Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental disorders manifesting in childhood and defined by deficits in communication and reciprocal social interaction and often accompanied by stereotypical behaviors (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (“DSM-IV”) 2000, Washington, D.C.). Although strong genetic links have been demonstrated in numerous reports (reviewed in Ashwood et al., J Leukoc Biol. (2006) 80(1):1-15), a clear etiologic basis for ASD is lacking. A role for immune system involvement in ASD development has been supported in a steadily increasing body of literature (Ashwood, supra; Enstrom et al., Curr Opin Investig Drugs. (2009) 10(5):463-73; and Li, et al., J Neuroimmunol. (2009) 207(1-2):111-6). Findings of abnormal immune responses, neuroinflammation and microglial activation, and the presence of maternal autoantibodies to rodent and human fetal brain tissue have been described (Vargas et al., Ann Neurol. (2005) 57(1):67-81; and Singer et al., J Neuroimmunol. (2009) 211(1-2):39-48.
We previously described significant associations between reactivity of plasma antibodies to human fetal brain tissue among mothers of children with an ASD. See, U.S. Pat. No. 7,452,681. In a case control cohort of mothers of ASD children, mothers of typically developing children and mothers of non-ASD developmentally delayed (DD) children, a significant association between IgG immunoreactivity to protein bands at 37 kD and 73 kD was demonstrated. Furthermore, an odds ration of 5.69 was observed for the band at 37 kD alone. See, Braunschweig et al., Neurotoxicology. (2008) 29(2):226-31.
Abnormalities in the maternal immune milieu during pregnancy have been implicated in ASD in several studies. Facilitated passage of IgG antibodies is a well established phenomenon thought to generally provide protection for the newborn child (Simister et al., Vaccine. (2003) 21(24):3365-9). However, together with IgG antibodies that are immunoprotective, autoantibodies that react to fetal ‘self’-proteins can also cross the placenta. A recent report demonstrated maternal IgG antibody reactivity to rodent Purkinje cells in a mother of multiple children with ASD, as well as the presence of behavioral deficits in pups of a mouse injected during gestation with her serum (Dalton et al., Ann Neurol. (2003) 53(4):533-7). In another study, mothers of children with autism and their affected children were found to have consistent patterns of antibody reactivity against rat pre-natal (day 18) brain proteins. In contrast, unaffected children and control mothers had alternative patterns of reactivity (Zimmerman et al., Brain Behav Immun. (2007) 21(3):351-7).
The preponderance of evidence suggests a pre-natal or early post-natal etiology for autism, potentially involving errant developmental cues. Advances in understanding the role of immune system components during fetal neurodevelopment combined with the cross-talk between the maternal and fetal immune systems, led us to investigate the profiles of autoantibody reactivity in mothers of children with autism and to compare them with profiles from mothers of typically developing children and from mothers of children with other developmental disorders excluding autism.