Talking about the Importance of Neuroimmune Crosstalk to Neurotoxicology

By Janet Leeds posted 03-25-2014 17:20


Mariane Stamous, a graduate student at University of California Davis Department of Molecular Biosciences, School of Veterinary Medicine, provided an overview of the interactions between immune cells—specifically microglia, the resident macrophage of the brain—and neuronal cells. Regardless of the trigger, neuroinflammation can cause adaptive responses, which provide protection of the cells from toxicants, or it can cascade to toxic sequelae. She provided the framework for later talks, explaining that neuroimmune interactions play a role in diseases as diverse as Alzheimer’s to autism spectrum disorder (ASD). She reviewed evidence that toxicants have effect on multiple CNS cell types from microglia to astrocytes and neurons.

In the second talk, graduate student Eloi Atkintunde described experiments she is conducting to evaluate the potential link between polybrominated diphenyl ethers (PBDE) and cognitive functioning in autism spectrum disorder (ASD). Researchers have found autoantibodies to brain proteins in children with ASD and a subset of mothers of children with ASD. PBDE-47 and PBDE-49 are two PBDEs with known neurotoxicity that persist in the environment. Although PBDE-47 has a higher body burden, PBDE-49 may be more toxic. Atkintunde’s hypothesis is that children with ASD have a dysregulated immune profile that may result from an increased susceptibility to environmental toxicants, such as the potent PBDE-49. A study exploring this hypothesis used peripheral blood mononuclear cells (PBMC) from individuals with and without ASD (TD= typical development) for their cytokine responses after incubation with PBDE-49 and looked for correlations between different cytokines levels and cognitive scores. Preliminary results indicated some differential responses to cytokine between ASD subjects and TD. They also found a difference between the two sexes. One correlation identified between behavioral outcome and immune response. Increased IL-4 and other cytokines were associated with lower adaptive function in children with ASD, not TD, in the ex vivo PBDE-49 experiment.

Jason Franklin, a graduate student at the Brody School of Medicine at East Caroline University in Greenville, North Carolina, discussed his research evaluating the development disorders and their link to microglia pruning activity in the presence of bisphenol acetone (BPA). He discussed preliminary experiments in which he injected low doses of lipopolysaccharide (LPS) to activate the immune system prior to adult female C56B6 mice prior to mating. The treatments continued through 42 days post weaning to the litters, and the mice were then tested in the Barnes Maze test. LPS treated mice had slower learning over the 4 days of testing (took more time to learn the task). Open field activity testing was used to confirm the results were not due to depressed activity levels. He is working to extend his results to another mouse strain.

Kimberly Kelly, a graduate student in Morgantown, West Virginia, is studying the neurotoxicity of methamphetamine (METH). A known dopaminergic neurotoxicant, METH, causes neuroinflammation, but Ms. Kelly’s work indicates that the gliosis damage occurs even when neuroinflammation is suppressed. A single subcutaneous dose of 20 mg/kg to male mice causes neuroinflammation and gliosis. However, prevention of inflammation using minocycline did not protect against toxicity due to METH. Cortisone (CORT) injections prior to METH also did not cause any reduction in toxicity, and pre-administration with CORT for a week prior to METH administration aggravated the inflammation and did not reduce the toxic damage. At this point, Ms. Kelly plans to conduct additional research to understand the link between neurotoxicity and inflammation.

Dr. Lana Shaiba of the Department of Pediatrics at the University of British Columbia is studying the potential pathogenicity of neuroautoantibodies that may be involved in neuron cell death and pathology. Dr Shaiba studies Hypoxic ischemic encephalopathy (HIE), a disease with an incidence ranging from two to 25 cases per 1,000 live births. HIE occurs more frequently in developing countries. The diagnosis includes the following criteria: profound umbilical arterial metabolic or mixed academia, an apgar score less than three for more than five minutes, neonatal neurologic sequelae, seizures, hypotonia, coma, and possibly multiple organ dysfunction. In an animal model, Dr. Shaiba looked for autoantibodies against specific proteins, such as myelin basic protein and neurofilaments. The results indicated an increase in IgM and IgG antibodies at four days post hypoxia, but these increased levels did return to background levels. Levels of Glial fibrillary acidic protein (GFAP) increased in the cerebellum in all animals overall, but were highest in HIE animals. Vascular endothelial growth factor (VEGF) antibodies were also observed after HIE injury, but it was unclear if this was a primary or secondary response. Overall, Dr. Shaiba’s preliminary studies found that neuroantibodies are detected throughout the time course of HIE pathology studies, but additional studies are warranted. In particular, Dr. Shaiba is interested in looking at the clinical translation. One example is a project collecting cord blood at birth to look for autoantibodies.

The work presented in this symposium included in vitro, in vivo, and in situ studies from clinical samples. While much of the work is preliminary, the studies are providing preliminary insight into the relationship between the neuronal cells and immune function, and the dysfunction that can occur in the presence of toxicants.