Maternal antibrain antibodies in autism

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Abstract

Autism is a neurodevelopmental disorder of prenatal onset that is behaviorally defined. There is increasing evidence for systemic and neuroimmune mechanisms in children with autism. Although genetic factors are important, atypical prenatal maternal immune responses may also be linked to the pathogenesis of autism. We tested serum reactivity in 11 mothers and their autistic children, maternal controls, and several groups of control children, to prenatal, postnatal, and adult rat brain proteins, by immunoblotting. Similar patterns of reactivity to prenatal (gestational day 18), but not postnatal (day 8) or adult rat brain proteins were identified in autistic children, their mothers, and children with other neurodevelopmental disorders, and differed from mothers of normal children, normal siblings of children with autism and normal child controls. Specific patterns of antibody reactivity were present in sera from the autism mothers, from 2 to 18 years after the birth of their affected children and were unrelated to birth order. Immunoblotting using specific antigens for myelin basic protein (MBP) and glial acidic fibrillary protein (GFAP) suggests that these proteins were not targets of the maternal antibodies. The identification of specific serum antibodies in mothers of children with autism that recognize prenatally expressed brain antigens suggests that these autoantibodies could cross the placenta and alter fetal brain development.

Introduction

Autism is a disabling heterogeneous disorder affecting early child neurodevelopment, with deficits in language and social skills, and atypical behaviors (Rapin, 1997). Various abnormal systemic immune functions have been described in children with autism (reviewed by Zimmerman, 2005) and recently neuroinflammation was described in postmortem brain tissue (Vargas et al., 2005). In addition to important genetic influences underlying the autism spectrum disorders, “environmental factors” may also contribute to their apparently increasing incidence (Newschaffer and Curran, 2003).

There is growing recognition that the intrauterine environment is important for the fetus, because it can affect long-term health outcomes in childhood and adult life (Hampton, 2004). Maternal infections during pregnancy have been linked to autism and schizophrenia (Patterson, 2002), and relationships between antibody formation and CNS disease have been proposed in Sydenham chorea (Church et al., 2003) and Tourette syndrome (Singer et al., 1998, Singer, 2005). Recently serum from a mother of a child with autism was shown to cause antibody binding to fetal Purkinje cells when it was injected into pregnant mice (Dalton et al., 2003). Maternal antibodies that recognize fetal brain antigens might therefore, alter normal brain development.

We hypothesized that serum from women with autistic children would react with proteins derived from prenatal rat brains more often than with proteins derived from postnatal and adult brains. We investigated patterns of serum antibodies in mothers of autistic children, mothers of typically developing children, children with autism, and several groups of control children, in their reactivity to prenatal, postnatal and adult rat brain preparations.

Section snippets

Group 1: mothers of children with autism

Eleven mothers (mean, 36.8 years; range, 30–48) of children with autism (the latter comprising Group 3) were recruited from families followed at the Developmental and Genetic Center of the University of Tennessee Medical Center, Knoxville (UTMCK). Three of these mothers have an autoimmune diagnosis (rheumatoid arthritis, systemic lupus erythematosus). During the pregnancies with their autistic children, two were treated with immune modulating drugs (azathioprine, prednisone). None was on

Results

Visual inspection of the immunoblots showed multiple reactive bands to proteins derived from postnatal and adult rat whole brain, however, these patterns were varied and did not differentiate one group of subjects from others after decoding (data not shown). However, all six groups of subjects showed five specific patterns of reactivity to proteins derived from fetal (GD18) rat brain extract. Representative patterns are shown in Fig. 1, and numbers of individuals exhibiting each pattern are

Discussion

This preliminary study reports for the first time that antibodies in sera from autism mothers recognize different fetal, but not postnatal or adult rat brain proteins, compared to mothers of normal children. This finding could be important in the development of autism since maternal antibodies could interfere with normal prenatal brain development. After these antigens have been identified, maternal immunoglobulin patterns may be useful in the future to help determine the prenatal risk for

Acknowledgments

We thank the children and mothers who participated in the study and the East Tennessee Chapter, Autism Society of America. Christina Morris and Colin Gause provided valuable laboratory assistance.

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    Supported by the Jonty Foundation, the Autism Society of America, East Tennessee Chapter, and NIH Grant T32 ES07026-27.

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