Braunschweig, D. et al. Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology 29, 226-231

Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, CA, USA.
NeuroToxicology (Impact Factor: 3.38). 04/2008; 29(2):226-31. DOI: 10.1016/j.neuro.2007.10.010
Source: PubMed


Autism is a profound disorder of neurodevelopment with poorly understood biological origins. A potential role for maternal autoantibodies in the etiology of some cases of autism has been proposed in previous studies. To investigate this hypothesis, maternal plasma antibodies against human fetal and adult brain proteins were analyzed by western blot in 61 mothers of children with autistic disorder and 102 controls matched for maternal age and birth year (62 mothers of typically developing children (TD) and 40 mothers of children with non-ASD developmental delays (DD)). We observed reactivity to two protein bands at approximately 73 and 37kDa in plasma from 7 of 61 (11.5%) mothers of children with autism (AU) against fetal but not adult brain, which was not noted in either control group (TD; 0/62 p=0.0061 and DD; 0/40 p=0.0401). Further, the presence of reactivity to these two bands was associated with parent report of behavioral regression in AU children when compared to the TD (p=0.0019) and DD (0.0089) groups. Individual reactivity to the 37kDa band was observed significantly more often in the AU population compared with TD (p=0.0086) and DD (p=0.002) mothers, yielding a 5.69-fold odds ratio (95% confidence interval 2.09-15.51) associated with this band. The presence of these antibodies in the plasma of some mothers of children with autism, as well as the differential findings between mothers of children with early onset and regressive autism may suggest an association between the transfer of IgG autoantibodies during early neurodevelopment and the risk of developing of autism in some children.

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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]. Paired reactivity at 37/73 kDa has since been replicated in a larger sample set [15], and the same pattern of reactivity has been observed in prospectively study using collected blood samples collected mid-gestation in mothers who subsequently gave birth to children with autism [16]. "
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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 · 3.03 Impact Factor
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    • "Maternal brain-reactive antibodies are thought to access the fetal brain during pregnancy as the fetal blood–brain barrier is not yet fully formed. Indeed, studies have identified the presence of antibodies that bind to human fetal brain tissue in a subset of women who have children with autism (Braunschweig et al., 2008; Croen et al., 2008; Singer et al., 2008; Zimmerman et al., 2007). Several studies have described antibodies that are reactive to cerebellar proteins in ASD (Dalton et al., 2003; Goines et al., 2011; Wills et al., 2009). "
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    ABSTRACT: The cerebellum has been long known for its importance in motor learning and coordination. Recently, anatomical, clinical, and neuroimaging studies strongly suggest that the cerebellum supports cognitive functions, including language and executive functions, as well as affective regulation. Furthermore, the cerebellum has emerged as one of the key brain regions affected in autism. Here, we discuss our current understanding of the role of the cerebellum in autism, including evidence from genetic, molecular, clinical, behavioral, and neuroimaging studies. Cerebellar findings in autism suggest developmental differences at multiple levels of neural structure and function, indicating that the cerebellum is an important player in the complex neural underpinnings of autism spectrum disorder, with behavioral implications beyond the motor domain.
    International Review of Neurobiology 12/2013; 113:1-34. DOI:10.1016/B978-0-12-418700-9.00001-0 · 1.92 Impact Factor
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    • "We focused on the subtypes of lung cancer, since particularly small-cell lung cancer is known to induce the production of autoantibodies that can cross-react with brain tissue [18–21,23]. Maternal antibodies can cross the placenta and cause neonatal disease or even alter the development of the infant, indicating that some neurodevelopmental disorders could be caused by maternal antibodies reacting against the developing nervous system of the fetus [6,7,10,11,43,44]. "
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    ABSTRACT: Maternal immune responses and brain-reactive antibodies have been proposed as possible causal mechanisms for schizophrenia and some child psychiatric disorders. According to this hypothesis maternal antibodies may cross the placenta and interact with the developing CNS of the fetus causing future neurodevelopmental disorders. Therefore, we investigated if children of mothers with cancer might be at higher risk of developing psychiatric disorders, with particular focus on small-cell lung cancer, which is known to induce production of antibodies binding to CNS elements. Nationwide population-based registers were linked, including the Danish Psychiatric Central Register and The Danish Cancer Registry. Data were analyzed as a cohort study using survival analysis techniques. Incidence rate ratios (IRRs) and accompanying 95% confidence intervals (CIs) were used as measures of relative risk. In general, parental cancer was not associated with schizophrenia in the offspring (IRR, 0.98; 95% CI, 0.95-1.01). Furthermore, we found no temporal associations with maternal cancer in general; neither around the pregnancy period. However, maternal small-cell lung cancer increased the risk of early-onset schizophrenia and maternal small-cell lung cancer diagnosed within 20 years after childbirth increased the risk of schizophrenia. Parental cancer was not associated with child psychiatric disorders (IRR, 1.01; 95% CI, 0.98-1.05) except for the smoking related cancers. There was a significantly increased risk of child psychiatric disorders in offspring of both mothers (IRR, 1.35; 95% CI, 1.16-1.58) and fathers (IRR, 1.47; 95% CI, 1.30-1.66) with lung cancer of all types. In general, parental cancer did not increase the risk of schizophrenia nor of child psychiatric disorders. However, maternal small-cell lung cancer increased the risk of schizophrenia in subgroups; and lung cancer in general increased the risk of child psychiatric disorders, which could be due to risk factors associated with parental smoking.
    PLoS ONE 11/2013; 8(11):e79031. DOI:10.1371/journal.pone.0079031 · 3.23 Impact Factor
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