Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder estimated to affect 1 in 110 children in the US, yet the pathology of this disorder is not fully understood. Abnormal levels of several growth factors have been demonstrated in adults with ASD, including epidermal growth factor (EGF) and hepatocyte growth factor (HGF). Both of these growth factors serve important roles in neurodevelopment and immune function. In this study, concentrations of EGF and HGF were assessed in the plasma of 49 children with ASD aged 2–4 years old and 31 typically developing controls of a similar age as part of the Autism Phenome Project (APP). Levels of EGF were significantly reduced in the ASD group compared to typically developing controls ( ). There were no significant differences in HGF levels in young children with ASD and typically developing controls. EGF plays an important role in regulating neural growth, proliferation, differentiation, and migration, and reduced levels of this molecule may negatively impact neurodevelopment in young children with ASD. 1. Introduction Autism Spectrum Disorder (ASD) is a developmental disorder characterized by impairments in social interaction and communication, and the presence of restricted behaviors or interests [1]. According to the most current CDC estimate, ASD affects 1 in 110 children in the US [2], yet the pathophysiology of the disorder is largely unknown. Recently, several growth factors have been found to be dysregulated in a substantial proportion of adults with ASD [3]. In the central nervous system, growth factors can regulate the processes of neuronal growth, differentiation, and proliferation, as well as regulating neuronal survival, neuronal migration, and the formation or elimination of synapses [3]. In addition to their central function in regulating neurodevelopment, current literature has also illustrated the dual nature of many growth factors as immune modulators and highlighted their involvement in crosstalk between the immune system and the central nervous system (CNS) [4–7]. Many studies suggest the presence of aberrant immune activity in ASD, in the CNS [8, 9] and in the periphery [10–12], which may be influenced by atypical growth factor activity. Growth factor dysregulation may contribute to ASD pathology by directly affecting CNS development, and/or by augmenting immune function. Epidermal growth factor (EGF) and hepatocyte growth factor (HGF) are both involved in the growth and proliferation of several cell types, including neurons and glia of the CNS. EGF is present at high levels in the
References
[1]
APA, Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Publishing, Inc., Arlington, Va, USA, 2000.
[2]
C. Rice, “Prevalence of autism spectrum disorders—autism and developmental disabilities monitoring network, United States, 2006,” Morbidity and Mortality Weekly Report, vol. 58, no. 10, pp. 1–20, 2009.
[3]
T. Nickl-Jockschat and T. M. Michel, “The role of neurotrophic factors in autism,” Molecular Psychiatry, vol. 16, pp. 478–490, 2011.
[4]
D. E. Heck, D. L. Laskin, C. R. Gardner, and J. D. Laskin, “Epidermal growth factor suppresses nitric oxide and hydrogen peroxide production by keratinocytes. Potential role for nitric oxide in the regulation of wound healing,” Journal of Biological Chemistry, vol. 267, no. 30, pp. 21277–21280, 1992.
[5]
K. Okunishi, M. Dohi, K. Nakagome et al., “A novel role of hepatocyte growth factor as an immune regulator through suppressing dendritic cell function,” Journal of Immunology, vol. 175, no. 7, pp. 4745–4753, 2005.
[6]
J. A. Vega, O. García-Suárez, J. Hannestad, M. Pérez-Pérez, and A. Germanà, “Neurotrophins and the immune system,” Journal of Anatomy, vol. 203, no. 1, pp. 1–19, 2003.
[7]
R. Tabakman, S. Lecht, S. Sephanova, H. Arien-Zakay, and P. Lazarovici, “Interactions between the cells of the immune and nervous system: neurotrophins as neuroprotection mediators in CNS injury,” Progress in Brain Research, vol. 146, pp. 387–401, 2004.
[8]
D. L. Vargas, C. Nascimbene, C. Krishnan, A. W. Zimmerman, and C. A. Pardo, “Neuroglial activation and neuroinflammation in the brain of patients with autism,” Annals of Neurology, vol. 57, no. 1, pp. 67–81, 2005.
[9]
X. Li, A. Chauhan, A. M. Sheikh et al., “Elevated immune response in the brain of autistic patients,” Journal of Neuroimmunology, vol. 207, no. 1-2, pp. 111–116, 2009.
[10]
P. Ashwood, P. Krakowiak, I. Hertz-Picciotto, R. Hansen, I. N. Pessah, and J. Van de Water, “Altered T cell responses in children with autism,” Brain, Behavior, and Immunity, vol. 25, no. 5, pp. 840–849, 2011.
[11]
A. M. Enstrom, C. E. Onore, J. A. Van de Water, and P. Ashwood, “Differential monocyte responses to TLR ligands in children with autism spectrum disorders,” Brain, Behavior, and Immunity, vol. 24, no. 1, pp. 64–71, 2010.
[12]
P. Ashwood, P. Krakowiak, I. Hertz-Picciotto, R. Hansen, I. Pessah, and J. Van de Water, “Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome,” Brain, Behavior, and Immunity, vol. 25, no. 1, pp. 40–45, 2011.
[13]
C. J. Xian and X. F. Zhou, “Roles of transforming growth factor-α and related molecules in the nervous system,” Molecular Neurobiology, vol. 20, no. 2-3, pp. 157–183, 1999.
[14]
C. J. Xian and X. F. Zhou, “EGF family of growth factors: essential roles and functional redundancy in the nerve system,” Frontiers in Bioscience, vol. 9, pp. 85–92, 2004.
[15]
S. Pastore and F. Mascia, “Novel acquisitions on the immunoprotective roles of the EGF receptor in the skin,” Expert Review of Dermatology, vol. 3, no. 5, pp. 525–527, 2008.
[16]
P. J. Miettinen, J. E. Berger, J. Meneses et al., “Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor,” Nature, vol. 376, no. 6538, pp. 337–341, 1995.
[17]
T. Toyoda, K. Nakamura, K. Yamada et al., “SNP analyses of growth factor genes EGF, TGFβ-1, and HGF reveal haplotypic association of EGF with autism,” Biochemical and Biophysical Research Communications, vol. 360, no. 4, pp. 715–720, 2007.
[18]
K. Suzuki, K. Hashimoto, Y. Iwata et al., “Decreased serum levels of epidermal growth factor in adult subjects with high-functioning autism,” Biological Psychiatry, vol. 62, no. 3, pp. 267–269, 2007.
[19]
P. Levitt, K. L. Eagleson, and E. M. Powell, “Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders,” Trends in Neurosciences, vol. 27, no. 7, pp. 400–406, 2004.
[20]
G. Sugihara, K. Hashimoto, Y. Iwata et al., “Decreased serum levels of hepatocyte growth factor in male adults with high-functioning autism,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 31, no. 2, pp. 412–415, 2007.
[21]
D. B. Campbell, R. D'Oronzio, K. Garbett et al., “Disruption of cerebral cortex MET signaling in autism spectrum disorder,” Annals of Neurology, vol. 62, no. 3, pp. 243–250, 2007.
[22]
E. Singer, ““Phenome” project set to pin down subgroups of autism,” Nature Medicine, vol. 11, no. 6, p. 583, 2005.
[23]
C. Lord, M. Rutter, S. Goode et al., “Autism diagnostic observation schedule: a standardized observation of communicative and social behavior,” Journal of Autism and Developmental Disorders, vol. 19, no. 2, pp. 185–212, 1989.
[24]
C. Lord, M. Rutter, and A. L. Couteur, “Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders,” Journal of Autism and Developmental Disorders, vol. 24, no. 5, pp. 659–685, 1994.
[25]
S. K. Berument, M. Rutter, C. Lord, A. Pickles, and A. Bailey, “Autism screening questionnaire: diagnostic validity,” British Journal of Psychiatry, vol. 175, pp. 444–451, 1999.
[26]
M. Careaga, J. Van de Water, and P. Ashwood, “Immune dysfunction in autism: a pathway to treatment,” Neurotherapeutics, vol. 7, no. 3, pp. 283–292, 2010.
[27]
C. G. Craig, V. Tropepe, C. M. Morshead, B. A. Reynolds, S. Weiss, and D. Van Der Kooy, “In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain,” Journal of Neuroscience, vol. 16, no. 8, pp. 2649–2658, 1996.
[28]
W. Pan and A. J. Kastin, “Entry of EGF into brain is rapid and saturable,” Peptides, vol. 20, no. 9, pp. 1091–1098, 1999.
[29]
R. J. Farrell, “Epidermal growth factor for ulcerative colitis,” New England Journal of Medicine, vol. 349, no. 4, pp. 395–397, 2003.
[30]
A. Sinha, J. Nightingale, K. P. West, J. Berlanga-Acosta, and R. J. Playford, “Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis,” New England Journal of Medicine, vol. 349, no. 4, pp. 350–357, 2003.
[31]
K. Horvath and J. A. Perman, “Autism and gastrointestinal symptoms,” Current Gastroenterology Reports, vol. 4, no. 3, pp. 251–258, 2002.
[32]
P. Ashwood, A. Anthony, A. A. Pellicer, F. Torrente, J. A. Walker-Smith, and A. J. Wakefield, “Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology,” Journal of Clinical Immunology, vol. 23, no. 6, pp. 504–517, 2003.
[33]
P. Ashwood, A. Anthony, F. Torrente, and A. J. Wakefield, “Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10,” Journal of Clinical Immunology, vol. 24, no. 6, pp. 664–673, 2004.
[34]
P. Ashwood and A. J. Wakefield, “Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms,” Journal of Neuroimmunology, vol. 173, no. 1-2, pp. 126–134, 2006.
[35]
R. Ramirez, D. Hsu, A. Patel et al., “Over-expression of hepatocyte growth factor/scatter factor (HGF/SF) and the HGF/SF receptor (cMET) are associated with a high risk of metastasis and recurrence for children and young adults with papillary thyroid carcinoma,” Clinical Endocrinology, vol. 53, no. 5, pp. 635–644, 2000.
