THE ROLES OF NEUROGLIA AND NEUROIMMUNE MODULATORS IN PATHOGENESIS OF ASD

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders of early onset that are highly variable in their clinical presentation. Although the causes of autism in most patients remain unknown, several lines of research support the view that polygenic and environmental factors influence the development of dysfunctional cortical circuitry that underlies the abnormal cognitive processes and behaviors in ASD. Our research has focused on immunopathological studies of brain and cerebrospinal fluid (CSF) to investigate the role of neuroimmune factors in ASD. Characterization of microglial and astroglial responses as well as profiles of immune mediators (e.g., cytokine/chemokines and oxidative stress) in brain tissues of ASD patients were performed by immunomorphological, protein and lipidomic profiling methods. Marked increased in microglial and astroglial responses were found in selected areas of the brain such as anterior cingulate and midfrontal gyri as well as cerebellum. These cellular responses were also associated to increases in pro-inflammatory (e.g. IL-6, MCP-1), anti-inflammatory cytokines (e.g., TGFβ1) and increased oxidative stress markers (e.g. 4-HNE, isoprostanes). Similarly, CSF from patients with autism reveled also a pro-inflammatory profile with increases in cytokines such as IL-6, interferon-γ, MCP-1 and other immune mediators. Our studies demonstrate involvement of neuroglial and cytokine/chemokine responses in pathogenic mechanisms in ASD and suggest the role of innate neuroimmune pathways in processes of synaptic and dendritic organization as well neuronal dysfunction. These observations support the view that non-genetic factors influences such as neuroimmune and environmental factors are involved in pathogenesis of neurobiological abnormalities in ASD.