Neuroglial activation and neuroinflammation in the brain of patients with autism

Abstract

Autism is a neurodevelopmental disorder characterized by impaired communication and social interaction and may be accompanied by mental retardation and epilepsy. Its cause remains unknown, despite evidence that genetic, environmental, and immunological factors may play a role in its pathogenesis. To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Fresh-frozen tissues available from seven patients and CSF from six living autistic patients were used for cytokine protein profiling. We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain.

Decreased Cortical Serotonin in Neonatal Rabbits Exposed to Endotoxin in Utero

“…The term cerebral palsy encompasses a group of motor-impairment syndromes that occurs due to injury to the developing brain, which may be associated with deficits in somatosensory perception and/or alterations in the normal development of the somatosensory system (Bax et al, 2005;Wingert et al, 2008). Infection-induced maternal immune activation leads to a fetal inflammatory response mediated by cytokines that has been implicated in the development of not only periventricular leukomalacia and cerebral palsy, but also neurodevelopmental disorders such as autism and schizophrenia (Patterson, 2009;Vargas et al, 2005;Yoon et al, 2000). The timing of the immune challenge with respect to the gestational age and neurologic development of the fetus may be crucial in the response elicited in the neonate (Meyer et al, 2006).…”

Immune Therapy in Autism: Historical Experience and Future Directions with Immunomodulatory Therapy

“…Elevation, particularly of interleukin-6 and also of other pro-inflammatory markers in the frontal cingulated cortex and CSF, has been described by Vargas et al 17 Patients with regressive autism studied between pre-school age and 12 years old have been shown to have elevated CSF:serum ratios of TNF-␣, interleukin (IL)-1␤, IL-6, and IL 13. 53 Elevation of inflammatory cytokines offers potential therapeutic targets with agents that inhibit cytokine elevations, the use of anti-inflammatory cytokines (such as IL-10), stem cell therapy to re-regulate cytokine dysfunction, and designer drugs of the future that are modeled after these mechanisms.…”

“…12 Recent research on postnatal immune issues identify various serum antibodies, as well as cord blood neurotrophins and cytokine levels as potential factors. [12][13][14][15][16][17] Atladottir et al 18 found an increased risk of ASDs in children with a maternal history of rheumatoid arthritis and celiac disease. Also, increased risk of infantile autism was observed for chil-dren with a family history of type 1 diabetes.…”

“…This may reflect human autism models of brain tissue and cerebrospinal fluids showing chronic activation of proinflammatory cytokines. 15,17,47 Human sera containing immune auto-antibodies have been found in mothers with autistic offspring. Transfer of these serum antibodies to pregnant mice or rats has caused offspring to elicit behaviors similar to autistic humans.…”

“…13,15,17,22,53 Maternal transfer of immune dysregulation also is inferred by the fact that 47 of 100 mothers with serum auto-antibodies (especially at the 37 kD site) had offspring diagnosed with regressive cases of autism. 30,48 This evidence suggests that mothers positive for autoantibodies have almost a 50% chance of having children with the specific regressive phenotype of autism, indicating a potential delay from in utero exposure to clinical onset.…”