Prenatal and Postnatal Epigenetic Programming: Implications for GI, Immune, and Neuronal Function in Autism

Figure 7

Cysteine and selenocysteine uptake in the terminal ileum regulates autoimmunity. EAAT3 transports diet-derived cysteine (CYS) and selenocysteine (Sel-CYS) into GI epithelial cells in the terminal ileum. Within the cell, cysteine is directed to GSH synthesis and selenocysteine is incorporated into selenoproteins, which maintain GSH in its reduced state. EAAT3 activity is regulated by multiple factors, including intracellular redox status, Nrf2-dependent transcription, growth-factor-dependent translocation to the cell surface, and the inhibitory effects of casein and gluten-derived opiate peptides. Systemic availability of cysteine and GSH depends upon these terminal ileum events, as does the local mucosal environment. Immune cells in the terminal ileum can be a source of auto-antibodies, including anti-folate receptor (FR) antibodies, which are commonly present in subjects with autism [80]. Under oxidative stress conditions, EAAT3-mediated uptake of cysteine by Treg cells is impaired, limiting their suppression of naïve CD4⁺ T cells, and increasing autoimmune responses to antigens present locally, such as the folate receptor.