Impact of environmental pollution, dietary factors and diabetes mellitus on Autism Spectrum Disorder (ASD).

Autism spectrum disorder (ASD) is complex neurodevelopmental condition described by impairments in three main behavioral areas: social deficits, impaired communication, and repetitive behaviors. Despite many years of vast study, the causes of ASD are still unknown. Various risk factors including genetic, infectious, metabolic and immunological have been investigated however, environmental, nutritional and diabetes related risk factors have not received sufficient attention. This study has provided an insight into the comprehensive interaction between environmental pollution, dietary factors and diabetes mellitus that could lead to the advancement of this debilitating neurodevelopment disorder. The literature search was done using PubMed and Google Scholar databases up to October 2018. Key words "Environmental Pollution", "Nutritional Factors", "Diabetes Mellitus", "Autism Spectrum Disorder" were selected.

Downregulation in Helios transcription factor signaling is associated with immune dysfunction in blood leukocytes of autistic children.

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.

Upregulation of peripheral CXC and CC chemokine receptor expression on CD4+ T cells is associated with immune dysregulation in children with autism.

Autism spectrum disorders (ASD) are characterized by disturbances in social interactions and communication, restricted repetitive interests, and stereotyped behavior. Cumulative evidence recommends that there are immune alterations in ASD. Chemokine receptors are known to play an important role in the central nervous system (CNS) and in many neuro inflammatory disorders. The main objective of this study was to explore the role of CXC and CC chemokine receptors signaling in children with autism. We examined chemokine receptor production of CXCR2, CXCR3, CXCR5, and CXCR7 in all peripheral blood mononuclear cells (PBMCs) and in CD4+ T cells of typically developing control children (TD) and autistic children (AU). We also examined chemokine receptor production of CCR3, CCR5, CCR7, and CCR9 in all PBMCs and in CD4+ T cells of AU and TD samples using flow cytometric analysis. In addition, we measured mRNA expression levels of CXC and CC chemokine receptors using quantitative RT-PCR analysis. Our results showed the increased production of CXCR2+, CXCR3+, CXCR5+, and CXCR7+ and CCR3+, CCR5+, CCR7+, and CCR9+ in all PBMCs and in CD4+ T cells of children with AU as compared to TD controls. Our results show that chemokine receptor signaling components might provide unique therapeutic targets for children with AU and other neurological disorders.

Upregulation of IL-9 and JAK-STAT signaling pathway in children with autism.

Autism spectrum disorder (ASD) gradually develops predominantly neurodevelopmental disorders, which are socially diagnosed in early childhood. Though the etiopathology of ASD is not clear, immune alteration has been suggested as autism's pathophysiological mechanism. Previous studies found that several cytokines and transcription factor activation pathways were significantly increased in ASD. IL-9 has been confirmed to play a significant role in the central nervous system (CNS). The aim of the present study was to investigate the understudied role of pro- and anti-inflammatory cytokines and the JAK-STAT signaling pathway in ASD. We examined the IL-1ß, IL-4, IFN-γ, and IL-9 positive immunostaining in all cells, and CD4+ T cells, in ASD and normally developing control children (TD), on peripheral blood mononuclear cells (PBMCs), using flow cytometry. We explored PBMC mRNA expression levels for IL-1ß, IL-4, IFN-γ, IL-9, JAK1, and STAT5, by using real-time PCR (RT-PCR). We also explored PBMC protein expression levels for IL-1ß, IL-4, IL-9, pJAK1, and pSTAT5 by using western blotting. We found that the children with ASD had increased IL-1ß, IL-4, IFN-γ, and IL-9 positive immunostaining in all cells, and in CD4+ cells, relative to the TD controls. The mRNA and protein expression for IL-1ß, IL-4, IFN-γ, IL-9, JAK1, pJAK1, STAT5, and pSTAT5 were also significantly elevated in ASD relative to TD controls. These results suggested that cytokines and JAK-STAT activation signaling have an essential role in immune dysfunction in ASD.

Toll-like receptors, NF-κB, and IL-27 mediate adenosine A2A receptor signaling in BTBR T+ Itpr3tf/J mice.

Autism is a predominant neurodevelopmental disorder characterized by impaired communication, social deficits, and repetitive behaviors. Recent research has proposed that the impairment of innate immunity may play an important role in autism. Toll-like receptors (TLRs) are potential therapeutic targets against neuroinflammation. The BTBR T+ Itpr3tf/J (BTBR) mouse is a well-known model of autism, showing repetitive behaviors such as cognitive inflexibility and increased grooming as compared to C57BL/6 (B6) mice. Adenosine A2A receptor (A2AR) signaling is involved in inflammation, brain injury, and lymphocyte infiltration into the CNS, but the role of A2AR in autism remains unknown. We investigated the effect of A2AR antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on the expression levels of TLRs, IL-27, NF-κB p65, and IκBα in BTBR mice. Treatment of BTBR mice with SCH increased the percentage of splenic CD14+TLR2+ cells, CD14+TLR3+ cells, CD14+TLR4+ cells, and decreased the percentage of CD14+IL-27+ cells, as compared to the untreated BTBR mice. Our results reveal that BTBR mice treated with CGS had reversal of SCH-induced immunological responses. Moreover, mRNA and protein expression analyses confirmed increased expression of TLR2, TLR3, TLR4, and NF-κB p65 in brain tissue, and decreased IL-27 and IκBα expression following SCH treatment, as compared to the untreated-BTBR and CGS-treated BTBR mice. Together, these results suggest that the A2AR agonist corrects neuroimmune dysfunction observed in BTBR mice, and thus has the potential as a therapeutic approach in autism.

Dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in children with autism.

Autism is a neurodevelopmental disorder characterized by stereotypic repetitive behaviors, impaired social interactions, and communication deficits. Numerous immune system abnormalities have been described in individuals with autism including abnormalities in the ratio of Th1/Th2/Th17 cells; however, the expression of the transcription factors responsible for the regulation and differentiation of Th1/Th2/Th17/Treg cells has not previously been evaluated. Peripheral blood mononuclear cells (PBMCs) from children with autism (AU) or typically developing (TD) control children were stimulated with phorbol-12-myristate 13-acetate (PMA) and ionomycin in the presence of brefeldin A. The expressions of Foxp3, RORγt, STAT-3, T-bet, and GATA-3 mRNAs and proteins were then assessed. Our study shows that children with AU displayed altered immune profiles and function, characterized by a systemic deficit of Foxp3+ T regulatory (Treg) cells and increased RORγt+, T-bet+, GATA-3+, and production by CD4+ T cells as compared to TD. This was confirmed by real-time PCR (RT-PCR) and western blot analyses. Our results suggest that autism impacts transcription factor signaling, which results in an immunological imbalance. Therefore, the restoration of transcription factor signaling may have a great therapeutic potential in the treatment of autistic disorders.

Resveratrol Ameliorates Dysregulation of Th1, Th2, Th17, and T Regulatory Cell-Related Transcription Factor Signaling in a BTBR T + tf/J Mouse Model of Autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder. It is characterized by impaired social communication, abnormal social interactions, and repetitive behaviors and/or restricted interests. BTBR T + tf/J (BTBR) inbred mice are commonly used as a model for ASD. Resveratrol is used widely as a beneficial therapeutic in the treatment of an extensive array of pathologies, including neurodegenerative diseases. In the present study, the effect of resveratrol administration (20 and 40 mg/kg) was evaluated in both BTBR and C57BL/6 (B6) mice. Behavioral (self-grooming), Foxp3, T-bet, GATA-3, RORγt, and IL-17A in CD4+ T cells were assessed. Our study showed that BTBR control mice exhibited a distinct immune profile from that of the B6 control mice. BTBR mice were characterized by lower levels of Foxp3+ and higher levels of RORγt+, T-bet+, and GATA-3+ production in CD4+ T cells when compared with B6 control. Resveratrol (20 and 40 mg/kg) treatment to B6 and BTBR mice showed substantial induction of Foxp3+ and reduction of T-bet+, GATA-3+, and IL-17A+ expression in CD4+ cells when compared with the respective control groups. Moreover, resveratrol treatment resulted in upregulated expression of Foxp3 mRNA and decreased expression levels of T-bet, GATA-3, RORγt, and IL-17A in the spleen and brain tissues. Western blot analysis confirmed that resveratrol treatment decreased the protein expression of T-bet, GATA-3, RORγ, and IL-17 and that it increased Foxp3 in B6 and BTBR mice. Our results suggest that autism is associated with dysregulation of transcription factor signaling that can be corrected by resveratrol treatment.

Imbalance between the anti- and pro-inflammatory milieu in blood leukocytes of autistic children.

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.

Resveratrol treatment attenuates chemokine receptor expression in the BTBR T+tf/J mouse model of autism.

Autism is a neurodevelopmental disorder categorized by qualitative impairments in social interaction, communication, and repetitive stereotypic behavior. Emerging evidence increasingly suggests that chemokine receptors have a pivotal role in the central nervous system and are involved in the pathogenesis of numerous neuroinflammatory diseases. Resveratrol is widely used to treat neurodegenerative diseases, but its effect on autism has not been investigated. We investigated the effect of resveratrol (20 and 40mg/kg) in the spleen and brain tissues of BTBR T+tf/J (BTBR) and C57BL/6J (B6) mice as well as on the C-C chemokine receptor (CCR) and C-X-C motif chemokine receptor (CXCR) (CCR3+, CCR5+, CCR7+ and CCR9+, CXCR3+ and CXCR5+) in cluster of differentiation 4-positive (CD4+) T cells in the spleen. We also assessed the mRNA expression of CCR and CXCR receptors in the spleen and brain tissues. Our study revealed that the BTBR and B6 control mice showed different immune profiles. The BTBR mice showed characteristic higher levels of both CCR and CXCR production and expression in CD4+ T cells than the B6 control mice did. Treatment of B6 and BTBR mice with resveratrol (20 and 40mg/kg) induced a substantial decrease in the CCR and CXCR production and expression in CD4+ T cells compared with the respective untreated control groups. Moreover, resveratrol treatment decreased the mRNA expression levels of CCR and CXCR in the spleen and brain tissues. Resveratrol downregulated the chemokine receptor levels, which might provide unique targets for future therapies for autism.

The positive association between elevated blood lead levels and brain-specific autoantibodies in autistic children from low lead-polluted areas.

The underlying pathogenic mechanism in autoimmune disorders is the formation of autoantibodies. In children with autism spectrum disorder (ASD), it has been documented increased levels of brain-specific autoantibodies. Furthermore, lead (Pb) has been identified as one of the main neurotoxicants acting as environmental triggers for ASD as it induces neuroinflammation and autoimmunity. The present study is the first to explore a potential relationship between the levels of blood lead (BPb) and seropositivity of anti-ribosomal P protein antibodies in ASD children. Levels of BPb and serum anti-ribosomal P protein antibodies were measured in 60 children with ASD and 60 healthy control matched children, aged between 5 and 12 years, recruited from low Pb-polluted areas. The levels of BPb were significantly higher in ASD children than in healthy control children (P < 0.001). Patients with ASD had significantly higher frequency of increased BPb levels ≥10 µg/dL (43.3 %) than healthy control children (13.3 %; P < 0.001). There were significant and positive correlations between the levels of BPb, and the values of Childhood Autism Rating Scale (CARS) (P < 0.01) and IQ in children with ASD (P < 0.001). Patients with ASD showing increased levels of BPb had significantly higher frequency of seropositivity of anti-ribosomal P antibodies (92.3 %) than patients with normal BPb levels (32.3 %; P < 0.001). The findings of the present study suggest that increased levels of BPb in some children with ASD may trigger the production of serum anti-ribosomal P antibodies. Further research is warranted to determine if the production of brain autoantibodies is triggered by environmental Pb exposure in children with ASD. The possible therapeutic role of Pb chelators in ASD children should also be studied.

The levels of blood mercury and inflammatory-related neuropeptides in the serum are correlated in children with autism spectrum disorder.

Tachykinins (substance P, neurokinin A, and neurokinin B) are pro-inflammatory neuropeptides that may play an important role in some autoimmune neuroinflammatory diseases, including autism spectrum disorder (ASD). Mercury (Hg) is a neurotoxicant, and potentially one of the main environmental triggers for ASD as it induces neuroinflammation with a subsequent release of neuropeptides. This is the first study to explore the potentially causal relationship between levels of serum neurokinin A and blood mercury (BHg) in children with ASD. Levels of serum neurokinin A and BHg were measured in 84 children with ASD, aged between 3 and 10 years, and 84 healthy-matched children. There was a positive linear relationship between the Childhood Autism Rating Scale (CARS) and both serum neurokinin A and BHg. ASD children had significantly higher levels of serum neurokinin A than healthy controls (P < 0.001). Increased levels of serum neurokinin A and BHg were respectively found in 54.8 % and 42.9 % of the two groups. There was significant and positive linear relationship between levels of serum neurokinin A and BHg in children with moderate and severe ASD, but not in healthy control children. It was found that 78.3 % of the ASD patients with increased serum levels of neurokinin A had elevated BHg levels (P < 0.001). Neuroinflammation, with increased levels of neurokinin A, is seen in some children with ASD, and may be caused by elevated BHg levels. Further research is recommended to determine the pathogenic role of increased levels of serum neurokinin A and BHg in ASD. The therapeutic role of tachykinin receptor antagonists, a potential new class of anti-inflammatory medications, and Hg chelators, should also be studied in ASD.

The possible link between elevated serum levels of epithelial cell-derived neutrophil-activating peptide-78 (ENA-78/CXCL5) and autoimmunity in autistic children.

BACKGROUND: In autoimmune disorders, the underlying pathogenic mechanism is the formation of antigen-antibody complexes which trigger an inflammatory response by inducing the infiltration of neutrophils. Epithelial cell-derived neutrophil-activating peptide-78 (ENA-78) is a chemokine that recruits and activates neutrophils, thus it could play a pathogenic role in inflammation and autoimmune disorders. Some autistic children have elevated levels of brain specific auto-antibodies. We are the first to evaluate serum expression of ENA-78 and its relation to antineuronal auto-antibodies in autistic children. METHODS: Serum ENA-78 and antineuronal auto-antibodies were measured by ELISA test in 62 autistic children aged between 4-11 years and 62 health-matched controls. RESULTS: Serum levels of ENA-78 were significantly higher in autistic children than healthy controls (P < 0.001). Increased serum levels of ENA-78 have been found in 69.35% of autistic patients. In addition, autistic children had significantly higher percent positivity of serum antineuronal auto-antibodies (64.5%) than healthy controls (6.45%), P < 0.001. There was a significant positive association between the positivity of serum antineuronal auto-antibodies and the elevated levels of serum ENA-78 (P < 0.001) in autistic children. CONCLUSIONS: Serum levels of ENA-78 were elevated in autistic children and they were significantly associated with the increased levels of serum antineuronal auto-antibodies. However, these data should be treated with caution until further research is conducted to determine the pathogenic role of ENA-78 in autism and its relation to brain specific auto-antibodies that have been found in some autistic children. The possible therapeutic role of ENA-78 antagonist in autistic children should be also studied.

Serum antinucleosome-specific antibody as a marker of autoimmunity in children with autism.

BACKGROUND: Increasing evidence of autoimmune phenomena in some individuals with autism could represent the presence of altered or inappropriate immune responses in this disorder. The role of the nucleosome in the induction of antibody response in some autoimmune-mediated tissue damage may provide novel targets for treatment. Due to the paucity of studies investigating the frequency of systemic auto-antibodies in autism, we are the first to investigate the frequency of antinucleosome-specific antibodies in a group of autistic children. METHODS: Serum antinucleosome-specific antibodies were measured by ELISA in 60 autistic children, between the ages of 3 and 12 years, in comparison to 60 healthy children. Autistic severity was assessed using the Childhood Autism Rating Scale (CARS). RESULTS: Autistic children had significantly higher serum antinucleosome-specific antibodies than healthy children (P <0.001). The seropositivity of antinucleosome-specific antibodies was found in 46.7% of autistic children. Autistic children with a family history of autoimmunity (40%) had a significantly higher frequency of serum antinucleosome-specific antibodies (83.3%) than patients without such a history (22.2%, P <0.001). CONCLUSIONS: Serum levels of antinucleosome-specific antibodies were increased in some autistic children. However, these data should be treated with caution until further investigations are performed with a larger subject population to determine whether these antibodies have a role in the induction of autoimmunity in a subgroup of autistic children. The role of immunotherapy in children with autism should be also studied.

The possible relationship between allergic manifestations and elevated serum levels of brain specific auto-antibodies in autistic children.

Etiology of autism has become an area of a significant controversy. Allergy induced autism is an area of research wherein immune responses to some allergens may play a pathogenic role in autism. Allergy may induce the production of brain specific auto-antibodies in a subgroup of autistic children. We are the first to investigate the possible link between allergic manifestations and serum levels of both anti-myelin basic protein (anti-MBP) and anti-myelin associated glycoprotein (anti-MAG) brain-specific auto-antibodies, which were measured by ELISA method, in 42 autistic children in comparison to 42 healthy-matched children. Allergic manifestations (bronchial asthma, atopic dermatitis and/or allergic rhinitis) were found in 47.6% of autistic patients. Increased serum levels of anti-MBP and anti-MAG auto-antibodies were found in 57.1% and 66.7%, respectively of autistic children. In addition, 78.5% of autistic children had increased serum levels of both anti-MBP and/or anti-MAG auto-antibodies. Autistic patients with allergic manifestations had significantly higher serum levels of anti-MBP and anti-MAG auto-antibodies than those without these manifestations (P<0.001 and P=0.001, respectively). In conclusion, allergy may be a contributing factor to the increased serum levels of anti-MBP and anti-MAG auto-antibodies in some autistic children. Indeed, we need to know more about the links between allergy, immune system and brain in autism for finding new therapeutic modalities in autism.

Elevated serum levels of macrophage-derived chemokine and thymus and activation-regulated chemokine in autistic children.

BACKGROUND: In some autistic children, there is an imbalance of T helper (Th)1/Th2 lymphocytes toward Th2, which may be responsible for the induction of the production of autoantibodies in these children. Th2 lymphocytes express CCR4 receptors. CCR4 ligands include macrophage-derived chemokine (MDC) and thymus and activation-regulated chemokine (TARC). They direct trafficking and recruitment of Th2 cells. We are the first to measure serum levels of CCR4 ligands in relation to the degree of the severity of autism. METHODS: Serum concentrations of MDC and TARC were measured, by quantitative sandwich enzyme immunoassay technique, in 56 autistic children and 32 healthy matched children. RESULTS: Autistic children had significantly higher serum levels of MDC and TARC than healthy controls (P <0.001 and P <0.001, respectively). Children with severe autism had significantly higher serum levels of MDC and TARC than patients with mild to moderate autism (P <0.001 and P = 0.01, respectively). In addition, there were significant positive correlations between CARS and serum levels of both MDC (P <0.001) and TARC (P <0.001) in children with autism. There were significant positive correlations between serum levels of MDC and TARC in autistic children (P <0.001). CONCLUSIONS: Serum levels of CCR4 ligands were elevated in autistic children and they were significantly correlated to the degree of the severity of autism. However, further research is warranted to determine the pathogenic role of CCR4 ligands in autism and to shed light on the therapeutic role of CCR4-ligand antagonism in autistic children.

Elevated serum levels of interleukin-17A in children with autism.

BACKGROUND: The T-helper (Th)1/Th2 dichotomy dominated the field of immune regulation until interleukin (IL)-17-expressing T cells (Th17) were proposed to be a third lineage of helper T cells, the key players in the pathogenesis of autoimmune disorders. Autoimmunity to brain tissue may play a pathogenic role in autism. IL-17A is a pro-inflammatory cytokine that has been shown to play an important role in various autoimmune neuroinflammatory diseases. The aim of this study was to measure serum levels of IL-17A in relation to the degree of the severity of autism. METHODS: Serum IL-17A levels were measured by ELISA in 45 children with autism and 40 matched healthy controls. RESULTS: Children with autism had significantly higher serum IL-17A levels than healthy controls (P <0.001), with increased serum levels of IL-17A found in 48.9% of the autism group. Patients with severe autism had significantly higher serum IL-17A levels than those with mild to moderate autism (P=0.01), and raised serum IL-17A levels were significantly more common in children with severe autism (67.9%) than in those with mild to moderate autism (17.6%), P=0.001. CONCLUSIONS: Serum IL-17A levels were raised in the group with autism, and the levels correlated significantly with the severity of autism. This is the first study to measure levels of IL-17A in relation to the severity of autism, to our knowledge. Further research, with a larger subject population, is warranted to determine whether the increase of serum IL-17A levels plasma has a pathogenic role in autism, and whether anti- IL-17A therapy could be useful.

A lack of association between elevated serum levels of S100B protein and autoimmunity in autistic children.

BACKGROUND: S100B is a calcium-binding protein that is produced primarily by astrocytes. Increased serum S100B protein levels reflect neurological damage. Autoimmunity may have a role in the pathogenesis of autism in some patients. Autoantibodies may cross the blood-brain barrier and combine with brain tissue antigens, forming immune complexes and resulting in neurological damage. We are the first to investigate the relationship between serum levels of S100B protein, a marker of neuronal damage, and antiribosomal P protein antibodies in autistic children. METHODS: Serum S100B protein and antiribosomal P antibodies were measured in 64 autistic children in comparison to 46 matched healthy children. RESULTS: Autistic children had significantly higher serum S100B protein levels than healthy controls (P < 0.001). Children with severe autism had significantly higher serum S100B protein than patients with mild to moderate autism (P = 0.01). Increased serum levels of antiribosomal P antibodies were found in 40.6% of autistic children. There were no significant correlations between serum levels of S100B protein and antiribosomal P antibodies (P = 0.29). CONCLUSIONS: S100B protein levels were elevated in autistic children and significantly correlated to autistic severity. This may indicate the presence of an underlying neuropathological condition in autistic patients. Antiribosomal P antibodies may not be a possible contributing factor to the elevated serum levels of S100B protein in some autistic children. However, further research is warranted to investigate the possible link between serum S100B protein levels and other autoantibodies, which are possible indicators of autoimmunity to central nervous system in autism.

The relationship between the increased frequency of serum antineuronal antibodies and the severity of autism in children.

BACKGROUND: Autism may involve an autoimmune pathogenesis. Immunotherapy may have a role in autistic children who have brain auto-antibodies. AIM: This study aimed to investigate the frequency of serum antineuronal auto-antibodies, as indicators of the presence of autoimmunity to brain, in a group of autistic children. We are the first to measure the relationship between these antibodies and the degree of the severity of autism. METHODS: Serum antineuronal antibodies were measured, by indirect immunofluorescence technique, in 80 autistic children, aged between 6 and 12 years, in comparison to 80 healthy-matched children. The severity of autism was assessed by using the Childhood Autism Rating Scale. RESULTS: Autistic children had significantly higher percent positivity of serum antineuronal antibodies (62.5%) than healthy controls (5%), P<0.001. The frequency of the positivity of serum antineuronal antibodies was significantly higher in children with severe autism (87.5%) than children with mild to moderate autism (25%), P<0.001. Similarly, the frequency of the positivity of these antibodies was significantly higher in female children with autism (90%) than male autistic children (53.3%), P=0.001. CONCLUSIONS: Serum antineuronal antibodies were found in a subgroup of autistic children and they were significantly correlated to the severity of autism. Thus, autism may be, in part, one of the pediatric autoimmune neuropsychiatric disorders. Further wide-scale studies are warranted to shed light on the etiopathogenic role of antineuronal antibodies in autism. The role of immunotherapy in autistic patients, who are seropositive for antineuronal antibodies, should also be studied.

A lack of association between hyperserotonemia and the increased frequency of serum anti-myelin basic protein auto-antibodies in autistic children.

BACKGROUND: One of the most consistent biological findings in autism is the elevated blood serotonin levels. Immune abnormalities, including autoimmunity with production of brain specific auto-antibodies, are also commonly observed in this disorder. Hyperserotonemia may be one of the contributing factors to autoimmunity in some patients with autism through the reduction of T-helper (Th) 1-type cytokines. We are the first to investigate the possible role of hyperserotonemia in the induction of autoimmunity, as indicated by serum anti-myelin-basic protein (anti-MBP) auto-antibodies, in autism. METHODS: Serum levels of serotonin and anti-MBP auto-antibodies were measured, by ELISA, in 50 autistic patients, aged between 5 and 12 years, and 30 healthy-matched children. RESULTS: Autistic children had significantly higher serum levels of serotonin and anti-MBP auto-antibodies than healthy children (P < 0.001 and P < 0.001, respectively). Increased serum levels of serotonin and anti-MBP auto-antibodies were found in 92% and 80%, respectively of autistic patients. Patients with severe autism had significantly higher serum serotonin levels than children with mild to moderate autism (P < 0.001). Serum serotonin levels had no significant correlations with serum levels of anti-MBP auto-antibodies in autistic patients (P = 0.39). CONCLUSIONS: Hyperserotonemia may not be one of the contributing factors to the increased frequency of serum anti-MBP auto-antibodies in some autistic children. These data should be treated with caution until further investigations are performed. However, inclusion of serum serotonin levels as a correlate may be useful in other future immune studies in autism to help unravel the long-standing mystery of hyperserotonemia and its possible role in the pathophysiology of this disorder.