.05), however, the IgG level against EBV in the serum of ASD patients showed no significant difference in comparison to healthy controls. So it can be said that although the mechanisms of viral infection in autism is unknown, but probably EBV infection is associated with an increased risk of autism.
... Research data also indicate decreases in the glutathione/oxidized glutathione ratio and redox antioxidant capacity, and the increased oxidative stress in the brain of patients with autism may have consequences such as chronic inflammation and increases in mitochondrial superoxide production, protein oxidation and DNA damage [12,13]. Inflammatory and immune dysfunction includes elevated brain-specific antibodies against neuron-axon filament protein (NAFP) and glial fibrillary acidic protein (GFAP) [14], as well as chronic microglial activation that may mediate the dysfunction of glutamatergic excitatory receptors [15], increases in the levels of TGFB1, TNFA, IL-6 and IL-17 and other inflammatory cytokines [16][17][18], and down-regulation of IL-2 in the blood cells of patients with autism [19]. Interestingly, while TNFα, inhibits methionine synthase (MTR) expression in cultured neuronal cells, and MTR expression is very high in the postmortem brains of normal individuals in early developmental periods (but decreases as age increases), in patients with autism not only is its early life peak absent but also a lifelong decrease in MTR expression is observed compared to the control subjects [20]. ...
Excessive inflammatory reactions and oxidative stress are well-recognized molecular findings in autism and these processes can affect or be affected by the epigenetic landscape. Nonetheless, adequate therapeutics are unavailable, as patient-specific brain molecular markers for individualized therapies remain challenging. Methods: We used iPSC-derived neurons and astrocytes of patients with autism vs. controls (5/group) to examine whether they replicate the postmortem brain expression/epigenetic alterations of autism. Additionally, DNA methylation of 10 postmortem brain samples (5/group) was analyzed for genes affected in PSC-derived cells. Results: We found hyperexpression of TGFB1, TGFB2, IL6 and IFI16 and decreased expression of HAP1, SIRT1, NURR1, RELN, GPX1, EN2, SLC1A2 and SLC1A3 in the astrocytes of patients with autism, along with DNA hypomethylation of TGFB2, IL6, TNFA and EN2 gene promoters and a decrease in HAP1 promoter 5-hydroxymethylation in the astrocytes of patients with autism. In neurons, HAP1 and IL6 expression trended alike. While HAP1 promoter was hypermethylated in neurons, IFI16 and SLC1A3 promoters were hypomethylated and TGFB2 exhibited increased promoter 5-hydroxymethlation. We also found a reduction in neuronal arborization, spine size, growth rate, and migration, but increased astrocyte size and a reduced growth rate in autism. In postmortem brain samples, we found DNA hypomethylation of TGFB2 and IFI16 promoter regions, but DNA hypermethylation of HAP1 and SLC1A2 promoters in autism. Conclusion: Autism-associated expression/epigenetic alterations in iPSC-derived cells replicated those reported in the literature, making them appropriate surrogates to study disease pathogenesis or patient-specific therapeutics.
... Such antigens may be produced in the generation of autoimmune reactions via the activation of inflammatory cells in hereditarily vulnerable subjects. 47 Possible neuroimmune mechanism leading development of autism was described previously. 48 According to this hypothesis during prenatal period, the body is exposed to infectious agents, which mimic neuron-specific antigens. ...
“Autism spectrum disorder (ASD) is complex neurodevelopmental disorder characterized by impairments in three core behavioral: social deficits, impaired communication, and repetitive behaviors.” There is developing indication and emerging data that irregular autoimmune responses to the central nervous system may play a pathogenic role in patients with autism spectrum disorder.”
The aim of this review was to discuss the updated research carried out at Autism research and treatment center, King Saud University, Riyadh, Kingdom of Saudi Arabia particularly on the role of autoimmunity in Autism spectrum disorder. This review also present state of information available about the role of autoimmunity biomarkers involved in the neuronal damage of central nervous system in autistic children. The systematic literature search was carried out using Google Scholar, Science direct and PubMed databases on the role of autoimmunity in autism and reviewed all relevant articles published in peer reviewed journals by Autism research and treatment center, King Saud University, Riyadh, Kingdom of Saudi Arabia till April, 2022. We searched relevant articles using key words Autism spectrum disorder, Autoimmunity, Neuroinflamation and Central nervous system. This review revealed that plasma levels of autoimmunity related factors/ markers were altered in patients with autism. Significant change in blood markers in subjects with ASD may resulted in several years of decreased neutrotrophic support along with increasing impairment in relationship with down-regulated inflammation that may play a role in the ASD.
Overall, the role of autoimmunity in ASD subjects with excess of anti-brain antibodies suggest that in some patients, autoantibodies that target the CNS may be pathological factor in neuronal growth in autistic children. Large cohort studies with well-defined and specially pheno typed autistic groups and matched healthy controls are required to examine the role of autoantibodies in the pathology of subjects with ASD.
... This finding reflects the large representation of Egypt in global studies on developmental disabilities, as highlighted by Carollo et al. (2021b). The research interest of the citing documents stems from relevant (cited) works that have previously explored the theme of autoimmunity in children with ASD/developmental disorders and in their families (e.g., Vojdani et al. (2003), Sweeten et al. (2003) and Mostafa and Kitchener (2009) with a frequency = 2, Cohly and Panja (2005) with a frequency = 4). Altogether, considering the presence of brain antibodies in children with ASD and the high incidence of autoimmune diseases among their parents (e.g., Sweeten et al. (2003) and Mostafa and Kitchener (2009)), citing and cited documents discuss the potential pathogenic role of autoimmunity in some children with ASD. ...
Background:
Developmental disabilities are disproportionately more investigated in higher-income countries. However, global prevalence of developmental disabilities indicate that a large proportion of individuals with disabilities reside in low- and middle-income nations.
Aims:
The present work therefore aims to conduct a scientometric review to survey available literature on developmental disabilities in low- and middle-income countries belonging to the continent of Africa.
Methods and procedures:
A literature search was conducted on Scopus, where a total of 1720 relevant publications (and an accompanying 66 thousand references) were found, representing research conducted between 1950 to 2022. Then, document co-citation analysis was performed to chart significant co-citation relationships between relevant articles and their cited references.
Outcomes and results:
The generated network based on document co-citation analysis revealed a total of 14 distinct thematic research clusters and 12 significant documents that have been frequently cited in the literature on developmental disabilities in Africa.
Conclusions and implications:
The scientometric review revealed a trend of broadening research towards systems of care, away from a medical model of disease. It is projected that future research will continue to capitalise on inter-disciplinary strengths to arrive at a more nuanced understanding of developmental disability from all levels - individuals, families, to communities.
... The neurological origin of ASD is largely unknown, increasing evidence suggested that it can be instigated by a range of factors including autoimmunity (Al-Ayadhi and Cohly and Panja, 2005). However, the connection between neuro-inflammation and autoimmunity needs to be investigated. ...
This study aimed to explore the effect of auditory integration therapy (AIT) on the forkhead box J1 protein and assessed its impact on behavioral, social, and sensory symptoms in children with autism. Behavioral, social, and sensory scores were calculated for each child using the childhood autism rating scale, social responsiveness scale, and short sensory profile before and after AIT. The plasma level of Foxj1 was [575 (351-2553) pg/mL] [median (interquartile range)] before AIT. This level did not change significantly (p˃0.05) immediately [1143(336-4599)], after one month [1268 (275-4932)], or three months [1058 (184-3462)] AIT. However, results revealed that behavioral, social, and sensory rating scales were improved after AIT. Pearson correlation (r) values before and after AIT between severity variables were calculated. Unchanged plasma levels of Foxj1 after AIT supported the non-therapeutic effect of AIT on Foxj1 in autistic children. A significant change in behavioral, social, and sensory symptoms was noticed in autistic children. Additional research, on a large population, is necessary to assess AIT's impact on behavioral and social changes in children with an autism spectrum disorder.
... The major histocompatibility complex (MHC) region is a complex genomic system localized on chromosome 6p21.3p22.1. It encompasses the human leukocyte antigen (HLA) gene cluster, that has important biological roles in immune system activity, as well as in neurodevelopment and neuroplasticity (41,(95)(96)(97)(98). HLA cluster is one of the most polymorphic regions in the human genome and includes three distinct functional classes annotated from I to III. ...
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by communication and social interaction deficits, and by restricted interests and stereotyped, repetitive behavior patterns. ASD has a strong genetic component and a complex architecture characterized by the interplay of rare and common genetic variants. Recently, increasing evidence suggest a significant contribution of immune system dysregulation in ASD. The present paper reviews the latest updates regarding the altered immune landscape of this complex disorder highlighting areas with potential for biomarkers discovery as well as personalization of therapeutic approaches. Cross-talk between the central nervous system and immune system has long been envisaged and recent evidence brings insights into the pathways connecting the brain to the immune system. Disturbance of cytokine levels plays an important role in the establishment of a neuroinflammatory milieu in ASD. Several other immune molecules involved in antigen presentation and inflammatory cellular phenotypes are also at play in ASD. Maternal immune activation, the presence of brain-reactive antibodies and autoimmunity are other potential prenatal and postnatal contributors to ASD pathophysiology. The molecular players involved in oxidative-stress response and mitochondrial system function, are discussed as contributors to the pro-inflammatory pattern. The gastrointestinal inflammation pathways proposed to play a role in ASD are also discussed. Moreover, the body of evidence regarding some of the genetic factors linked to the immune system dysregulation is reviewed and discussed. Last, but not least, the epigenetic traits and their interactions with the immune system are reviewed as an expanding field in ASD research. Understanding the immune-mediated pathways that influence brain development and function, metabolism, and intestinal homeostasis, may lead to the identification of robust diagnostic or predictive biomarkers for ASD individuals. Thus, novel therapeutic approaches could be developed, ultimately aiming to improve their quality of life.
... 25) In addition, the immune and inflammatory system has been implicated in the pathogenesis of ADHD 26) and other psychiatric disorders such as autism. 27) Polymorphisms in IL10 may be involved in increased risk for major depressive disorder. 28) On the other hand, SLC5A9 is a sodium-dependent transport channel of D-mannose, D-glucose, and D-fructose; its role in the pathogenesis of ADHD remains unclear. ...
Objectives:
The molecular mechanisms underlying attention-deficit hyperactivity disorder (ADHD) remain unclear. Therefore, this study aimed to identify the genetic susceptibility loci for ADHD in Korean children with ADHD. We performed a case-control and a family-based genome-wide association study (GWAS), as well as genome-wide quantitative trait locus (QTL) analyses, for two symptom traits.
Methods:
A total of 135 subjects (71 cases and 64 controls), for the case-control analysis, and 54 subjects (27 probands and 27 unaffected siblings), for the family-based analysis, were included.
Results:
The genome-wide QTL analysis identified four single nucleotide polymorphisms (SNPs) (rs7684645 near APELA, rs12538843 near YAE1D1 and POU6F2, rs11074258 near MCTP2, and rs34396552 near CIDEA) that were significantly associated with the number of inattention symptoms in ADHD. These SNPs showed possible association with ADHD in the family-based GWAS, and with hyperactivity-impulsivity in genome-wide QTL analyses. Moreover, association signals in the family-based QTL analysis for the number of inattention symptoms were clustered near genes IL10, IL19, SCL5A9, and SKINTL.
Conclusion:
We have identified four QTLs with genome-wide significance and several promising candidates that could potentially be associated with ADHD (CXCR4, UPF1, SETD5, NALCN-AS1, ERC1, SOX2-OT, FGFR2, ANO4, and TBL1XR1). Further replication studies with larger sample sizes are needed.
... Some children with ASD have secondary symptoms caused by the accumulation of psychological stress, such as insomnia, depression and anxiety [2,3], and a high proportion of them show aggressive behaviors, self-mutilation behaviors and pica [4]. On the other hand, factors associated with encephalopathy in ASD, such as autoimmune disorders, inflammatory changes in the brain and mitochondrial dysfunction, have been reported, and oxidative stress is assumed to be enhanced in these conditions [5][6][7]. At present, ASD is diagnosed and evaluated according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5) criteria, but there are no objective/biological test criteria. ...
There are several studies on oxidative stress of Autism Spectrum Disorder (ASD), but in these cases there is no study to measure oxidative stress and antioxidant capacity at the same time or studies considering childhood development. Therefore, this study comprehensively assessed the level of oxidative stress in ASD children by simultaneously measuring reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP). The subjects were Japanese, 77 typical development (TD) children, 98 ASD children, samples were plasma. The subjects were divided into age groups: toddlers/preschool age (2–6 years) and school age (7–15 years), to compare the relationships among the d-ROMs levels and BAP/d-ROMs ratios. Furthermore, the correlations between the Parent-interview ASD Rating Scales (PARS) scores and the measured values were analyzed. The levels of d-ROMs were significantly higher in the ASD (7–15 years) than in TD (7–15 years). The PARS scores were significantly higher in the ASD and were significantly correlated with d-ROMs levels. These results suggested that d-ROMs and BAP/d-ROMs ratios could be objective, measured indicators that could be used in clinical practice to assess stress in ASD children.
... In the serum of patients with ASD, along with dramatic increase of MMR antibodies, autoantibodies to brain tissue such as MBP and neuron-axon filament protein are also elevated (Singh et al., 1998, Kozlovskaia et al., 2000. This raised the hypothesis that virus-induced autoimmunity may be a cause of ASD (Cohly & Panja, 2005). A potential mechanism is that following virus infection, antigen-presenting cells can be stimulated and trigger Th1 lymphocyte activation, which would produce interferon-γ leading to altered cell permeability in the bloodbrain barrier (BBB) (Neumann, Cavalie, Jenne, & Wekerle, 1995). ...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1.7 % of US pediatric population, with a growing prevalence world-wide. Autoimmunity is one of potential pathogenic factors for ASD, which is attracting much attention and undergoing extensive investigations. For more than a decade, many groups have been studying the association between autoantibodies and ASD. Although several narrative reviews have been published on autoantibodies and ASD, no systematic review or meta-analysis has been performed. In this study, we conducted the first systematic review and evaluated available evidence for the association between ASD and major autoantibodies to identifiable antigens, together with a broader discussion of autoantibodies with no identifiable antigens. The goal is to examine studies of pediatric subjects specifically and overall, we found that children with ASD expressed trends of higher levels of antibodies reactive to folate receptor α autoantibody, anti-myelin basic protein antibodies, anti-myelin-associated glycoprotein antibodies, anti-ribosomal P protein antibodies, anti-endothelial cell antibodies, and anti-nuclear antibody, compared to healthy controls. However, the quality of evidence is low across the board because most studies were small and many did not include comparison controls. In addition, we were not able to perform a meta-analysis due to large between-study heterogeneity or lack of quantitative measures in most studies. Finally, we discussed future directions for the development of diagnostic guidelines and therapeutic targets for possible autoimmune-mediated ASD subtypes.
... Increased TNF-α level has direct effects on neural tissue function in the CNS (Ashwood, Nguyen, Hessl, Hagerman, & Tassone, 2010). Elevated expression of inflammatory cytokines is also associated with neurotransmitter imbalances in patients with ASD (Cohly & Panja, 2005). Our data revealed that increased numbers of IFN-γproducing CCR6 + cells were observed in children with ASD. ...
... Maternal antibodies may trigger autism as a mechanism of autoimmunity. MMR vaccination may increase risk for autism via an autoimmune mechanism in autism [81]. Epidemiological studies have shown a relationship with maternal immune disturbances during pregnancy and ASD. ...
... Moreover the child's lack of social empathy may cause many misunderstandings and conflicts in their family life. Several studies report that rigid, oppositional and aggressive behaviours are highly prevalent, as is the overlap with ADHD, sleeping and eating 8,9,10 disorders . Therefore, one may understand that parents experience the rearing of a child with ASD as tremendously burdening making them more vulnerable to develop a depression or an anxiety 11,12 disorder . ...
Background: Many parents experienced considerable problems combining daily activities withcare, had financial problems or suffered from depressive mood in raising child with autism.Aim:To assess the parents experiences in raising a child with ASD.Material and method:Questionnaire, a scale composed of 10 items relating to core and behavioral symptoms of autism and quality of life of parents. Result: Findings revealed that parentswho have a child with autism experienced multiple challenges in different aspects of care, impacting onparents’ stress and adaptation.Conclusion:The burden on parents of raising a child with ASD is too high. Outreaching professionals who provide practical assistance are most highly valued.
... Finally, cell-mediated immunity is impaired in ASD, as shown by low numbers of CD4 cells and associated T-cell polarity with an imbalance of Th1/Th2 subsets toward Th2 (Filiano et al., 2015). Deviations in the level of natural killer (NK) cells and macrophages have been observed in individuals with autism compared to controls (Cohly and Panja, 2005;Vojdani et al., 2008). Taken together these studies suggest that immune system abnormalities are prevalent in ASD patients. ...
Currently, 1 out of every 59 children in the United States is diagnosed with autism. While initial research to find the possible causes for autism were mostly focused on the genome, more recent studies indicate a significant role for epigenetic regulation of gene expression and the microbiome. In this review article, we examine the connections between early disruption of the developing microbiome and gastrointestinal tract function, with particular regard to susceptibility to autism. The biological mechanisms that accompany individuals with autism are reviewed in this manuscript including immune system dysregulation, inflammation, oxidative stress, metabolic and methylation abnormalities as well as gastrointestinal distress. We propose that these autism-associated biological mechanisms may be caused and/or sustained by dysbiosis, an alteration to the composition of resident commensal communities relative to the community found in healthy individuals and its redox and epigenetic consequences, changes that in part can be due to early use and over-use of antibiotics across generations. Further studies are warranted to clarify the contribution of oxidative stress and gut microbiome in the pathophysiology of autism. A better understanding of the microbiome and gastrointestinal tract in relation to autism will provide promising new opportunities to develop novel treatment modalities.
... Oxidative stress during developmental stages majorly affects the functions of brain and disturbing the time of brain development. [5][6] Environmental factors have major contribution in the development of autism, which includes mercury, lead, measles, rubella virus, retinoic acid, maternal thalidomide, valproic acid. These teratogens enter the fetus brain and disturb the brain development by oxidative stress. ...
The present research work is aimed to investigate the anti-oxidant/neuroprotective role of Resveratrol in reversing the valproic acid induced autism in postnatal swiss albino mice. Separate 13 day old/ Post natal day (PND) 13 swiss albino mice of either sex into 5 groups, each group consists of six mice of either sex, groups namely Group I - Control, Group II - Resveratrol, Group III - Negative control, Group IV and V - Resveratrol treatment groups. On PND 14 administer single dose of Valproic acid (VPA) or Sodium Valproate (400 mg/kg, subcutaneously) to III, IV and V groups to induce autism. Treatment is given in two doses 10 mg/kg, intraperitoneally (i.p) as Low dose and 40 mg/kg, i.p as High dose from the 13th day to the end of study. Assessment of autism is done by different behavioral screening methods during PND 14 to 40. Treatment with resveratrol significantly decline the autism symptoms compared with negative control. At the end of study on PND 41 all the animals were sacrificed to assess the biochemical estimations like Anticholinesterase enzyme, Total Protein, antioxidant enzyme (Catalase, Superoxide and Glutathione) activity and cerebellar histopathological examination. Treatment with Resveratrol has shown a significant beneficial difference on behavioral alterations, oxidative markers, neurotransmitters, and restoration of the altered purkinje cells of autism. This research work we conclude that resvertrol have a potent anti-oxidant, neuroprotective, anxiolytic, learning and memory enhancing agent against valproic acid induced autism.
... A strong immune system requires sufficiently long telomeres, as an effective immune response relies on the ability of naϊve lymphocytes to undergo massive cell divisions [113,114]. The most prevailing opinion is that autism is a neuro-immune disorder [115,116]. So, there is one more correlation between fast growth, autism, immune system and telomere attrition. ...
... Recently, evaluation of the activity of alpha-N-acetylgalactosaminidase (Nagalase) has been made commercially available as a diagnostic laboratory measurement. It is a nonspecific biomarker, which appears to be an important indicator of secondary immunosuppression [21,22] (Figure 3). ...
... 185,186 In addition, LPS acts at the luminal surface of the brain microvascular endothelial cell monolayer, which induces abluminal secretion of cytokines and other factors that in turn act on pericytes; the pericytes then secrete substances that enhance viral transcytosis across the BBB. 187 Therefore, BBB breakdown may precede, accelerate, exacerbate or contribute to chronic disease processes in neurodegenerative disorders including ASD. [188][189][190] 6. Autoimmunity and/or Neuroautoimmunity Autoimmunity to brain tissue has been detected in a subgroup of children with ASD and the possible pathogenic role of these antibodies in autism has been discussed 5, [191][192][193][194][195] . ...
In this article, we aim to illustrate the various possible mechanisms that play a role in the multi-faceted neuroinflammation seen in Autism Spectrum Disorders, which involve the gastrointestinal, immune and nervous systems. As with other environmentally-induced autoimmune disorders, autism is a combination of genetic susceptibility, environmental
triggers and barrier dysfunction. The pathogenesis of autism can take many avenues, from gut dysbiosis, to loss of intestinal barrier integrity, to systemic inflammation, to breach of the blood-brain barrier, to neuroinflammation and neuroautoimmunity. The gut-brain axis has been shown to play an important role in the induction of neuroautoimmune disorders. The connective inter-relation between gut and brain means that dysfunctions or damage to the intestinal barrier or blood-brain barrier can seriously affect one or the other. Environmental triggers actually begin their assault while someone is still in the
womb; studies have shown that the efficiency of a person’s immune system or his susceptibility to autoimmune disease can be affected by prenatal conditions, maternal exposures, and continuing exposure throughout a person’s lifetime. Toxic chemicals abound in all aspects of existence, from food to medication to packaging to pollution. Individuals may be immune-reactive to particular chemicals bound to human tissue or food proteins. Infections can affect the immune system and breach the immune barriers. The triggering factors may also bind to human tissue, including neural tissue, causing tissue reactivity and neuroautoimmunity. By understanding the mechanisms by which these environmental triggers lead to neuroautoimmunity, clinicians may be able to identify the triggers, remove them from a patient’s environment, and devise protocols to repair the barriers and improve the patient’s health.
... The sustained neuroinflammation, for example, is capable of altering membrane expression of neurotransmitter receptors, glutamate and GABA and, consequently, impairing spatial learning, cognitive and motor functions by altering neurotransmission [5]. Therefore, neuroinflammation seems to be involved in different neurodegenerative diseases [4] and psychiatric disorders including autism, schizophrenia, and major depression [6][7][8]. Also, as will be better explained ahead, altered neurotransmission appears to be related to several neurological diseases such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), depression, and schizophrenia, which exhibit alterations of one or more neurotransmitters and either their absence or their excess may result in a pathological situation. ...
Some classical psychiatric disorders, such as schizophrenia, autism, major depression, bipolar and obsessive‐compulsive disorders, have been related to neuroinflammatory process, immunological abnormalities, and neurotransmission impairment beyond genetic mutations. Neuroinflammation is mostly regulated by glial cells, which respond to physiological and pathological stimuli by anti‐ and pro‐inflammatory cytokine and chemokine signaling; moreover, recent studies have indicated that glial cells also respond to the neurotransmitters. Neurotransmitters regulate many biological processes, such as cell proliferation and synaptogenesis, which contribute to the formation of functional circuits. Alterations in the neurotransmission can lead to many pathological changes that occur in brain disorders. For example, studies have shown that neuroinflammation can alter the metabolism of glutamate as well as the function of its transporters, resulting in cognitive, behavioral, and psychiatric impairments. Cytokines as IL‐1β and IL‐6 appear to have an important influence in the dopaminergic and serotoninergic neurons. These data together suggest that glial cells via cytokines and abnormal regulation of neurotransmitters can influence psychiatric disorders. The present knowledge about this issue does not allow answering whether neuroinflammation is the cause or the consequence of neurotransmission imbalance and emphasizes the importance to improve in vivo imaging methods and models to elucidate this enigma.
... Recent studies have provided increasing evidence that immunological factors, particularly pro-inflammatory ones, may play an important role in the etiology of autism [9][10][11][12] and indicate that abnormalities in the innate immune system could be a predominant feature of ASD. Cytokines as a broad category of small proteins secreted from immune cells like macrophages and T lymphocytes are critical mediators of the immune response. ...
Recent studies have suggested that the etiology of Autism Spectrum Disorder (ASD) may be caused by immunological factors, particularly abnormalities in the innate immune system. However, it is still unclear which specific cytokines may be of most importance. The current study therefore investigated which cytokines showed altered concentrations in blood in ASD compared with healthy control children and which were also correlated with symptom severity. Our study sample included 32 children diagnosed with ASD and 28 age and sex-matched typically developing children. Autism symptoms were measured using the Autistic Behavior Checklist (ABC) and blood samples were taken from all subjects. We used Milliplex cytokine kits to determine serum concentrations of 11 Th1, Th2 and Th17 related cytokines. Additionally, expression of THRIL (TNFα and hnRNPL related immunoregulatory LincRNA), a long non-coding RNA involved in the regulation of tumor necrosis factor- α (TNF-α), was determined using real-time PCR. Of the 11 cytokines measured only concentrations of TNF-α (p=0.002), IL-1β (p=0.02) and IL-17a (p=0.049) were significantly increased in ASD children compared to typically developing controls, but only TNF-α concentrations were positively correlated with severity of ASD symptoms on all 5 different ABC sub-scales and were predictive of an ASD phenotype (area under the curve = 0.74). Furthermore, THRIL RNA expression was significantly decreased in ASD children. Our results provide further support for altered innate immunity being an important autism pathogenic factor, with autistic children showing increased blood TNF-α concentrations associated with symptom severity, and decreased expression of the THRIL gene involved in regulating TNF-α.
... It is highlighted that these disorders have similar genetic and biological points and these are likely to be frequently seen in the same person. 7,8 The role of U-II in the pathophysiology of neuropsychiatric disorders is inspiring interest in recent years. Urotensin-II (U-II) is a cyclic undecapeptide first isolated in 1969 from the caudal neurosecretory system of a fish. ...
... Other studies have shown that children with autism exhibit immune system abnormalities, in particular for antibodies against brain and central nervous system proteins, as well as against maternal proteins [18][19][20][21][22][23][24][25], and increased plasma pro-inflammatory cytokine levels [26,27]. The relationship of serum anti-neuronal antibodies and increased autism severity has been demonstrated [28]. ...
Several studies highlight a key involvement of endocannabinoid (EC) system in autism pathophysiology. The EC system is a complex network of lipid signaling pathways comprised of arachidonic acid-derived compounds (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. In addition to autism, the EC system is also involved in several other psychiatric disorders (i.e., anxiety, major depression, bipolar disorder and schizophrenia). This system is a key regulator of metabolic and cellular pathways involved in autism, such as food intake, energy metabolism and immune system control. Early studies in autism animal models have demonstrated alterations in the brain’s EC system. Autism is also characterized by immune system dysregulation. This alteration includes differential monocyte and macrophage responses, and abnormal cytokine and T cell levels. EC system dysfunction in a monocyte and macrophagic cellular model of autism has been demonstrated by showing that the mRNA and protein for CB2 receptor and EC enzymes were significantly dysregulated, further indicating the involvement of the EC system in autism-associated immunological disruptions. Taken together, these new findings offer a novel perspective in autism research and indicate that the EC system could represent a novel target option for autism pharmacotherapy.
... In autistic children, there are increased autoantibodies against specific dietary peptides, bacterial antigens, mercury 8,9 and also against brain proteins eg., anti-myelin-associated glycoprotein antibodies 10 and antinucleosome antibodies 6 . In response, oxidative stress 11-13 , increased cytokine production and inflammation [14][15][16] are detected in brain and serum of autistic subjects and are likely to mediate tissue damage 17 . Cholinergic deficit underlying social impairment in autism has also been suggested 18 . ...
Autism is a neurodevelopmental disorder of early childhood with unknown aetiology. In this study we aimed to investigate the changes in biochemical markers of inflammation, apoptosis, and mitochondrial function in the serum of children affected with autism spectrum disorder. Moreover we evaluated the changes in cholinesterase activity as a cholinergic marker in serum of these subjects. Twenty autistic children aged 3 to 12 years were gender and age-matched with 20 typically developing (TD) children. Changes in the levels of the proinflammatory cytokine monocyte chemoattractant protein-1 (MCP-1), the transcription factor nuclear respiratory factor 2 (NRF-2), the antiapoptotic factor -cell leukemia/lymphoma 2 (Bcl2) as well as cholinesterase activity were measured in serum of autistic children and controls. We found significant increments in serum MCP-1, NRF-2 and Bcl2 of autistic children by 185.3%, 41.8% and 63.5%, respectively, compared to corresponding control values. There was also marked increase in serum cholinesterase activity by 97.5% (P<0.001) in autistic patients compared to controls. These results indicate an increased inflammatory response in serum of autistic children and suggest that serum levels of BChE, Bcl2 and NRF-2 are elevated in autism, possibly as an adaptive mechanism to the chronic inflammatory process. Serum BChE might serve as a biomarker of inflammation in autistic subjects. © 2018 Oriental Scientific Publishing Company. All rights reserved.
... Sixty-one percent of severe autistics have allergies, while 25 percent of moderately autistic children show less severe allergies. 21 With the allergic patients, the immunological pattern Th1/Th2 tends to go to Th2 with the consequent increasing of IgE, IL-4, IL-5, IL-9, IL-13 and eotaxin-3 with an attendant increase in eosinophil and mast cell survival. There is also an increase of C4B null allele, a reduction of TCD4+ lymphocytes. ...
Introduction: Allergies are frequently found among patients with autism and autism shows an increased frequency among the allergic patients. Objective: To demonstrate that allergies and autism share some similar immunological patterns. Methods: The autoserum skin test (ASST) was used to demonstrate the presence of anti-IgE and/or anti-IgE receptor antibodies (FcεRIα). Results: The ASST demonstrated similar frequency, positives/positives and negatives/negatives, considering allergic and autistic patients. These similarities didn't exist when comparing with the control group. A positive correlation had been found with the results of autistic patients and their mothers. Conclusions: Autistic and allergic patients share some immunological similarities. Both differ from normal controls. It is not uncommon autistics with allergic symptoms and allergic patients with autism. If the immunological findings represent a clinical bridge between both processes, it is under discussion. Also it was demonstrated a possible genetic correlation between the patients with autism and their mothers.
... Une analyse des tendances de la recherche révèle que la dysrégulation immunitaire a fait l'objet de nombreuses études, qui ont produit les éléments de preuve les plus soli des des anomalies physiologiques dans les cas de TSA 12 . Les premiers éléments de preuve ont indiqué l'existence d'un lien possible entre le TSA et deux types principaux de dysfonction immunitaire, soit l'autoimmunité et l'inflammation du cerveau 182 . On a en outre observé une réduction importante de la concentration d'immunoglobuline G dans le sang des nouveau-nés dans des spécimens archivés provenant de nouveau-nés chez lesquels on a diagnostiqué par la suite un TSA, par rapport aux nouveau-nés chez lesquels on n'a diagnostiqué aucun TSA par la suite 183 . ...
Introduction
Le nombre d’enfants chez lesquels on diagnostique un trouble du spectre de l’autisme (TSA) grimpe rapidement depuis une décennie. L’étiologie de ce trouble est toutefois en grande partie inconnue, même si la contribution de l’environnement est importante par rapport à celle de la génétique. Nous avons procédé à une étude de délimitation pour évaluer en détail l’état actuel des connaissances sur les facteurs environnementaux présents depuis le stade de la préconception jusqu’au début de la vie que l’on associe au TSA et pour dégager les lacunes de la recherche.
Méthodologie
Nous avons cherché dans les bases de données électroniques MEDLINE, PsycINFO et ERIC des articles portant sur des facteurs de risque potentiels ou des facteurs de protection des environnements physiques et sociaux associés au TSA et à ses sous-catégories entre le 1er janvier 2003 et le 12 juillet 2013. Nous avons regroupé les articles en thèmes généraux en fonction de l’exposition environnementale : facteurs chimiques, physiologiques, nutritionnels et sociaux.
Résultats
Nous avons trouvé plus de 50 000 publications, mais après élimination des études inadmissibles il est resté 315 articles. La plupart de ces études portaient sur les facteurs psychologiques, suivis de près par les facteurs chimiques et, à un degré beaucoup moindre, les facteurs nutritionnels et sociaux associés au TSA. En dépit d’une masse importante de publications et de nombreuses études hétérogènes, quelques facteurs de risque se sont démarqués régulièrement : facteurs chimiques comme les polluants atmosphériques causés par la circulation; facteurs physiologiques, dont l’âge avancé des parents, les naissances prématurées, l’insuffisance de poids à la naissance, l’hyperbilirubinémie et les grappes de complications de la grossesse et enfin le statut de la mère vis-à-vis de l’immigration. En dépit de recherches poussées sur les vaccins, les faits révèlent de façon écrasante que rien n’appuie l’existence d’un lien avec le TSA.
Conclusion
Le manque d’uniformité, de temporalité et de spécificité des liens entre les facteurs environnementaux et le TSA demeure l’obstacle le plus important dans l’établissement de liens de cause à effet. Une recherche plus robuste s’impose pour supprimer le manque d’uniformité dans les publications. Les recherches futures devraient porter sur des mécanismes sous-jacents des liens entre facteurs de risque que nous avons identifiés et le TSA.
... Astrocytes regulate several key functions within the brain, particularly, blood-brain barrier (BBB) maintenance, immune responsiveness, neurotransmission, etc. [1,2]. Increased astrocyte expression stimulates astrogliosis and inflammation [3]. Alternatively, the loss of astrocytes impedes the normal central nervous system functioning [4,5]. ...
We previously demonstrated that arsenic, cadmium, and lead mixture at environmentally relevant doses induces astrocyte apoptosis in the developing brain. Here, we investigated the mechanism and contribution of each metal in inducing the apoptosis. We hypothesized participation of transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), reported to affect astrocyte survival. We treated cultured rat astrocytes with single metals and their combinations and performed apoptosis assay and measured PPARγ expression levels. We found that cadmium demonstrated maximum increase in PPARγ as well as apoptosis, followed by arsenic and then lead. Interestingly, we observed that the metals mimicked PPARγ agonist, troglitazone, and enhanced PPARγ-transcriptional activity. Co-treatment with PPARγ-siRNA or PPARγ-antagonist, GW9662, suppressed the astrocyte apoptosis, suggesting a prominent participation of PPARγ in metal(s)-induced astrocyte loss. We explored PPARγ-transcriptional activity and identify its target gene in apoptosis, performed in silico screening. We spotted PPARγ-response elements (PPREs) within poly(ADP-ribose) polymerase (PARP) gene, and through gel-shift assay verified metal(s)-mediated increased PPARγ binding to PARP-PPREs. Chromatin-immunoprecipitation and luciferase-reporter assays followed by real-time PCR and Western blotting proved PPRE-mediated PARP expression, where cadmium contributed most and lead least, and the effects of metal mixture were comparable with troglitazone. Eventually, dose-dependent increased cleaved-PARP/PARP ratio confirmed astrocyte apoptosis. Additionally, we found that PPARγ and PARP expressions were c-Jun N-terminal kinases and cyclin-dependent kinase5-dependent. In vivo treatment of developing rats with the metals corroborated enhanced PPARγ-dependent PARP and astrocyte apoptosis, where yet again cadmium contributed most. Overall, our study enlightens a novel PPARγ-dependent mechanism of As-, Cd-, and Pb-induced astrocyte apoptosis.
... 144,[178][179][180][181] Immune abnormalities According to a review of research trends, immune dysregulation has been widely studied and possesses the strongest evidence base of the physiological abnormalities in ASD. 12 Early evidence found a potential link between ASD and two main types of immune dysfunction: autoimmunity and brain inflammation. 182 In addition, significantly reduced neonatal blood immunoglobulin G has been observed in archived specimens from newborns subsequently diagnosed with ASD relative to ...
Introduction
The number of children diagnosed with autism spectrum disorder (ASD) has been rapidly rising in the past decade. The etiology of this disorder, however, is largely unknown, although the environmental relative to the genetic contribution is substantial. We conducted a scoping review to comprehensively assess the current state of knowledge of the environmental factors present from preconception to early life associated with ASD, and to identify research gaps.
Methods
We searched electronic databases MEDLINE, PsycINFO and ERIC for articles on potential risk factors or protective factors from the physical and social environments associated with ASD and its subclassifications published between 1 January, 2003, and 12 July, 2013. We categorized articles into broad themes: chemical, physiological, nutritional and social factors, based on environmental exposure.
Results
We identified over 50 000 publications, but after ineligible studies were screened out, 315 articles remained. Most of these studies examined physiological factors, followed closely by chemical factors, and to a much lesser extent, nutritional and social factors, associated with ASD. Despite a vast literature and many heterogeneous studies, several risk factors emerged consistently: chemical factors such as traffic-related air pollutants; physiological factors including advanced parental age, preterm birth, low birth weight, hyperbilirubinemia and clustering of pregnancy complications; and maternal immigrant status. Despite extensive research on vaccines, findings overwhelmingly demonstrate no support for an association with ASD.
Conclusion
The lack of consistency, temporality and specificity of associations between environmental factors and ASD remains the largest barrier to establishing causal relationships. More robust research is required to resolve inconsistencies in the literature. Future research should explore underlying mechanisms of associations between the risk factors that we identified and ASD.
... Production of autoantibodies due to myelin basic protein is one of the basic effects [62]. Similar evidence have been reported, which shows a same pattern to this literature and altered immune functions were observed as main outcomes in autistic children [63][64][65]. ...
Mercury (Hg) is toxic and hazardous metal that causes natural disasters in the earth's crust. Exposure to Hg occurs via various routes; like oral (fish), inhalation, dental amalgams, and skin from cosmetics. In this review, we have discussed the sources of Hg and its potential for causing toxicity in humans. In addition, it's bio-chemical cycling in the environment; its systemic, immunotoxic, genotoxic/carcinogenic and teratogenic health effects; and the dietary influences; as well as the important considerations in risk assessment and management of Hg poisoning have been discussed in detail. Many harmful outcomes have been reported which will provide more awareness.
... While cytokines act primarily as mediators of immunological activity, they also have significant interactions with the CNS (Goines et al., 2011). In fact, it has been suggested that the synthesis or transport of cytokines in the brain may contribute to neuroinflammation and possibly to neurotransmitter imbalances in autism (Cohly and Panja, 2005). Furthermore, the presence of IL-21 + cells in human brain tissue during different neuroinflammatory conditions was recently reported (Tzartos et al., 2011). ...
Accumulating evidence suggests an association between immune dysfunction and autism disorders in a significant subset of children. In addition, an imbalance between pro- and anti-inflammatory pathways has been proposed to play an important role in the pathogenesis of several neurodevelopmental disorders including autism; however, the role of anti-inflammatory molecules IL-27 and CTLA-4 and pro-inflammatory cytokines IL-21 and IL-22 has not previously been explored in autistic children. In the current study, we investigated the expression of IL-21, IL-22, IL-27, and CD152 (CTLA-4) following an in-vitro immunological challenge of peripheral blood mononuclear cells (PBMCs) from children with autism (AU) or typically-developing children (TD) with phorbol-12-myristate 13-acetate (PMA) and ionomycin. In our study, cells from children with AU had increased IL-21 and IL-22 and decreased CTLA-4 expression on CD4(+) T cells as compared with cells from the TD control. Similarly, AU cells showed decreased IL-27 production by CD14(+) cells compared to that of TD control cells. These results were confirmed by real-time PCR and western blot analyses. Our study shows dysregulation of the immune balance in cells from autistic children as depicted by enhanced pro-inflammatory cytokines, 'IL-21/IL-22' and decreased anti-inflammatory molecules, 'IL-27/CTLA-4'. Thus, further study of this immune imbalance in autistic children is warranted in order to facilitate development of biomarkers and therapeutics.
Biochemical biomarker studies of ASD individuals have been undertaken in order to identify biochemical alterations that might advance the understanding of the atypical neurodevelopment seen in ASD. In addition, there is the promise that biochemical biomarkers might be useful in predicting risk and in subtyping. Most of the studies to date have examined neurochemical biomarkers related to neural transmission in the central and peripheral nervous systems. We first deal with neurochemical studies measuring levels of neurotransmitters, their metabolites, and associated enzymes in blood, urine, and cerebrospinal fluid (CSF). Separate sections cover serotonin, dopamine, and stress response systems (including the central noradrenergic, sympathoadrenomedullary, and hypothalamic‐pituitary‐adrenal axis systems). Following sections review research on melatonin, sex hormones, neuropeptides including oxytocin, amino acids and acetylcholine, purines and related compounds, immune‐related measures, oxidative stress/redox status, and “omics” research.
The cytokine-activated Janus kinase (JAK)–signal transducer and activator of transcription (STAT) cascade is a pleiotropic pathway that involves receptor subunit multimerization. The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine-threonine kinase that perceives and integrates a variety of intracellular and environmental stimuli to regulate essential activities such as cell development and metabolism. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a prototypical metabolic nuclear receptor involved in neural differentiation and axon polarity. The JAK-STAT, mTOR, and PPARγ signaling pathways serve as a highly conserved signaling hub that coordinates neuronal activity and brain development. Additionally, overactivation of JAK/STAT, mTOR, and inhibition of PPARγ signaling have been linked to various neurocomplications, including neuroinflammation, apoptosis, and oxidative stress. Emerging research suggests that even minor disruptions in these cellular and molecular processes can have significant consequences manifested as neurological and neuropsychiatric diseases. Of interest, target modulators have been proven to alleviate neuronal complications associated with acute and chronic neurological deficits. This research-based review explores the therapeutic role of JAK-STAT, mTOR, and PPARγ signaling modulators in preventing neuronal dysfunctions in preclinical and clinical investigations.
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by persistent challenges in social interactions and repetitive behavioral patterns. It is a significant problem emerging worldwide, as one in 100 children is affected by this disorder globally. In this study, a meta-analysis was performed for the identification of differentially expressed genes (DEGs) along with the expression analysis of regulatory genes. Functional enrichment analysis was an integral part of current findings to notify the significant pathways of this complex disorder. The study was conducted with two RNA-Seq datasets, viz., GSE64018 and GSE62098, for ASD patients and control samples from the GEO database. The identification of up-regulatory and down-regulatory genes was performed by the interaction analysis of transcription factors (TF) and DEGs. As an outcome of the meta-analysis, 2543 DEGs were identified as common across both of the datasets in which 1402 DEGs exhibited upregulation and 1130 genes have shown downregulation. In network analysis, upregulatory genes have shown strong interaction while downregulatory genes exhibit weak or null interaction. Further, in the enrichment analysis of screened upregulatory DEGs, three major significant pathways were identified namely the ATP synthesis pathway, FAS signaling pathway, and the Huntington’s disease pathway. The common expression of CYC 1 gene in all the identified pathways has indicated that it is an important key regulator gene for the majorly associated pathways. The study concludes that all the potential DEGs were found to show their related high expression in neurobiological regulations specifically with ASD.
Communicated by Ramaswamy S. Sarma
Background:
Autism spectrum disorder (ASD) is a clinically and genetically heterogeneous group of neurodevelopmental disorders. Despite the extensive efforts of scientists, the etiology of ASD is far from completely elucidated. In an effort to enlighten the genetic architecture of ASDs, a meta-analysis of all available genetic association studies (GAS) was conducted.
Methods:
We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available case-control GAS of ASDs. The threshold for meta-analysis was two studies per genetic variant. The association between genotype distribution and ASDs was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast.
Results:
Overall, 57 candidate genes and 128 polymorphisms were investigated in 159 articles. In total 28 genetic polymorphisms have been shown to be associated with ASDs, that are harbored in 19 genes. Statistically significant results were revealed for the variants of the following genes adenosine deaminase (ADA), bone marrow stromal cell antigen-1 (CD157/BST1), Dopamine receptor D1 (DRD1), engrailed homolog 2 (EN2), met proto-oncogene (MET), methylenetetrahydrofolate reductase (MTHFR), solute carrier family 6 member 4 (SLC6A4), Synaptosomal-associated protein, 25kDa (SNAP-25) and vitamin D receptor (VDR). In the allele contrast model of cases versus healthy controls, significant associations were observed for Adrenoceptor Alpha 1B (ADRA1B), acetyl serotonin O - methyltransferase (ASMT), complement component 4B (C4B), dopamine receptor D3 (DRD3), met proto-oncogene (MET), neuroligin 4, X-linked (NLGN4), neurexin 1 (NRXN1), oxytocin receptor (OXTR), Serine/Threonine-Protein Kinase PFTAIRE-1 (PFTK1), Reelin (RELN) and Ras-like without CAAX 2 (RIT2).
Conclusion:
These significant findings provide further evidence for genetic factors' implication in ASDs offering new perspectives in means of prevention and prognosis.
Objective:
Cognitive developmental delay is a picture of the group of early-onset chronic diseases that affect 1.5-10% of children. Autism spectrum disorders are neurodevelopmental diseases with a genetic basis and abnormal brain development, characterized by disorders in areas that make up interpersonal relationships, such as communication, social cognition, and processing of emotional signals. Immune system dysfunction is thought to play a role in the pathogenesis of some neurological disorders, including autism. Progranulin is thought to be a regulator of the innate immune response. The purpose of this study was to look at plasma levels of progranulin, an anti-inflammatory neurotrophic factor, in children with autism spectrum disorder and cognitive developmental delay.
Materials and methods:
The study was conducted on 52 children who were patients and 35 healthy children. Of the 52 children of the patient group, 32 were diagnosed with CDD and 20 were diagnosed with cognitive developmental delay-autism spectrum disorder. Serum progranulin concentrations were measured using a human-specific sandwich enzyme-linked immunosorbent assay.
Results:
Serum progranulin concentration was statistically lower in the patient group (110.746 ± 26.04) than in the healthy control group (137.346 ± 30.02). There was a statistically significant difference between the groups in levels of serum progranulin (P=.000). Receiver operating characteristic analysis was performed to evaluate the potential of progranulin as a biomarker to distinguish patients with cognitive developmental delay-autism spectrum disorder from healthy children. It detected a moderate area under the curve (0.743 ± 0.06) value and a more significant P value for progranulin (P=.000).
Conclusion:
Progranulin deficiency in patients with autism spectrum disorder-cognitive developmental delay may result in decreased neurotrophic support for many years, with cumulative damage associated with unregulated inflammation that may play a role in autism spectrum disorder-cognitive developmental delay. We believe that low progranulin levels could be a biomarker for autism spectrum disorder-cognitive developmental delay.
TAM receptor family belongs to receptor tyrosine kinases (TAMRTKs). It includes three receptors; Tyro-3, Axl and Mer. TAMRTKs has a great role in resolution of inflammation due to their role in clearance of apoptotic cells by macrophages. Dysregulated TAM signaling pathways are associated with many autoimmune diseases and chronic inflammatory disorders. Autism may be an autoimmune disease in some patients. This work was the first study that investigated serum levels of the soluble ectodomain shed TAMRTKs in a group of autistic children. Serum levels of TAMRTKs were measured by ELISA in 30 autistic children aged between 3.5 and 11 years and 30 age and sex-matched healthy control children. Serum levels of TAMRTKs were significantly higher in autistic children than healthy control children (P < 0.001). Patients with severe autism had significantly higher serum levels of TAMRTKs than patients with mild to moderate autism (P < 0.01). In addition, there were significant positive correlations between scores of the Childhood Autism Rating Scale (CARS) and serum levels of TAMRTKs in autistic patients, (P < 0.01). In conclusions, serum levels of TAMRTKs were up-regulated in autistic children with significant positive correlations with the degree of the disease severity. This initial report requires further studies to investigate the relationship between TAMRTKs and autism.
This research monograph describes desvtibes the mathernal pathologing and the clinical studywith of infant hyperactivity and attention deficit disorder ADHD, the sungroup pf ADHD, the child deficit of learning and memory and aggresivity-In addition we have reported the cliivical study of Autism spectrum disorder (ASD), the brain-gut relationship in ASD, and the reported Neuroscience Theories, Hypothesis and Approaches on Autism Spectrum Disorder (ASD).
Autism spectrum disorder (ASD) is a common neurobehavioral disorder with considerable complexity and without clearly defined etiologic underpinnings. A variety of factors are intertwined in this condition including genetic, biochemical, and cellular characteristics. A major aspect of ASD management is behavioral therapy, though pharmacologic agents produce major benefits as well. This work considers current pharmacologic principles in treatment of ASD in children, adolescents, and adults. Pharmacologic intervention is particularly helpful for treatment of the conditions that are frequently co-morbid with ASD—including anxiety, depression, aggressive/violent behaviors, repetitive behaviors, inattention with hyperactivity, and sleep disorders.
Hyperserotonemia and brain-specific autoantibodies are detected in some autistic children. Nerve growth factor (NGF) stimulates the proliferation of B lymphocytes with production of antibodies and also increases mast cell serotonin release. This work was the first to investigate the relationship between plasma NGF and both hyperserotonemia and the frequency of serum anti-myelin basic protein (anti-MBP) auto-antibodies in 22 autistic children aged between 4 and 12 years and 22 healthy-matched controls. Levels of NGF, serotonin and anti-MBP were significantly higher in autistic children than healthy control children (P < 0.001). There was a significant positive correlation between NGF and serotonin levels in autistic patients (P < 0.01). In contrast, there was a non-significant correlation between NGF and anti-MBP levels (P > 0.05). In conclusions, serum NGF levels were elevated and significantly correlated to hyperserotonemia found in many autistic children.
Background:
Autistic spectrum disorder (ASD) is a common problem in the Kingdom of Saudi Arabia. However, little research explored the extent of anxiety and depressive disorders in parents of children with ASD.
Method:
Descriptive questionnaire-based cross-sectional survey of a sample of parents of children with ASD who attended Prince Mohammed Bin Salman Autistic Centre, Ministry of defense, Taif city.
Results:
The study included (n = 50) parents. The prevalence of mild depression was 30%, whereas the prevalence of moderately severe depression was 68%. Increased ASD severity level was associated with a significant impact on the PHQ-9 total score (level II was 1.293 times level I to have an increased PHQ-9 score, and level III was 1.530 times level I to have an increased PHQ-9 score). Economic status did not significantly alter depressive symptoms.
Discussion and conclusion:
ASD diagnosis in Saudi children is associated with high parental depressive prevalence. However, this result could be bidirectional. Stigma, future-related worry, and stress could mediate parental depressive symptoms. Our findings in Saudi parents of children with ASD corroborate the established association between parental depressive symptoms and ASD severity. Our results corroborated previous findings that neither parental gender nor child gender exert any substantial effect on predictability of depressive symptoms among parents of children with ASD. Comprehensive therapeutic packages for children with ASD should include treatment of emotional problems arising out of carer burden among their parents. Screening for parental emotional problems should be routine in autism treatment facilities.
Sexual dimorphism has been reported in the prevalence, onset and progression of neurodevelopmental and neurodegenerative disorders. We hypothesize that immunological signaling in the developing brain, notably the complement cascade underlying microglial synaptic pruning, could be one mechanism for this dimorphism. Here we show that genes differentially expressed between male and female normal cortical development are enriched for pathways associated with the activation of the innate immune system, complement cascade and phagocytic processes. Specifically, the male brain is enriched for the expression of genes associated with phagocytic function of microglia through complement-dependent synaptic pruning especially at the developmental stages before birth. Our results suggest the existence of a common regulatory module involved in both prenatal immune activation in males and postnatal immune activation in females. The activation of immune pruning pathways at different stages of normal male and female development could provide valuable insights about critical periods of plasticity and refinement in the human cortex that could explain the different vulnerabilities of males and females to neurological disorders.
According to the results of our laboratory the theory of immune dysfunction, the theory on the genetic architecture of ASD, the disrupted cortical connectivity theory and the theory on the contribution of cerebellum to ASD have shown fundamental experimental evidences to support the core symptoms of the complex and enigmatic physiopathology of autism spectrum disorder. The additional hypothesis about the neurogenesis in the amygdala, the contribution of oxytocin, vasopressin, the mirror neuron network, and mitochondrial dysfunction described are stimulating and interesting approaches that deserve further systematic basic and clinical neuroscience research.
The review article presents the characteristics of the main adjuvant groups (mineral salts of aluminum, synthetic squalenebased adjuvants - MF59 and AS03, CpG-oligodeoxynucleotides, virosomes, polyoxidonium, sovidone) included in the licensed influenza vaccine. The main mechanisms of adjuvant action, advantages and disadvantages of these adjuvants are shown. The vaccines adjuvants in the phase of experimental studies and clinical trials (ISCOMs, Advax™, chitosan) are described too. Particular attention is paid to sulfated polysaccharides (fucoidans) from marine brown algae as vaccine adjuvants. Numerous results of their application in compositions of experimental vaccines are presented. The prospects of sulfated polysaccharides using in the design of influenza vaccines are estimated. These prospects are determined by high biocompatibility, low toxicity and good tolerance of the human body to fucoidans, as well as mechanisms of their adjuvant activity. Sulfated polysaccharides are agonists of toll-like receptors of innate immunity cells and powerful inducers of the cellular and humoral immune response, which is important for the development of influenza vaccines. The review is based on the information presented in the bibliographic and abstract databases of scientific publications, search engines and publishers: RSCI, Web of Science, Scopus, MEDLINE, Google Scholar, PubMed, Springer Nature, Elsevier and others.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by a deficit in social interactions and communication with repetitive and restrictive behavior. No curative treatments are available for ASD. Pharmacological treatments do not address the core ASD behaviors, but target comorbid symptoms. Dysregulation of the core neurodevelopmental pathways is associated with the clinical presentation of ASD, and the canonical WNT/β-catenin pathway is one of the major pathways involved. The canonical WNT/β-catenin pathway participates in the development of the central nervous system, and its dysregulation involves developmental cognitive disorders. In numerous tissues, the canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPARγ) act in an opposed manner. In ASD, the canonical WNT/β-catenin pathway is increased while PPARγ seems to be decreased. PPARγ agonists present a beneficial effect in treatment for ASD children through their anti-inflammatory role. Moreover, they induce the inhibition of the canonical WNT/β-catenin pathway in several pathophysiological states. We focus this review on the hypothesis of an opposed interplay between PPARγ and the canonical WNT/β-catenin pathway in ASD and the potential role of PPARγ agonists as treatment for ASD.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, verbal and non-verbal communication, and stereotypic behaviors. Many studies support a significant relationship between many different environmental factors in ASD etiology. These factors include increased daily exposure to various toxic metal-based environmental pollutants, which represent a cause for concern in public health. This article reviews the most relevant toxic metals, commonly found, environmental pollutants, i.e., lead (Pb), mercury (Hg), aluminum (Al), and the metalloid arsenic (As). Additionally, it discusses how pollutants can be a possible pathogenetic cause of ASD through various mechanisms including neuroinflammation in different regions of the brain, fundamentally occurring through elevation of the proinflammatory profile of cytokines and aberrant expression of nuclear factor kappa B (NF-κB). Due to the worldwide increase in toxic environmental pollution, studies on the role of pollutants in neurodevelopmental disorders, including direct effects on the developing brain and the subjects' genetic susceptibility and polymorphism, are of utmost importance to achieve the best therapeutic approach and preventive strategies.
Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder in which immunological imbalance has been suggested to be a major etiological component. Helios, a transcription factor, has been studied extensively in the context of human T cell regulation in health and disease, yet the role of Helios signaling has not been examined in children with ASD. In the present study, we investigated the production of Helios in CD4+, CD8+, and TIM-3+, CXCR3+ cells in typically developing (TD) controls and children with ASD and in peripheral blood mononuclear cells (PBMCs). We assayed the production of IFN-γ+Helios+, IL-21+Helios+, T-bet+Helios+, and Foxp3+Helios+ cells, and determined Helios mRNA and protein expression levels in PBMCs, in TD controls and children with ASD. Our results revealed that children with ASD had lower numbers of CD4+Helios+ CD8+Helios+, TIM-3+Helios+, and CXCR3+Helios+ cells as compared to TD controls. Our results also showed that children with ASD had decreased IFN-γ+Helios+, IL-21+Helios+, T-bet+Helios+, and Helios+Foxp3+ production compared to that in TD controls. Moreover, our results indicated that children with ASD had lower Helios mRNA and protein expression levels compared to those in TD controls. These results suggest that the Helios transcription factor may be critical to immune alterations in children with ASD. Therefore, our results suggest that targeting Helios signaling might offer a strategy for developing ASD therapies.
Autism is a neurodevelopmental disorder characterized by stereotyped interests and behaviors and abnormalities in verbal and nonverbal communication. Autism is reported as a multifactorial disorder resulting from interactions between genetic, environmental, and immunological factors. Excitotoxicity and oxidative stress are potential mechanisms, which are likely to serve as a converging point to these risk factors. Numerous studies suggest that excitotoxicity is a likely cause of neuronal dysfunction in autistic patients. Glutamate is the main excitatory neurotransmitter generated in the CNS, and overactivation of glutamate receptors triggers excitotoxicity. Hyperactivation of glutamatergic receptors, NMDA and AMPA, leads to activation of enzymes, which damage cellular structure, membrane permeability, and electrochemical gradients. The role of excitotoxicity in autistic subjects is summarized in this chapter. © Springer Science+Business Media New York 2014. All rights reserved.
Class I major histocompatibility complex (class I MHC) molecules, known to be important for immune responses to antigen, are
expressed also by neurons that undergo activity-dependent, long-term structural and synaptic modifications. Here, we show
that in mice genetically deficient for cell surface class I MHC or for a class I MHC receptor component, CD3ζ, refinement
of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants,N-methyl-d-aspartate receptor–dependent long-term potentiation (LTP) is enhanced, and long-term depression (LTD) is absent. Specific
class I MHC messenger RNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions.
These results demonstrate an important role for these molecules in the activity-dependent remodeling and plasticity of connections
in the developing and mature mammalian central nervous system (CNS).
Both genetic and environmental factors contribute to the development of autoimmunity. Animals and humans exposed to natural infections have a reduced rate of autoimmune diseases. There is increasing evidence that immune stimulation prevents autoimmune diseases. Our hypothesis is that the process of the development of pathogenic cells involved in autoimmunity can be modulated by early stimulation of the immune system in autoimmunity prone individuals This allows for the upregulation of cytokines and growth factors that influence the generation of regulatory cells involved in autoimmunity. As we live in a ‘cleaner environment’ the decreasing chances of natural infection in the general population may contribute to the induction of autoimmunity because the developing immune system is not exposed to stimulation that may be necessary to generate regulatory cells involved in the modulation and prevention of autoimmunity. Immunization with certain vaccines may provide an alternative approach to stimulate the immune system to modulate or prevent the generation of pathogenic cells involved in autoimmunity by induction of regulatory cells.
MRI and autopsy evidence of early maldevelopment of cerebellar vermis and hemispheres in autism raise the question of how cerebellar maldevelopment contributes to the cognitive and social deficits characteristic of autism. Compared with normal controls, autistic patients and patients with acquired cerebellar lesions were similarly impaired in a task requiring rapid and accurate shifts of attention between auditory and visual stimuli. Neurophysiologic and behavioral evidence rules out motor dysfunction as the cause of this deficit. These findings are consistent with the proposal that in autism cerebellar maldevelopment may contribute to an inability to execute rapid attention shifts, which in turn undermines social and cognitive development, and also with the proposal that the human cerebellum is involved in the coordination of rapid attention shifts in a fashion analogous to its role in the coordination of movement.
Dental amalgam fillings are the most important source of mercury exposure in the general population, but their potential to cause systemic health consequences is disputed. In this study, inbred mice genetically susceptible to mercury-induced immune aberrations were used to examine whether dental amalgam may interfere with the immune system and cause autoimmunity. Female SJL/N mice were implanted in the peritoneal cavity with 8-100 mg silver amalgam or silver alloy for 10 weeks or 6 months. Chronic hyperimmunoglobulinemia, serum IgG autoantibodies targeting the nucleolar protein fibrillarin, and systemic immune-complex deposits developed in a time- and dose-dependent manner after implantation of amalgam or alloy. Splenocytes from mice implanted with amalgam or alloy showed an increased expression of class II molecules. The functional capacity of splenic T and B cells was affected in a dose-dependent way: 10 weeks of low-dose and 6 months of high-dose amalgam implantation strongly increased mitogen-induced T and B cell proliferation, whereas 10 weeks of high-dose implantation decreased the proliferation. Not only mercury but also silver accumulated in the spleen and kidneys after amalgam implantation. In conclusion, dental amalgam implantation in a physiological body milieu causes chronic stimulation of the immune system with induction of systemic autoimmunity in genetically sensitive mice. Implantation of silver alloy not containing mercury also induced autoimmunity, suggesting that other elements, especially silver, have the potential to induce autoimmunity in genetically susceptible vertebrates. Accumulation of heavy metals, from dental amalgam and other sources, may lower the threshold of an individual metal to elicit immunological aberrations. We hypothesize that under appropriate conditions of genetic susceptibility and adequate body burden, heavy metal exposure from dental amalgam may contribute to immunological aberrations, which could lead to overt autoimmunity.
Measles virus (MV) causes a productive infection in humans and certain simian hosts. Rodent cells such as Chinese hamster ovary (CHO) and murine cell lines normally resist MV infection. Human CD46, or membrane cofactor protein, a complement regulatory protein, recently has been reported as the cellular receptor for MV. Multiple isoforms of the CD46 protein exist; four of these isoforms are commonly expressed on human cells. Expression of each of the four isoforms in CHO cells followed by exposure to MV led to the appearance of viral proteins within the cells and on the cell surface as detected by immunofluorescence. Syncytium formation also was observed in the cultures. CHO cells expressing any of the four isoforms and exposed to MV formed infectious centers when plated on Vero cell monolayers, indicating that the cells can transmit virus to uninfected cells. The murine cell line MC57 expressing the BC1 isoform of CD46 also stained positively for MV antigens and was positive in the infectious center assay after exposure to MV. Treatment of CD46-expressing cells with antibody to human CD46 inhibited MV binding in a dose-dependent manner. These observations indicate that any of the four primary isoforms of CD46 are able to serve as a receptor for MV.
A monoclonal antibody (MCI20.6) which inhibited measles virus (MV) binding to host cells was previously used to characterize a 57- to 67-kDa cell surface glycoprotein as a potential MV receptor. In the present work, this glycoprotein (gp57/67) was immunopurified, and N-terminal amino acid sequencing identified it as human membrane cofactor protein (CD46), a member of the regulators of complement activation gene cluster. Transfection of nonpermissive murine cells with a recombinant expression vector containing CD46 cDNA conferred three major properties expected of cells permissive to MV infection. First, expression of CD46 enabled MV to bind to murine cells. Second, the CD46-expressing murine cells were able to undergo cell-cell fusion when both MV hemagglutinin and MV fusion glycoproteins were expressed after infection with a vaccinia virus recombinant encoding both MV glycoproteins. Third, M12.CD46 murine B cells were able to support MV replication, as shown by production of infectious virus and by cell biosynthesis of viral hemagglutinin after metabolic labeling of infected cells with [35S]methionine. These results show that the human CD46 molecule serves as an MV receptor allowing virus-cell binding, fusion, and viral replication and open new perspectives in the study of MV pathogenesis.
This study examined the effect of the pro-inflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) on the induction of MHC class I–related genes in functionally mature brain neurons derived from cultures of dissociated rat hippocampal tissue. Patch clamp electrophysiology combined with single cell RT-PCR demonstrated that ∼50% of the untreated neurons contained mRNA for MHC class I heavy chains, while, with few exceptions, the cells failed to transcribe β2-microglobulin and TAP1/TAP2 gene transcripts. No constitutive expression of MHC class I protein was detectable by confocal laser microscopy on the surface of neurons.
All neurons transcribed the α-chain of the interferon-type II receptor (binding IFN-γ) along with the p55 receptor for TNF-α. Sustained exposure to IFN-γ resulted in transcription of β2microglobulin and TAP1/TAP2 genes and MHC class I surface expression in a minor part of the neurons, but did not alter their electrophysiological activities as assessed by whole cell electrophysiology. Suppression of neuronal electric activity by the sodium channel blocker tetrodotoxin drastically increased to almost 100% IFN-γ-mediated induction of MHC class I chains, of both TAP transporters, and of membrane expression of MHC class I protein. The effect of tetrodotoxin is at least partly reverted by the neurotransmitter glutamate.
In contrast to IFN-γ, treatment with TNF-α did neither upregulate TAP1/TAP2 nor β2microglobulin gene expression, but induced MHC class I heavy chain gene transcription in all neurons. Consequently, no MHC class I molecules were detectable on the membranes of TNF-α-treated neurons.
In this study it is shown that both membrane-bound and soluble forms of signaling lymphocytic activation molecule (SLAM) induce proliferation and Ig synthesis by activated human B cells. Activated B cells express the membrane-bound form of SLAM (mSLAM), the soluble (s) and the cytoplasmic (c) isoforms of SLAM, and the expression levels of mSLAM on B cells are rapidly upregulated after activation in vitro. Importantly, recombinant sSLAM and L cells transfected with mSLAM efficiently enhance B cell proliferation induced by anti-mu mAbs, anti-CD40 mAbs or Staphylococcus aureus Cowan I (SAC) in the presence or absence of IL-2, IL-4, IL-10, IL-12, or IL-15. sSLAM strongly enhances proliferation of both freshly isolated B cells and B cells derived from long-term in vitro cultures, indicating that SLAM acts not only during the initial phase of B cell activation but also during the expansion of preactivated B cells. In addition, sSLAM enhances production of IgM, IgG, and IgA by B cells activated by anti-CD40 mAbs. SLAM has recently been shown to be a high affinity self-ligand, and the present data suggest that signaling through homophilic SLAM-SLAM binding during B-B and B-T cell interactions enhances the expansion and differentiation of activated B cells.
The heavy metal mercury elicits a genetically restricted, anti-nucleolar autoantibody response that targets fibrillarin, a 34-kDa protein component of many small nucleolar ribonucleoprotein particles. The mechanisms by which a toxin such as mercury elicits an autoantibody response that predominantly targets a single intracellular protein autoantigen remain uncertain, but may be prefaced by mercury gaining access to the intracellular environment. Mercury-induced cell death was associated with loss of fibrillarin antigenicity and modification of the molecular properties of fibrillarin as revealed by aberrant migration under nonreducing conditions in SDS-PAGE. Addition of mercury to isolated nuclei also resulted in aberrant migration of fibrillarin, but not other nuclear autoantigens. The sensitivity of the HgCl2-induced modification of fibrillarin to 2-ME, iodoacetamide, and hydrogen peroxide suggested interaction of mercury with the two cysteines in the fibrillarin sequence. This was confirmed by mutation of the cysteines to alanines, which abolished the aberrant migration of fibrillarin in the presence of HgCl2. The modification of the molecular structure of fibrillarin by mercury reduced immunoprecipitation by anti-fibrillarin autoantibodies, pointing to unmodified fibrillarin as the B cell Ag and implicating mercury-modified fibrillarin as the source of T cell antigenicity. These observations demonstrate for the first time that an environmental toxin can alter the physicochemical properties of an autoantigen and may help to explain the antigenic specificity of mercury-induced murine autoimmunity.
Secondary infections due to a marked immunosuppression have long been recognized as a major cause of the high morbidity and
mortality rate associated with acute measles. The mechanisms underlying the inhibition of cell-mediated immunity are not clearly
understood but dysfunctions of monocytes as antigen-presenting cells (APC) are implicated. In this report, we demonstrate
that measles virus (MV) replicates weakly in the resting dendritic cells (DC) as in lipopolysaccharide-activated monocytes,
but intensively in CD40-activated DC. The interaction of MV-infected DC with T cells not only induces syncytia formation where
MV undergoes massive replication, but also leads to an impairment of DC and T cell function and cell death. CD40-activated
DC decrease their capacity to produce interleukin (IL) 12, and T cells are unable to proliferate in response to MV-infected
DC stimulation. A massive apoptosis of both DC and T cells is observed in the MV pulsed DC–T cell cocultures. This study
suggests that DC represent a major target of MV. The enhanced MV replication during DC–T cell interaction, leading to an
IL-12 production decrease and the deletion of DC and T cells, may be the essential mechanism of immunosuppression induced
by MV.
With the use of a newly developed Imaging Cryomicrotome to determine the spatial location of fluorescent microspheres in organs, we validate and report our processing algorithms for measuring regional blood flow in small laboratory animals. Microspheres (15-mum diameter) of four different fluorescent colors and one radioactive label were simultaneously injected into the left ventricle of a pig. The heart and kidneys were dissected, and the numbers of fluorescent and radioactive microspheres were determined in 10 randomly selected pieces. All microsphere counts fell well within the 95% expected confidence limits as determined from the radioactive counts. Fluorescent microspheres (15-mum diameter) of four different colors were also injected into the tail vein of a rat and the left ventricle of a rabbit. After correction for Poisson noise, correlation coefficients between the colors were 0.99 +/- 0.02 (means +/- SD) for the rabbit heart and 0.99 +/- 0.02 for the rat lung. Mathematical dissection algorithms, statistics to analyze the spatial data, and methods to visualize blood flow distributions in small animal organs are presented.
A neuropathological study of autism was established and brain tissue examined from six mentally handicapped subjects with autism. Clinical and educational records were obtained and standardized diagnostic interviews conducted with the parents of cases not seen before death. Four of the six brains were megalencephalic, and areas of cortical abnormality were identified in four cases. There were also developmental abnormalities of the brainstem, particularly of the inferior olives. Purkinje cell number was reduced in all the adult cases, and this reduction was sometimes accompanied by gliosis. The findings do not support previous claims of localized neurodevelopmental abnormalities. They do point to the likely involvement of the cerebral cortex in autism.
We reported that the major histocompatibility complex (MHC) including the null allele of the C4B gene and the extended haplotype B44-C30-DR4 is associated with autism. We report now that the third hypervariable region (HVR-3) of certain DR β l alleles have very strong association with autism. The HVR-3 of DRβ1∗ 0401 or the shared HVR-3 alleles DR01∗ 0404 and DRβ1∗ 0101, was expressed on extended haplotypes in 23 of 50 (46%) autistic subjects as compared to only 6 of 79 (7.5%) normal subjects. Another HVR-3 sequence, the DRβ1∗ 0701 allele, was carried on extended haplotypes in 16 (32.0%) of the autistic subjects as compared to 8 (10.1 %) of the normal subjects.
Different viruses were compared with the double-stranded RNA poly(rI).poly(rC) and interleukin (IL) 1 for their IL 6-inducing potential in several human and animal cell types. The laboratory viruses Sendai, Mengo and Newcastle disease virus were found to dose dependently stimulate IL 6 production in diploid fibroblasts. A similar effect was obtained with the human pathogens, measles and rubella virus. Concomitantly with IL 6, two other cytokine activities, i.e., interferon-beta and colony-stimulating activity for granulocytes and monocytes, were induced. In addition, these three activities were also produced by fibroblasts in response to Escherichia coli, whereas lipopolysaccharide was only marginally active. The specificity of the induction phenomenon was confirmed by the lack of IL 6 induction with inactivated infectious agents and by the complete neutralization of produced IL 6 by specific antibodies. This study indicates that the coordinate production of hemopoietic growth factors and interferon, originating from cells that do not classically belong to the immune system, can influence the local and systemic reactions observed during host defence against various infectious agents.
During the past decade, mechanisms involved in the immune surveillance of the central nervous system (CNS) have moved to the forefront of neuropathological research mainly because of the recognition that most neurological disorders involve activation and, possibly, dysregulation of microglia, the intrinsic macrophages of the CNS. Increasing evidence indicates that, in addition to their well-established phagocytic function, microglia may also participate in the regulation of non specific inflammation as well as adaptive immune responses. This article focuses on the signals regulating microglia innate immune functions, the role of microglia in antigen presentation, and their possible involvement in the development of CNS immunopathology. GLIA 36:165–179, 2001. © 2001 Wiley-Liss, Inc.
Neurodevelopmental disorders could be caused by maternal antibodies or other serum factors. We detected serum antibodies binding to rodent Purkinje cells and other neurons in a mother of three children: the first normal, the second with autism, and the third with a severe specific language disorder. We injected the serum (0.5–1.0ml/day) into pregnant mice during gestation and found altered exploration and motor coordination and changes in cerebellar magnetic resonance spectroscopy in the mouse offspring, comparing with offspring of mice injected with sera from mothers of healthy children. This evidence supports a role for maternal antibodies in some forms of neurodevelopmental disorder. Ann Neurol 2003;53:533–537
Measles virus normally causes disease in human beings, and the host range of this virus may be determined by a specific receptor on the surface of primate cells. Human-rodent somatic cell hybrids were tested for their ability to bind measles virus, and only cells that contained human chromosome 1 were capable of binding virus. A study of lymphocyte markers suggested that the complement regulator known either as membrane cofactor protein or CD46 was the measles virus receptor. We proved this hypothesis by demonstrating that hamster cell lines that expressed human CD46 could subsequently bind virus. Furthermore, infected CD46+ cells produced syncytia and viral proteins. Finally, polyclonal antisera against CD46 inhibited virus binding and infection. These results prove that human CD46 permits cells both to bind measles virus and to support infection.
To facilitate investigation of cytokine regulation of reactive astrogliosis, primary astrocyte cultures from neonatal murine forebrain and brainstem were established. Forebrain and brainstem astrocytes proliferated at a similar rate under basal culture conditions, and both were growth-inhibited by treatment with recombinant murine interferon-gamma. The growth of cultured brainstem astrocytes was significantly enhanced by exposure to recombinant human transforming growth factor-beta 1. In contrast, proliferation of forebrain astrocytes was not significantly affected by transforming growth factor-beta 1. The disparate responses of brainstem and forebrain astrocytes to transforming growth factor-beta 1 treatment were not limited to effects on cell growth, since transforming growth factor-beta 1 could block interferon-gamma-induced MHC class-II antigen expression on cultured brainstem astrocytes but not on forebrain cells. Results could not be attributed to use of an heterologous cytokine/cellular target system, since similar variability in transforming growth factor-beta 1 modulation of major histocompatibility complex antigen expression could be demonstrated using two human astrocytoma cell lines. This report is the first to document mitogenic response to transforming growth factor-beta 1 for neuroepithelial cells. The role of transforming growth factor-beta 1 in regulating aspects of reactive astrogliosis, particularly in the context of inflammatory demyelination, requires further investigation. Furthermore, these studies may provide insight into regional variability in the sequelae of inflammation within the central nervous system.
Mercury and its compounds are toxic substances that are widely used in industry and agriculture. Mercury poisoning is an uncommon but important clinical entity that often presents with psychiatric disturbances as a prominent part of the clinical picture. In this paper, a case of mercury poisoning in a 12-year-old girl with prominent psychiatric manifestations is presented. Relevant literature concerning the psychiatric manifestations of mercury poisoning is discussed. The importance of considering mercury poisoning, and toxic conditions in general, in the differential diagnosis of psychiatric disorders is emphasized.
We previously reported that the complement C4B null allele appears to be associated with infantile autism. Since the C4B null allele is known to be part of the extended or ancestral haplotype [B44-SC30-DR4], we investigated the incidence of [B44-SC30-DR4] in 21 autistic children and their parents. This extended haplotype was increased by almost six-fold in the autistic subjects as compared with healthy controls. Moreover, the total number of extended haplotypes expressed on chromosomes of autistic subjects was significantly increased as compared with those expressed on chromosomes of healthy subjects. We conclude that a gene related to, or included in, the extended major histocompatibility complex may be associated with autism.
Inflammation and phagocytosis are highly complex events involving many humoral and cellular factors, with complement components playing a key role. As described here by Mike Frank and Louis Fries, complement peptides trigger cell function, aid in the recognition of invading pathogens and regulate the phagocytic process via interactions with specific cell surface receptors.
Associations between C4 deficiency and autoimmune disorders have been found over the past several years. Since autism has several autoimmune features, the frequencies of null (no protein produced) alleles at the C4A and C4B loci were studied in 19 subjects with autism and their family members. The autistic subjects and their mothers had significantly increased phenotypic frequencies of the C4B null allele (58% in both the autistic subjects and mothers, compared with 27% in control subjects). The siblings of the autistic subjects also had an increased frequency of the C4B null allele, but this increase was not significant. The fathers had normal frequencies of this null allele. All family members had normal frequencies of the C4A null allele, all normal C4A and C4B alleles and all BF and C2 alleles.
Autism and autistic-like conditions of childhood continue to be the focus of child psychiatric and neurobiological research attention all over the world. This paper reviews some of the most interesting research in the field during the latter part of the 1980s
Maternal antibodies reactive with antigenic proteins expressed on the cell surface of paternal lymphocytes can be detected in couples with histories of more than one miscarriage or stillbirth. It is possible, but not proven, that these antibodies also react with tissues of the fetus and result in fetal death. Since many mothers of autistic children have a history of pregnancy disorder, antibodies were studied in 11 mothers of autistic children who were 6 years of age or younger. Six of the mothers had antibodies that reacted with lymphocytes of the autistic child. Five of these six mothers had a history of pregnancy disorder. Since antigens expressed on lymphocytes are found on cells of the central nervous system and, perhaps, other tissues of the developing embryo, it is suggested that aberrant maternal immunity may be associated with the development of some cases of infantile autism.
The basic phenomenology of disordered lymphocyte function because of the infection by a lymphotropic virus is neither novel nor unexpected. The problem of measles virus-induced immunosuppression is contemporaneous with modern immunology and virology. This chapter explains that immunosuppression associated with HIV infection currently commands significant attention in biomedical research. Any unexplained disorder of immune response, either heightened or suppressed, might well be investigated with an infectious etiology in mind. Measles virus infects a wide range of epithelial and lymphoblastoid cell lines in vitro. The cell membrane receptor for measles virus is a nonsialated oligosaccharide present on many cells. Productive infection of cells by measles virus is not lytic and constitutive cellular protein synthesis is not altered. Active tuberculosis infection is a common sequela of measles virus infection. Researchers showed that blastogenic response of lymphocytes from the peripheral blood of tuberculosis-immune individuals to tuberculin antigen is significantly reduced during acute measles virus infection. The suppression by measles virus of the proliferative response to mitogen occurs with lymphocytes from both the nonimmune and the measles-immune donors, but serum containing measles antibody abrogates the suppression. During chronic HIV infection in vivo and in vitro, proviral DNA exists in both integrated and nonintegrated forms. Unlike the other lentiviruses and most retroviruses, a cellular receptor for HIV has been well characterized. The immunosuppression in AIDS patients has been characterized by global dysfunction of cellular immunity and polyclonal B cell activation. A significant part of this chapter discusses the immune dysfunction during HIV infection prior to the onset of AIDS and on the effects of HIV infection of lymphocytes and monocytes in vivo.
In an attempt to elucidate the mechanisms of methylmercury (MeHg) action on the developing brain, MeHg effects on neuronal migration and on proliferative neuroepithelial germinal cells within the ventricular zone of telencephalic vesicles were investigated in C57BL/6J mice. 3H-thymidine autoradiographic studies following acute and chronic MeHg intoxication in embryonic mice showed that heavily labeled neurons (generated on E-16) within specified regions of the cerebral cortex of prenatally intoxicated offspring were distributed irregularly throughout layers II and III, whereas those in controls were tightly clustered within the upper part of layer II. These findings support the hypothesis that prenatal MeHg poisoning results in anomalous cytoarchitectonic patterning of the cerebral cortex, and provide a possible morphological basis for some of the neurobehavioral abnormalities that may follow sublethal prenatal MeHg intoxication. Whether the irregular distribution of labeled neurons was due to the effects of MeHg on the dividing neuroepithelial germinal cells, on the process of neuronal migration, or on the final positioning of postmigratory neurons within the cerebral cortex remained unclear. Ultrastructural studies of telencephalic vesicles during acute phases of MeHg intoxication revealed the presence of acute degenerative changes within ventricular cells, characterized by spongy change and vacuolization of the cytoplasmic matrix and by loss of microtubules. 3H-thymidine autoradiography demonstrated features suggestive of disturbed interkinetic nuclear migration. Also noted were reduction of the mitotic indices of neuroepithelial germinal cells at the ventricular surface at 4 to 12 hours and early-phase mitotic arrest. These findings suggest that MeHg exerts significant effects on proliferating neuroepithelial germinal cells during the acute phases of MeHg poisoning, and may eventually affect the architectonic makeup of the cortical plate as the brain matures. Additional studies in our laboratory demonstrated 1) a failure of histotypic re-organization of dissociated embryonic cerebral cortical cells in rotation-mediated re-aggregation culture, 2) disturbances in neural cell adhesion molecule expression in PC12 cells, 3) modifications in the density of excitatory neurotransmitter L-glutamate receptors, 4) marked disturbances in the glutamate uptake mechanism of fetal astrocytes in vitro, and 5) reductions in cholinoceptive muscarinic receptor (M1 and M2) binding in selected regions of the cerebrum. Thus, MeHg may affect the developing brain through diverse pathogenetic pathways. Possible effects of mercurial compounds on the interaction between certain serine proteases and protease inhibitors during brain development are also discussed.
We have begun an investigation on the immune systems of patients with autism in attempt to determine if immune mechanisms are involved in the development of this severe developmental disorder. A study of 31 autistic patients has revealed several immune-system abnormalities, including reduced responsiveness in the lymphocyte blastogenesis assay to phytohemagglutinin, concanavalin A, and pokeweed mitogen; decreased numbers of T lymphocytes; and an altered ratio of helper to suppressor T cells. Immune-system abnormalities may be directly related to underlying biologic processes of autism, or these changes may be an indirect reflection of the actual pathologic mechanism.
Autism is a neurologic disorder that severely impairs social, language, and cognitive development. Whether autism involves maldevelopment of neuroanatomical structures is not known. The size of the cerebellar vermis in patients with autism was measured on magnetic resonance scans and compared with its size in controls. The neocerebellar vermal lobules VI and VII were found to be significantly smaller in the patients. This appeared to be a result of developmental hypoplasia rather than shrinkage or deterioration after full development had been achieved. In contrast, the adjacent vermal lobules I to V, which are ontogenetically, developmentally, and anatomically distinct from lobules VI and VII, were found to be of normal size. Maldevelopment of the vermal neocerebellum had occurred in both retarded and nonretarded patients with autism. This localized maldevelopment may serve as a temporal marker to identify the events that damage the brain in autism, as well as other neural structures that may be concomitantly damaged. Our findings suggest that in patients with autism, neocerebellar abnormality may directly impair cognitive functions that some investigators have attributed to the neocerebellum; may indirectly affect, through its connections to the brain stem, hypothalamus, and thalamus, the development and functioning of one or more systems involved in cognitive, sensory, autonomic, and motor activities; or may occur concomitantly with damage to other neural sites whose dysfunction directly underlies the cognitive deficits in autism.
Natural killer (NK) cells arc believed to afford protection against malignancy and viral infections. In addition, these cells may be involved in regulating the immune response because altered NK activity is often associated with autoimmune disorders. An investigation of the natural cytotoxic potential of peripheral blood mononuclear cells from 31 patients with autism has been carried out using K562 tumor cells as target cells. Cells of 12 of the patients induced significantly reduced levels of cytotoxicity; this was not correlated with a quantitative alteration in patient NK cells as determined by use of the Leu-11 monoclonal antibody. This observation of altered NK cell activity, and previously reported findings of other immune abnormalities in autism, suggest that immune changes may be directly related to underlying biological processes of autism or that these changes may be an indirect reflection of the actual pathological mechanism.
As part of an autopsy research project, the brains of four autistic subjects were examined and compared with those of three comparison subjects without CNS pathology and one with phenytoin toxicity. The cerebellum was selected for initial investigation because pathognomonic symptoms and neurophysiological measures suggest that pathology may exist in the cerebellar-vestibular axis in certain patients. Total Purkinje cell counts were significantly lower in the cerebellar hemisphere and vermis of each autistic subject than in the comparison subjects.
Cells in the brain express unusually low levels of antigens encoded by the major histocompatibility complex (MHC). This is somewhat surprising as class I (H-2) and class II (Ia) MHC antigens have critical roles in immune responses. The activation of T lymphocytes is associated with the enhanced expression of these antigens and this effect is mediated by a specific T-cell lymphokine, gamma-interferon (IFN-gamma). Here we show that IFN-gamma induces a dramatic increase in the expression of H-2 antigens on the cells of the brain. After exposure to IFN-gamma in vitro, all surviving cells, including most astrocytes, oligodendrocytes, microglia and at least some neurones, express H-2 antigens. Direct injection of IFN-gamma into the brains of mice indicated that H-2 antigens were also induced in vivo. Furthermore, IFN-gamma induced Ia antigens on a subpopulation of astrocytes. The induction of H-2 antigens by IFN-gamma may render brain cells competent to initiate and participate in immune reactions and may therefore contribute to both immunoprotective and immunopathological responses in the brain.
Early infantile autism is the most severe of a group of neurodevelopmental syndromes called the pervasive developmental disorders. The clinical features of autism vary greatly, but, by definition, include deficits in social relatedness, communication, and interests or routines. The onset of autistic signs and behaviors typ ically occurs in infancy, and the syndrome is usually fully present by the fourth year. The presence of mental retardation affects the clinical picture greatly. Severely autistic children may be retarded and mute and are often preoccupied with repetitive activities; they often exhibit motor stereotypes, such as rocking or hand flapping. They can be profoundly withdrawn and may show extreme aversion to social or physical contact. More mildly affected children may have normal or even superior intelligence, with well-developed language skills. Their deficits in social relatedness and preoccupation with rituals and routines may set them apart as very odd, but not necessarily as autistic. Autism occurs in 1 of 2000 live births; boys outnumber girls about 3 or 4:1. Although there are no localizing neurological signs in autism, mild or "soft" neurological signs are common and grand mal seizures are frequently present after puberty (Lotspeich LJ, Ciaranello RD. The neurobiology and genetics of infantile autism. In: Bradley R, editor. International reviews of neurobiology. San Diego: Academic Press 1993:87-129). The Neuroscientist 1:361-367, 1995
Optimal T-cell activation and T-cell expansion require triggering by T-cell antigen receptors and co-stimulatory signals provided by accessory cells. A major co-stimulatory pathway involves crosslinking the CD28 molecule on T cells by its ligands CD80 or CD86 expressed on antigen-presenting cells. But recent studies on CD28-deficient mice have indicated that CD28 is not required for all T-cell responses and that additional T-cell co-stimulatory pathways exist. Here we describe a novel glycoprotein, of relative molecular mass 70,000 (M(r) 70K), designated SLAM, that belongs to the immunoglobulin gene superfamily, which is involved in T-cell stimulation. SLAM is constitutively expressed on peripheral-blood CD45ROhigh memory T cells, T-cell clones, immature thymocytes, and a proportion of B cells, and is rapidly induced on naive T cells after activation. Engagement of SLAM enhances antigen-specific proliferation and cytokine production by T cells carrying the CD4 antigen (CD4+). Particularly, the production of interferon-gamma (IFN-gamma) is strongly upregulated, even in T helper type 2 (Th2) CD4+ T-cell clones, whereas no induction of interleukin (IL)-4 or IL-5 production was observed in Th1 clones. In addition, the engagement of SLAM induces directly the proliferation of CD4+ T-cell clones and preactivated T cells, in the absence of any other stimuli, and without CD28 involvement. Thus SLAM is a novel receptor on T cells that, when engaged, potentiates T-cell expansion in a CD28-independent manner and induces a Th0/Th1 cytokine production profile.
Whether neurons express major histocompatibility complex (MHC) class I genes has not been firmly established. The techniques
of confocal laser microscopy, patch clamp electrophysiology, and reverse transcriptase-polymerase chain reaction were combined
here to directly examine the inducibility of MHC class I genes in individual cultured rat hippocampal neurons. Transcription
of MHC class I genes was very rare in neurons with spontaneous action potentials. In electrically silent neurons, transcription
was noted, with expression of beta 2-microglobulin under tighter control than in class I heavy chain molecules. Surface expression
of class I molecules occurred only in electrically silent neurons treated with interferon gamma. Immunosurveillance by cytotoxic
T cells may be focused on functionally impaired neurons.
Based on a possible pathological relationship of autoimmunity to autism, antibodies reactive with myelin basic protein (anti-MBP) were investigated in the sera of autistic children. Using a screening serum dilution of 1:400 in the protein-immunoblotting technique, approximately 58% (19 of 33) sera of autistic children (< or = 10 years of age) were found to be positive for anti-MBP. This result in autistics was significantly (p < or = .0001) different from the controls (8 of 88 or only 9% positive), which included age-matched children with normal health, idiopathic mental retardation (MR) and Down syndrome (DS), and normal adults of 20 to 40 years of age. Since autism is a syndrome of unknown etiology, it is possible that anti-MBP antibodies are associated with the development of autistic behavior.
Heavy metals have been shown to exert immunotoxic effects on humoral immunity. To ascertain the mechanisms by which these immunotoxic effects are exerted, the effects of CdCl2 and HgCl2 on the biology of murine B-lymphocytes were studied. It was shown that CdCl2 and HgCl2 inhibited B-cell RNA and DNA synthesis. The IC50 (the concentration required to inhibit a specific B-cell function by 50%) for CdCl2 was 30 microM for RNA synthesis and DNA synthesis. The IC50 for HgCl2 was 50 and 120 nM for RNA and DNA synthesis, respectively. Cell cycle analysis revealed that B-cells were arrested throughout the cell cycle with CdCl2 and HgCl2. The inhibitory effects exerted by CdCl2 and HgCl2 were rapid, inhibiting RNA synthesis within 2 h of activation. Differentiation to Ig secretion was inhibited by CdCl2 and HgCl2 in culture and there appeared to be selective effects on specific Ig isotypes. IgG3 production was most sensitive to inhibition by CdCl2 and HgCl2 followed by IgG1 and IgG2b and then IgM and IgG2a. Changes in the expression of B-cell surface antigens induced by LPS were also influenced by CdCl2. LPS-induced increases in class II MHC expression was inhibited by CdCl2, as was the constitutive expression of class I MHC antigen. A summary of the IC50 for CdCl2 and HgCl2 are presented. In summary, both CdCl2 and HgCl2 exert early, inhibitory effects on B-cell activation. This is manifested by the inhibition of RNA, DNA and antibody synthesis. However, selective effects on the production of specific Ig isotypes by these metals may influence the ability of B-cells to mount effective immune responses to pathogens.
Measles is associated with a vigorous antibody response without production of significant measles virus-specific delayed type
hypersensitivity. Generalized disruption of immune responses also occurs during measles, including depressed skin test responses
and decreased in vitro lymphocyte proliferation to mitogens. To determine if preferential activation of a subset of CD4 cells
might explain these observations, the patterns of cytokines produced in vivo and in vitro during measles were determined.
Soluble CD4 was elevated in plasma at all times. Interleukin (IL)-2 was increased in plasma during and shortly after the clearance
of the rash and then declined. Plasma IL-4 became elevated after resolution ofthe rash and remained elevated in some patients
through the 7-week study period. Mononuclear cells proliferated poorly in response to stimulation with anti-CD3 and produced
low levels of IL-2 and interferon-γ and high levels of IL-4 and IL-6 in vitro. The defect in lymphoproliferation during convalescence
was partially corrected by in vitro neutralization of IL-4. Preferential activation of type 2 cells late during measles may
explain the predominant humoral immune response and the generalized suppression of cellular immune responses.
In this pilot study, brain high energy phosphate and membrane phospholipid metabolism were investigated in the dorsal prefrontal cortex of 11 high-functioning autistic adolescent and young adult men (the age range is 12-36 years) and 11 age-, gender-, IQ, race- and socioeconomic status-matched normal controls using in vivo 31P nuclear magnetic resonance spectroscopy (MRS). The autistic group had decreased levels of phosphocreatine and esterified ends (alpha ATP + alpha ADP + dinucleotides + diphosphosugars) compared to the controls. When the metabolite levels were compared within each subject group with neuropsychologic and language test scores, a common pattern of correlations was observed across measures in the autistic group, but not in the control group. As test performance declined in the autistic subjects, levels of the most labile high energy phosphate compound and of membrane building blocks decreased, and levels of membrane breakdown products increased. No significant correlations were present with age in either group or with IQ in the control group, suggesting that these findings were not the consequence of age or IQ effects. This pilot study provides tentative evidence of alterations in brain energy and phospholipid metabolism in autism that correlate with the neuropsychologic and language deficits. The findings are consistent with a hypermetabolic energy state and undersynthesis of brain membranes and may relate to the neurophysiologic and neuropathologic abnormalities in autism.
We characterize the expression, biochemical structure, and function of a novel glycoprotein, IPO-3, up-regulated on activated human lymphocytes. IPO-3 is found on activated B cells, B cell lines, and hairy cell leukemias but is not expressed on T cell or nonlymphoid cell lines. IPO-3 is not B cell-specific as it is detected at low levels on CD45RO+ CD45RA- peripheral blood T cells and CD4+CD8+CD45RO+ CD45RA- thymocytes. The IPO-3 Ag is a single-chain heavily N-glycosylated phosphoglycoprotein approximately 75 to 95 kDa in size with a 42-kDa protein core. In vitro kinase assays revealed that IPO-3 has a protein kinase activity associated with it that is maintained even in Nonidet P-40 lysates. IPO-3 is up-regulated on resting B cells within 16 h after activation with different signals including anti-IgM, IL-4, or mAb to CD40, CD20, or Bgp95. It could also be induced on T cells via CD3-cross-linking, but the kinetics of IPO-3 induction was slower on T cells than on B cells. Cross-linking IPO-3 on B cells with mAb did not induce proliferation alone but did augment proliferation promoted by IL-4 and anti-CD40 and did trigger increases in [Ca2+]i in resting B cells. Binding of IPO-3 could not be inhibited by a variety of mAb to previously identified activation markers. Thus, the IPO-3 glycoprotein appears to be a novel marker of activated B and T lymphocytes, which may play a role in the regulation of lymphocyte activation.
Autism likely results from several different etiologies or a combination of pathological mechanisms. Recent studies suggest that this disorder may be associated with immune abnormalities, pathogen-autoimmune processes and perhaps the major histocompatibility complex (MHC). In a preliminary study we found that 22 autistic subjects had an increased frequency of the extended or ancestral MHC haplotype B44-SC30-DR4. The current study attempted to confirm this observation by studying 23 additional randomly chosen autistic subjects, most of their parents and 64 unrelated normal subjects. In agreement with earlier findings B44-SC30-DR4 was associated with autism. In combining the data from the original and current studies, B44-SC30-DR4 or a substantial fragment of this extended haplotype was represented in 40% of the autistic subjects and/or their mothers as compared to about 2% of the unrelated subjects. It is concluded that one or more genes of the MHC is (are) involved in the development of some cases of autism.
Immune factors such as autoimmunity have been implicated in the genesis of autism, a neurodevelopmental disorder. Since autoimmune response involves immune activation, the plasma levels of interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), interleukin-12 (IL-12), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and soluble intercellular adhesion molecule-1 (sICAM-1) were measured in autistic patients and age-matched normal controls. The levels of IL-12 and IFN-gamma were significantly (P < or = 0.05) higher in patients as compared to controls. However, IFN-alpha, IL-6, TNF-alpha, and sICAM-1 levels did not significantly differ between the two groups. Because macrophage-derived IL-12 is known to selectively induce IFN-gamma in T helper type-1 (Th-1) cells, it is suggested that IL-12 and IFN-gamma increases may indicate antigenic stimulation of Th-1 cells pathogenetically linked to autoimmunity in autism.
Mercury can induce autoimmune disease in susceptible mouse strains. We found that in vitro mercuric chloride induced a high proliferative response in spleen lymphocytes from mercury-susceptible SJL mice, but a low response in resistant mice, such as C57BL/6 (H-2b), A/J (H-2a) and CBA (H-2k) mice. However, a high proliferative response was obtained with lymphocytes from all tested low-responder mice by pretreating them in vitro for 1-3 days with mercuric chloride and then wash away the excess mercury. Both CD4+ and CD8+ T cells were activated in the restored response, but CD4+ T cells was the major responding cell population, as in high-responder mice. We also measured the cytokine production at the protein level after mercury stimulation in vitro. We found that in mercury stimulation the different culture conditions resulted in different patterns of cytokine production. The continuous presence of mercury induced interleukin-2 (IL-2) and interferon-gamma, but not IL-4 production in spleen cells from both high- and low-responder mice. In contrast, by pretreating the cells with mercury and then washing, spleen cells from both high and low-responder mice produced IL-4. Our results suggest that spleen cells from both mercury-susceptible and -resistant mice have the potential to respond to mercury in vitro and produce both Th1- and Th2-type cytokines. But the mercury-induced cytokine profile can shift depending on the conditions for activation.
As well as inducing a protective immune response against reinfection, acute measles is associated with a marked suppression of immune functions against superinfecting agents and recall antigens, and this association is the major cause of the current high morbidity and mortality rate associated with measles virus (MV) infections. Dendritic cells (DCs) are antigen-presenting cells crucially involved in the initiation of primary and secondary immune responses, so we set out to define the interaction of MV with these cells. We found that both mature and precursor human DCs generated from peripheral blood monocytic cells express the major MV protein receptor CD46 and are highly susceptible to infection with both MV vaccine (ED) and wild-type (WTF) strains, albeit with different kinetics. Except for the down-regulation of CD46, the expression pattern of functionally important surface antigens on mature DCs was not markedly altered after MV infection. However, precursor DCs up-regulated HLA-DR, CD83, and CD86 within 24 h of WTF infection and 72 h after ED infection, indicating their functional maturation. In addition, interleukin 12 synthesis was markedly enhanced after both ED and WTF infection in DCs. On the other hand, MV-infected DCs strongly interfered with mitogen-dependent proliferation of freshly isolated peripheral blood lymphocytes in vitro. These data indicate that the differentiation of effector functions of DCs is not impaired but rather is stimulated by MV infection. Yet, mature, activated DCs expressing MV surface antigens do give a negative signal to inhibit lymphocyte proliferation and thus contribute to MV-induced immunosuppression.
As our knowledge of the interactions of the immune, nervous and endocrine systems progresses, complex links with the origin and course of psychopathology in childhood are revealed. In this article the neuroimmunological literature on autism is reviewed. Relevant aspects of immune functioning and the neuroendocrine-immune network are described. We present the immunological findings in autistic patients within two related conceptual frameworks: a viral and an autoimmune hypothesis. Interpretation of data is hampered by conceptual and methodological differences between studies. Both the clinical significance of the immune changes and the causal connection between immune changes and psychopathological phenomena in autism remain to be elucidated. Recommendations for further research are given.