Antibrain antibodies in children with autism and their unaffected siblings
Introduction
Autistic spectrum disorders, including autistic disorder, Asperger syndrome, high functioning autism, atypical (with genetic dysmorphic features) and a late regression form, herein called autistic spectrum disorders, are characterized by the core features of impaired socialization, impaired verbal and nonverbal communication, and restrictive patterns of behavior (Filipek et al., 1999). Autism is a common disorder of childhood affecting approximately 2 in 1000 children, with an increasing prevalence ranging from 0.6 to 4.6 per 1000 (Mandell and Palmer, 2005). Symptoms are often identified in children from 18 to 30 months of age and traits persist into adulthood with varied outcomes (Rapin, 1997).
A variety of pathophysiological mechanisms have been proposed to underlie development of autism, including genetic, biochemical and environmental causes. Despite numerous reports suggesting a high rate of inheritance, no specific single genes have been identified that are more than risk factors (Bespalova and Buxbaum, 2003, Santangelo and Tsatsanis, 2005). Prenatal environmental factors, such as obstetrical suboptimality, alcohol exposure and intrauterine infection, have also been reported to influence the occurrence of autism (Larsson et al., 2005). One additional mechanism that has received serious consideration is an abnormality of immune function.
Several lines of evidence suggest that immune factors may have a prominent role in autism. Patients with autism have clustering of autoimmune disorders in their families (Comi et al., 1999, Croen et al., 2005), evidence of immune dysregulation (Gupta, 2000) and abnormal levels of plasma immunoglobulins (Plioplys et al., 1994). Pathologically, an active neuroinflammatory process has been identified in the cerebral cortex, white matter and cerebellum of autistic patients (Vargas et al., 2005). Although the authors of the latter report focused on potential abnormalities of cytokines, other investigators have emphasized a role for autoantibodies. Multiparametric analyses of repertoires of plasma autoantibodies to human brain have shown significant differences between children with autism and controls (Silva et al., 2004). In the autistic population, serum antibodies are more prevalent against rodent caudate, cortex and cerebellum (Singh and Rivas, 2004), and antibodies have been found against specific brain proteins, e.g., glial fibrillary acidic protein and myelin basic protein (Singh et al., 1993, Singh et al., 1997). Lastly, behavioral changes have been induced in embryonic rodents after, exposure to anti-Purkinje cell antibodies from the mother of an autistic child (Dalton et al., 2003).
The goal of this study was to investigate serum autoantibodies to human brain in children with autism, their non-autistic siblings and a healthy control group. Specific brain regions were selected for inclusion on the basis of postmortem, magnetic resonance imaging and autoantibody studies in autistic patients (Ritvo et al., 1986, Bauman, 1991, Courchesne et al., 1988, Zilbovicius et al., 1995, Singh and Rivas, 2004). Enzyme-linked immunosorbent assays (ELISA) and Western immunoblotting were performed using supernatant fractions from fresh human postmortem tissue with the goal of determining reactivity against multiple antigens. It was hypothesized that, if some subtypes of autism were related to an autoantibody, affected individuals would have definable patterns on immunoblotting and possibly higher optical density readings on ELISA. Comparisons with non-autistic siblings would identify whether there were common familial autoreactivities that were unrelated to autistic pathophysiology.
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Subjects
After informed consent was obtained, serum was collected from 29 children with autism (mean age 6.8 years, range 3–12): 22 with typical-autism (autistic disorder: IQ < 70, mean age 6.5 years, range 3–9), three with atypical autism (one each with genetic dysmorphic features, Smith-Lemli-Opitz syndrome and mitochondrial dysfunction), two with high functioning autism (IQ > 70), one with Asperger syndrome and one with late regression (childhood disintegrative disorder). Serum was also available from
Western blots for brain proteins
Western immunoblot analyses with BA10, caudate, cerebellum, cerebellar deep nuclei, cingulate gyrus and putamen identified numerous bands in all subjects (Fig. 1). Blots showed similar mean numbers of measurable antibody reactivity peaks on Quantity One images for all subject groups. No molecular weight range showed activity exclusive to a specific group for any of the brain regions. Although the number of autistic subjects in several subgroups was limited, no obvious differences among the
Discussion
The presence of autoantibodies against components of the central nervous system, serum immunoglobulin abnormalities, altered T-cell functions and abnormalities of cytokines have led investigators to hypothesize that autism may result from autoimmunity (Zimmerman, 2005). The present study of serum, in which immunoblotting and an analysis of scanned blots were examined, showed that more children with autism than controls had autoimmune complexes in the basal ganglia and frontal lobe at 100 kDa.
Acknowledgements
This research was supported in part from a National Alliance for Autism Research grant (#1213). The authors thank Pamela Talalay for her editorial review.
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