Immune dysregulation as a cause of autoinflammation in fragile X premutation carriers: link between FMRI CGG repeat number and decreased cytokine responses.

BackgroundIncreased rates of autoinflammatory and autoimmune disorders have been observed in female premutation carriers of CGG repeat expansion alleles of between 55-200 repeats in the fragile X mental retardation 1 (FMR1) gene. To determine whether an abnormal immune profile was present at a cellular level that may predispose female carriers to autoinflammatory conditions, we investigated dynamic cytokine production following stimulation of blood cells. In addition, splenocyte responses were examined in an FMR1 CGG knock-in mouse model of the fragile X premutation.MethodsHuman monocyte and peripheral blood leukocytes (PBLs) were isolated from the blood of 36 female FMR1 premutation carriers and 15 age-matched controls. Cells were cultured with media alone, LPS or PHA. In the animal model, splenocytes were isolated from 32 CGG knock-in mice and 32 wild type littermates. Splenocytes were cultured with media alone or LPS or PMA/Ionomycin. Concentrations of cytokines (GM-CSF, IL-1β, IL-6, IL-10, IL-13, IL-17, IFNγ, TNFα, and MCP-1) were determined from the supernatants of cellular cultures via Luminex multiplex assay. Additionally, phenotypic cellular markers were assessed on cells isolated from human subjects via flow cytometry.ResultsWe found decreases in cytokine production in human premutation carriers as well as in the FMR1 knock-in mice when compared with controls. Levels of cytokines were found to be associated with CGG repeat length in both human and mouse. Furthermore, T cells from human premutation carriers showed decreases in cell surface markers of activation when compared with controls.ConclusionsIn this study, FMR1 CGG repeat expansions are associated with decreased immune responses and immune dysregulation in both humans and mice. Deficits in immune responses in female premutation carriers may lead to increased susceptibility to autoimmunity and further research is warranted to determine the link between FMR1 CGG repeat lengths and onset of autoinflammatory conditions

Increased Anti-Phospholipid Antibodies in Autism Spectrum Disorders

Autism spectrum disorders (ASD) are characterized by impairments in communication, social interactions, and repetitive behaviors. While the etiology of ASD is complex and likely involves the interplay of genetic and environmental factors, growing evidence suggests that immune dysfunction and the presence of autoimmune responses including autoantibodies may play a role in ASD. Anti-phospholipid antibodies are believed to occur from both genetic and environmental factors and have been linked to a number of neuropsychiatric symptoms such as cognitive impairments, anxiety, and repetitive behaviors. In the current study, we investigated whether there were elevated levels of anti-phospholipid antibodies in a cross-sectional analysis of plasma of young children with ASD compared to age-matched typically developing (TD) controls and children with developmental delays (DD) other than ASD. We found that levels of anti-cardiolipin, β2-glycoprotein 1, and anti-phosphoserine antibodies were elevated in children with ASD compared with age-matched TD and DD controls. Further, the increase in antibody levels was associated with more impaired behaviors reported by parents. This study provides the first evidence for elevated production of anti-phospholipid antibodies in young children with ASD and provides a unique avenue for future research into determining possible pathogenic mechanisms that may underlie some cases of ASD