Article

Brain-reactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder

Center for Autoimmune and Musculoskeletal Diseases, Manhasset, NY, USA.
Molecular Psychiatry (Impact Factor: 15.15). 08/2013; 18(11). DOI: 10.1038/mp.2013.101
Source: PubMed

ABSTRACT It is believed that in utero environmental factors contribute to autism spectrum disorder (ASD). The goal of this study was to demonstrate, using the largest cohort reported so far, that mothers of an ASD child have an elevated frequency of anti-brain antibodies and to assess whether brain reactivity is associated with an autoimmune diathesis of the mother. We screened plasma of 2431 mothers of an ASD child from Simon Simplex Collection and plasma of 653 unselected women of child-bearing age for anti-brain antibodies using immunohistology on mouse brain. Positive and negative plasma from mothers with an ASD child were analyzed for anti-nuclear antibodies and for autoimmune disorders. Mothers of an ASD child were four times more likely to harbor anti-brain antibodies than unselected women of child-bearing age (10.5 vs 2.6%). A second cohort from The Autism Genetic Resource Exchange with multiplex families displayed an 8.8% prevalence of anti-brain antibodies in the mothers of these families. Fifty-three percent of these mothers with anti-brain antibodies also exhibited anti-nuclear autoantibodies compared with 13.4% of mothers of an ASD child without anti-brain antibodies and 15% of control women of child-bearing age. The analysis of ASD mothers with brain-reactive antibodies also revealed an increased prevalence of autoimmune diseases, especially rheumatoid arthritis and systemic lupus erythematosus. This study provides robust evidence that brain-reactive antibodies are increased in mothers of an ASD child and may be associated with autoimmunity. The current study serves as a benchmark and justification for studying the potential pathogenicity of these antibodies on the developing brain. The detailed characterization of the specificity of these antibodies will provide practical benefits for the management and prevention of this disorder.Molecular Psychiatry advance online publication, 20 August 2013; doi:10.1038/mp.2013.101.

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    • "Several groups have independently identified a strong association between maternal antibody reactivity towards fetal brain proteins and ASD diagnosis in the child [12] [13] [14]. Braunschweig et al. was the first to characterize paired reactivity to fetal brain proteins at 37 kDa and 73 kDa in approximately 12% of mothers of children with ASD [12]. "
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    ABSTRACT: Multiple studies have implicated a role of maternal autoantibodies reactive against fetal brain proteins specific to autism in the etiology of autism spectrum disorders (ASD). In the current study, we examined the impact of brain-reactive maternal autoantibodies of mothers of children with autism (MAU) on offspring behavior in mice compared to offspring exposed to non-reactive IgG of mothers of typically developing children (MTD). Embryonic offspring were exposed to a single intraventricular injection of MAU or MTD IgG on embryonic day 14. Offspring were allowed to mature to adulthood and were subsequently tested for sociability and stereotypic behaviors using a 3-chambered social approach task, marble burying task, and assessment of spontaneous grooming behaviors in response to a novel environment. Results indicate that MAU offspring display autistic-like stereotypic behavior in both marble burying and spontaneous grooming behaviors. Additionally, small alterations in social approach behavior were also observed in MAU offspring compared to MTD offspring. This report demonstrates for the first time the effects of a single, low dose intraventricular exposure of IgG derived from individual MAU samples on offspring behavior.
    Behavioural brain research 06/2014; 266:46-51. DOI:10.1016/j.bbr.2014.02.045 · 3.39 Impact Factor
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    • "Meanwhile maternal antibodies have also been reported, specifically recognizing proteins highly expressed in fetal brain tissue and exerting a negative impact on neural development during gestation ; these maternal antibrain antibodies display greater prevalence in mothers of autistic children than in mothers of typically developing children (Dalton et al., 2003; Zimmerman et al., 2007; Braunschweig et al., 2008; Brimberg et al., 2013; Nordahl et al., 2013; Rossi et al., 2013; for review see Braunschweig and Van de Water, 2012). In fact, early in prenatal life, the fetus relies on maternal IgG passing across the placenta into the fetal circulation for protective immunity. "
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    ABSTRACT: Circulating 45 and 62 kDa antibodies targeting the cerebellum were previously associated with Autism Spectrum Disorder (ASD), lower adaptive/cognitive function and aberrant behaviors. Moreover, 37, 39 and 73 kDa maternal antibodies (mAb) targeting the fetal brain were previously correlated with broad autism spectrum, irritability, abnormal brain enlargement and impaired expressive language. The present study aims towards clinically characterizing individuals with brain-targeted IgG and/or exposed to maternal antibrain antibodies in a large sample of Italian autistic children (N = 355), their unaffected siblings (N = 142) and mothers (N=333). The presence of patient- and mother-produced anti-brain antibodies does not confer increased risk of autism within the same sibship. However, the 45 and 62 kDa antibodies are correlated with autism severity: the 45 kDa Ab is associated with cognitive impairment and lower scores at the Vineland Adaptive Behavior Scales, the 62 kDa Ab with motor stereotypies, while both correlate with larger head circumference (all P<0.05). On the other hand, maternal 37, 39 and 73 kDa antibrain antibodies, either alone or in combination, are correlated with impaired verbal and non-verbal language development, neurodevelopmental delay and sleep/wake cycle disturbances in their autistic children (P<0.05). Presence of the 62 kDa autoAb in the child is significantly associated with presence of the 39 and/or 73 kDa antibodies in his/her mother. Our results confirm and extend previous observations in an ethnically distinct sample, providing further evidence of a pathomorphic role for anti-brain antibodies in autism while demonstrating their familial clustering.
    Brain Behavior and Immunity 01/2014; 38. DOI:10.1016/j.bbi.2013.12.020 · 6.13 Impact Factor
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