Disequilibrium in the Thioredoxin Reductase-1/Thioredoxin-1 Redox Couple Is Associated with Increased T-Cell Apoptosis in Children with Autism

Abstract

Autism spectrum disorder (ASD) is a neuropsychiatric childhood disorder that affects social skill and language development, and is characterized by persistent stereotypic behaviors, restricted social interests, and impaired language/social skills. ASD subjects have dysregulated immune responses due to impairment in inflammatory and antioxidant signaling in immune cells, such as T cells. Thioredoxin reductase-1 (TrxR1) and thioredoxin-1 (Trx1) play a crucial role in the maintenance of redox equilibrium in several immune cells, including T cells. T-cell apoptosis plays a crucial role in the pathogenesis of several inflammatory diseases. However, it remains to be explored how the TrxR1/Trx1 redox couple affects T-cells apoptosis in ASD and typically developing control (TDC) groups. Therefore, this single-center cross-sectional study explored the expression/activity of TrxR1/Trx1, and Bcl2, 7-AAD/annexin V immunostaining in T cells of ASD (n = 25) and TDC (n = 22) groups. Further, effects of the LPS were determined on apoptosis in TDC and ASD T cells. Our data show that T cells have increased TrxR1 expression, while having decreased Trx1 expression in the ASD group. Further, TrxR enzymatic activity was also elevated in T cells of the ASD group. Furthermore, T cells of the ASD group had a decreased Bcl2 expression and an increased % of annexin V immunostaining. Treatment of T cells with LPS caused greater apoptosis in the ASD group than the TDC group, with same treatment. These data reveal that the redox couple TrxR1/Trx1 is dysregulated in T cells of ASD subjects, which is associated with decreased Bcl2 expression and increased apoptosis. This may lead to decreased survival of T cells in ASD subjects during chronic inflammation. Future studies should investigate environmental factors, such as gut dysbiosis and pollutants, that may cause abnormal immune responses in the T cells of ASD subjects due to chronic inflammation.

Early life adversity drives sex-dependent changes in 5-mC DNA methylation of parvalbumin cells in the prefrontal cortex in rats

“…Purified DNA (adjusted per sample to 100ng/μl) for each subject was pipetted into well plates in singlets with experimental condition varying randomly across the plate. Preliminary analyses and normalization were conducted according to manufacturer’s instructions (Alshamrani et al, 2023; Okuda et al, 2023). Percent 5-mC was detected according to optical density readings using the SPECTROstar Nano microplate reader (BMG Labtech) at 450nm.…”

Neuroplasticity of children in autism spectrum disorder

“…T cell apoptosis plays a crucial role in the pathogenesis of inflammatory diseases. Whereas in T lymphocytes from subjects with ASD, dysregulation of thioredoxin reductase-1 (TrxR1)/thioredoxin-1 (Trx1) redox reactions, which is associated with reduced Bcl2 expression and increased apoptosis, leads to reduced T cell survival in ASD patients ( 135 ). Depletion of CD4 T cells results in memory deficits that are exacerbated over time ( 136 ).…”

Thioredoxin 1 and Thioredoxin Reductase 1 Redox System Is Dysregulated in Neutrophils of Subjects with Autism: In Vitro Effects of Environmental Toxicant, Methylmercury

“…These antioxidants have been studied both in systemic compartment and CNS of ASD subjects. The Trx/TrxR system has also been studied in blood of ASD subjects [ 28 , 29 , 30 ], however, Trx1/TrxR1 system has not been explored in neutrophils with respect to mercury exposure in ASD subjects.…”