Antibodies against fetal brain in sera of mothers with autistic children
Introduction
Autism, with an estimated incidence of 1:150, is currently recognized as the most common developmental disability among children (CDC, 2007). Clinically, a period of apparent normal neurodevelopment often precedes the identification of classical deficits in areas of social interaction, communication and language, and stereotypic behaviors (Rapin, 1997). At birth, autistic brains are typically smaller than those of healthy infants, but between 6 and 14 months of age undergo a period of accelerated growth (Courchesne et al., 2003). Genetic, biochemical, and environmental factors are most commonly mentioned as etiological mechanisms in autism (Korvatska et al., 2002, Lawler et al., 2004), but abnormalities of immune function have also been proposed (Cohly and Panja, 2005, Pardo et al., 2005).
To date, evidence that immune factors have a role in autism is primarily circumstantial. Families with autism show clustering of autoimmune disorders (Comi et al., 1999, Croen et al., 2005), evidence of immune dysregulation (Gupta, 2000), and abnormal levels of plasma immunoglobulins (Plioplys et al., 1994). Children affected with autism have serum antibody reactivity against epitopes located in both adult human and rodent cortical, subcortical, and cerebellar brain regions (Cabanlit et al., 2007, Silva et al., 2004, Singer et al., 2006), as well as against specific brain proteins, e.g., glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) (Singh et al., 1997, Singh et al., 1993). Based on these findings, an acquired autoimmune abnormality that affects dendritic fields and synaptogenesis has been proposed for some cases of autism. A second autoimmune hypothesis, in contrast, has suggested that the process begins in utero and is associated with the placental transfer of maternal antibodies that, in turn, interfere with fetal brain development. Evidence for the intrauterine immune hypothesis is limited. A small pilot study has identified serum antibodies against embryonic rodent brain in mothers with autistic offspring that were absent or reduced in mothers of unaffected children (Zimmerman et al., 2007). Further, animal models have demonstrated that maternal antibrain antibodies are capable of crossing rodent placenta and causing behavioral alterations in their offspring (Dalton et al., 2003, Vincent et al., 2002).
The goal of this study is to expand our knowledge of serum antibrain antibodies in mothers of children with autistic disorder (MCAD). Western immunoblotting was performed with use of fetal and adult brain tissues derived from both humans and rodents. These tissue samples were selected in order to identify serum reactivity against fetal human epitopes, provide comparisons with prior reports (Braunschweig et al., 2006, Zimmerman et al., 2007), and evaluate differences in reactivity against developing and mature brain tissues. Adult human brain regions selected for use in this study were chosen on the basis of identified neuroanatomical abnormalities in postmortem autism brains, magnetic resonance imaging, and autoantibody studies in autistic patients (Bauman, 1991, Courchesne et al., 1988, Singer et al., 2006, Singh and Rivas, 2004, Zilbovicius et al., 1995). Results of specific antibrain antibodies were correlated with clinical histories, including family history of autoimmune disease, pregnancy, birth order, maternal and paternal ages, and evidence of developmental regression in the child with autism. We hypothesized that serum reactivity would differ in mothers of children with autistic disorder and that results obtained from use of fetal tissues would be associated with specific clinical characteristics.
Section snippets
Subjects
One hundred mothers of children with autistic disorder (mean age 41 ± 6 years; range 27–66) were recruited from the Center for Autism and Related Disorders at the Kennedy Krieger Institute. The study was approved by the Institutional Review Board of the Johns Hopkins Medical Institutions. Autism was diagnosed in children by the presence of abnormalities in social and communication development, marked repetitive behavior, and limited imagination using the Diagnostic and Statistical Manual for
Clinical population
Information on maternal history, birth order, timing of blood draw, and offspring regression are presented in Table 1. All mothers were healthy at the time of blood draw. Eighty-seven mothers had one child with autistic disorder, nine had two affected children with autistic disorder, and four had one child with autistic disorder plus one or more with Asperger syndrome or PDD-NOS. Of 101 offspring with autistic disorder, representing one per family with the exception of two from a mother with
Discussion
The majority of prior studies investigating an autoimmune mechanism in autism have focused on the presence of abnormal serum antibodies in subjects diagnosed with this disorder (Cabanlit et al., 2007, Silva et al., 2004, Singer et al., 2006, Singh and Rivas, 2004). Although providing important contributions, these studies have not addressed whether the immune trigger could be the result of prenatal environmental factors, such as the maternal–fetal transfer of autoantibodies. In order to answer
Acknowledgements
This research was supported in part by a grant from National Alliance for Autism Research. The authors also thank Shilpa Vernekar, M.D. for her assistance in performing laboratory assays.
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