Elsevier

Biological Psychiatry

Volume 59, Issue 4, 15 February 2006, Pages 354-363
Biological Psychiatry

Original article
Brain-Derived Neurotrophic Factor and Autoantibodies to Neural Antigens in Sera of Children with Autistic Spectrum Disorders, Landau-Kleffner Syndrome, and Epilepsy

https://doi.org/10.1016/j.biopsych.2005.07.004Get rights and content

Background

Brain derived neurotrophic factor (BDNF) elevation in newborn sera predicts intellectual/social developmental abnormalities. Other autoantibodies (AAs) to endothelial cells (ECs) and myelin basic protein (MBP) are also elevated in some children. We tested relationships between BDNF, BDNF AAs, and other AAs in children with these disorders.

Methods

BDNF levels and IgG/IgM autoantibodies to BDNF, ECs, MBP, and histones were measured in children with autism, childhood disintegrative disorder (CDD), pervasive developmental delay-not otherwise specified (PDD-nos), acquired epilepsy, Landau-Kleffner syndrome (LKS); healthy children (HC), and children with non-neurological illnesses (NNI).

Results

Mean BDNF levels were elevated in children with autism and CDD, (p ≤ 0.0002) compared to HC or NNI. Mean IgG and IgM BDNF AAs were elevated in children with autism, CDD and epilepsy (p ≤ 0.0005) compared to HC but not to NNI. Mean IgM AA EC titers detected by immunocytochemistry were higher in autism, PDD-NOS, epilepsy, and LKS (p ≤ 0.005) compared to HC and NNI. While mean ELISA IgG EC AAs were higher in autism and PPD-NOS (p < 0.005) compared to HC but not NNI, ELISA IgM EC AAs were higher in children with autism, CDD, PDD-NOS, and epilepsy compared to both HC and NNI (p < 0.0005). Mean anti-MBP IgG and IgM titers were higher in all study groups (p < 0.005) except for LKS compared to both HC and NNI.

Conclusion

Children with developmental disorders and epilepsy have higher AAs to several neural antigens compared to controls. The presence of both BDNF AAs and elevated BDNF levels in some children with autism and CDD suggests a previously unrecognized interaction between the immune system and BDNF.

Section snippets

Subjects

Each child was examined by one of the authors (M.C., J.M.K., J.J.R., R.G.R., or R.K.D.) and assigned a diagnosis of autism (n = 37; 19 girls, 18 boys; 5.9 ± 3.9 years), childhood disintegrative disorder with regression after age 2 years (n = 19; 2 girls, 17 boys; 7.0 ± 2.4 years), pervasive developmental disorder-not otherwise specified (n = 14; 5 girls, 9 boys; 4.8 ± 3.9 years), Landau-Kleffner syndrome (n = 9; 9 boys; 7.4 ± 2.3 years), or epilepsy (n = 33; 16 girls, 17 boys; 5.9 ± 3.8 years).

BDNF Concentrations

Mean BDNF levels in autism and CDD were 32,279 pg/mL and 36,872 pg/mL, respectively, versus 8,708 pg/mL and 8,964 pg/mL for HC and NNI (p all < .0005) (Figure 1).

Immunocytochemistry of Human Cortex

Healthy children in our study (n = 29) showed no IgG, IgM positive immunostaining, or ANA values above 1:40. Only 2 of 21 children with NNI showed positive IgG or IgM autoantibodies to endothelial cells. Interestingly, the two children with NNI illnesses who had autoantibodies by immunocytochemistry also had probable autoimmune

Discussion

Recently, excesses of specific neurotrophins and neuropeptides present in newborn infants blood have been shown to have predictive value in determining those children who will later have disruption of intellectual and or social development (Nelson et al 2001). Using recycling immunoaffinity chromatography, Nelson et al (2001) found that neonatal concentrations of BDNF, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), and neurotrophin 4/5 (NT4/5) were higher in

References (62)

  • J.L. Jankowsky et al.

    Cytokine and growth factor involvement in long-term potentiation

    Mol Cell Neurosci

    (1999)
  • K. Kanemoto et al.

    Association of partial epilepsy with brain-derived neurotrophic factor (BDNF) gene polymorphisms

    Epilepsy Res

    (2003)
  • F. Karege et al.

    Decreased serum brain-derived neurotrophic factor levels in major depressed patients

    Psychiatry Res

    (2002)
  • R.L. Naylor et al.

    A discrete domain of the human TrkB receptor defines the binding sites for BDNF and NT-4

    Biochem Biophys Res Commun

    (2002)
  • S. Nevsimalova et al.

    A role of autoimmunity in the etiopathogenesis of Landau-Kleffner syndrome?

    Brain Dev

    (1992)
  • M.J. Noetzel et al.

    Anti-neurofilament protein antibodies in opsoclonus-myoclonus

    J Neuroimmunol

    (1987)
  • V.K. Singh et al.

    Immunoreactive S100 proteins of blood immunocytes and brain cells

    J Neuroimmunol

    (1996)
  • V.K. Singh et al.

    Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism

    Clin Immunol Immunopathol

    (1998)
  • V.K. Singh et al.

    Antibodies to myelin basic protein in children with autistic behavior

    Brain Behav Immun

    (1993)
  • A.M. Soprano et al.

    Acquired epileptic aphasiaNeuropsychologic follow-up of 12 patients

    Pediatr Neurol

    (1994)
  • P.E. Tanguay

    Pervasive developmental disordersA 10-year review

    J Am Acad Child Adolesc Psychiatry

    (2000)
  • R.D. Todd et al.

    Antibrain antibodies in infantile autism

    Biol Psychiatry

    (1988)
  • R.P. Warren et al.

    Reduced natural killer cell activity in autism

    J Am Acad Child Adolesc Psychiatry

    (1987)
  • L.A. Aarden et al.

    Immunology of DNA. III. Crithidia luciliae, a simple substrate for the determination of anti-dsDNA with the immunofluorescence technique

    Ann N Y Acad Sci

    (1975)
  • Diagnostic and Statistical Manual-Text Revision (DSM-IV-TR TM)

    (2000)
  • R.E. Appleton

    The Landau-Kleffner syndrome

    Arch Dis Child

    (1995)
  • A. Bailey et al.

    Autism as a strongly genetic disorderEvidence from a British twin study

    Psychol Med

    (1995)
  • A. Bailey et al.

    AutismTowards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives

    J Child Psychol Psychiatry

    (1996)
  • S. Chakrabarti et al.

    Pervasive developmental disorders in preschool children

    JAMA

    (2001)
  • M. Chavko et al.

    Activation of BDNF mRNA and protein after seizures in hyperbaric oxygenImplications for sensitization to seizures in re-exposures

    Neurochem Res

    (2002)
  • M.G. Chez et al.

    The presence of autoantibodies in idiopathic/acquired versus genetic variants of pediatric epilepsy

    Epilepsia

    (2000)
  • Cited by (0)

    View full text