The modulation of the redox microenvironment is an important regulator of immune cell activation and proliferation. To investigate immune cell redox status in autism we quantified the intracellular glutathione redox couple (GSH/GSSG) in resting peripheral blood mononuclear cells (PBMCs), activated monocytes and CD4 T cells and the extracellular cysteine/cystine redox couple in the plasma from 43 children with autism and 41 age-matched control children. Resting PBMCs and activated monocytes from children with autism exhibited significantly higher oxidized glutathione (GSSG) and percent oxidized glutathione equivalents and decreased glutathione redox status (GSH/GSSG). In activated CD4 T cells from children with autism, the percent oxidized glutathione equivalents were similarly increased, and GSH and GSH/GSSG were decreased. In the plasma, both glutathione and cysteine redox ratios were decreased in autistic compared to control children. Consistent with decreased intracellular and extracellular redox status, generation of free radicals was significantly elevated in lymphocytes from the autistic children. These data indicate primary immune cells from autistic children have a more oxidized intracellular and extracellular microenvironment and a deficit in glutathione-mediated redox/antioxidant capacity compared to control children. These results suggest that the loss of glutathione redox homeostasis and chronic oxidative stress may contribute to immune dysregulation in autism. 1. Introduction Autism is a behaviorally defined neurodevelopmental disorder that usually presents in early childhood and is characterized by significant impairments in social interaction and communication and by abnormal repetitive hyper-focused behaviors. The prevalence of autism spectrum disorders has increased more than 10-fold in the last two decades, now affecting one in 110 US children, yet the etiology of these disorders remains elusive [1]. Glutathione depletion and oxidative stress have been implicated in the pathology of numerous neurobehavioral disorders including schizophrenia [2], bipolar disorder [3], and Alzheimer’s disease [4]. Accumulating evidence suggests that redox imbalance and oxidative stress may also contribute to autism pathophysiology. Multiple biomarkers of oxidative stress have been identified in blood samples from children with autism [5–12]. Our group has reported a decrease in concentrations of glutathione (GSH) and several of its metabolic precursors, an increase in oxidized glutathione disulfide (GSSG), and a decrease in glutathione redox ratio
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