EGF is involved in growth and differentiation of cells of the CNS and the gastrointestinal tract. The growth factor has been found to cause proliferation, differentiation, and migration of neural progenitor cells and is associated with the differentiation of these cells into astrocytes and neurons.22
EGF appears to be necessary for normal development of intestinal mucosa. Mice deficient in EGF receptor suffer from symptoms similar to necrotizing enterocolitis,23
and EGF promotes wound healing in animal models of ulcerative colitis.24
Recently, EGF has been shown to have antiinflammatory effects on the immature human intestine.25
Increased serum levels of HMGB1 protein have been found in patients with autistic disorder.26
We have also found significantly increased plasma HMGB1 in our autistic group (P =
0.02; unpublished data).
In this study, we have found significantly decreased EGF plasma levels, which correlate with increased HMGB1 levels, as well as increased hyperactivity symptoms, in autistic children. We also found that children with PDD had significantly lower EGF when compared with controls. These levels were not, however, as low as the EGF plasma levels. Because PDD-NOS individuals were diagnosed (DSM-IV) with symptoms less severe than symptoms of children with autism, this suggests a relationship between decreased EGF and severity of disease.
We previously reported that autistic children (mean age of approximately 10 years) with severe gastrointestinal (GI) disease had significantly decreased levels of HGF.26
The same autistic group had significantly increased plasma levels of GABA and HGF levels correlated with increased GABA levels, but these concentrations did not correlate significantly with any symptom severity (unpublished data). Since the results of this report suggest that EGF correlates with hyperactivity related symptoms, and HGF does not correlate with symptoms, it is reasonable to suggest that EGF is more important than HGF as a putative biomarker.
GABA is the most abundant inhibitory neurotransmitter in the mammalian brain, where it is widely distributed.29
HGF has been shown to modulate GABAergic activity28
and enhance NMDA currents in the hippocampus.30
uPAR encodes an urokinase plasminogen activator (uPA) which is required for the proper processing of the HGF.28
GABA is released by interneurons, which contain the GABA synthesizing enzymes glutamic acid decarboxylase 65 (GAD2) and GAD67. These enzymes convert glutamate into GABA.31
We found a correlation between decreased EGF and increased GABA in children with autism. However, we did not find any correlation between EGF levels and any of these GABA modulatory molecules. This suggests that EGF deficiency may not be associated with HGF or glutamate processing to GABA formation in children with autism.
Recent findings that immune cells synthesize GABA and have the machinery for GABA catabolism, and that antigen-presenting cells (APCs) express functional GABA receptors and respond electrophysiologically to GABA, suggest that the immune system harbors all of the necessary constituents for GABA signaling and GABA itself may function as a paracrine or autocrine factor.32
Our data suggest higher inflammation (HMGB1) and higher GABA plasma levels in autistic children. It is possible that inflammatory cells, resulting from increased inflammation, are involved in the increased synthesis of GABA. Since decreased EGF has been associated with inflammatory conditions such as colitis23,24
and has been shown to have antiinflammatory effects,25
it is reasonable to suggest that low EGF could be associated with high inflammation in children with autism. Therefore, we suggest that increased GABA may be the result of decreased EGF, which results, in turn, in increased inflammation in children with autism.
We did not find a significant difference in plasma EGF levels between autistic children with GI disease and children without GI disease (unpublished data). This suggests that decreased EGF may be associated with increased inflammation but not necessarily with increased inflammation often associated with GI disease in children with autism.
We also found that decreased EGF is associated with hyperactivity, the tendency for tiptoeing and decreased gross motor skills in children with autism. Because of this, we suggest that EGF may play a significant role in the etiology of abnormal behavior in at least a subpopulation of autistic children.
In summary, our data support recent findings that EGF plasma levels in children with autism are significantly decreased.27
We suggest that decreased EGF is associated with increased plasma GABA levels, possibly through increased inflammation, but not with GABA modulatory biomarkers related to HGF (uPAR, uPA) or GAD. We also suggest that EGF may play a significant role in the etiology of abnormal behavior in children with autism.