Immune Dysfunction in Fragile X Syndrome and Autism

Background:  Fragile X Syndrome (FXS) is the leading cause of inheritable intellectual disability in male children, and is predominantly caused by a single gene mutation resulting in expanded trinucleotide CGG-repeats within the 5’ untranslated region of the fragile X mental retardation (FMR1) gene.   Although prevalence estimates vary across studies, it is estimated that 30-70% of children with FXS meet the criteria for autism spectrum disorder (ASD).  Reports have suggested the presence of immune dysregulation in FXS, and previous analysis of peripheral cytokines levels in the blood of children with FXS suggest a similar immune dysregulation to that reported in children with ASD.   

Objectives:  In order to ascertain if immune dysregulation is present in children with FXS, dynamic cellular responses to immune stimulation were determined.

Methods:  Peripheral blood mononuclear cells (PBMC) were isolated over a histopaque gradient from male children with FXS (n=11) and from male age-matched typically developing (TD) controls (n=7). PBMC were cultured for 48 hours in RPMI media supplemented with 10% fetal bovine serum with or without phytohaemagglutinin (PHA; 8 ug/mL) to stimulate the adaptive immune response. Supernatants were harvested and cytokine levels assessed using Luminex multiplexing technology.

Results:  Children with FXS displayed an altered response following immune challenge compared with TD controls. Following stimulation with PHA a profile of T_H1 associated cytokines, such as IFNγ, and IL-12 were significantly decreased in FXS subjects relative to TD controls (p < 0.03). In contrast, T_H2 associated cytokine profiles, in particular IL-13, were elevated. The skew towards a T_H2 profile was further verified by comparing the ratio (IL-13/INFγ) of T_H2 vs. T_H1 cytokines and was significantly increased in FXS subjects (3.9 ± 1.8; mean ± SEM) compared with TD controls (0.5 ± 0.4; p < 0.04).  Of note FXS subjects with ASD showed a less pronounced skewing (0.78 ± 0.4; n=5) than those with FXS alone (5.6 ± 2.6; n=6).

Conclusions:  These findings suggest that dynamic cellular responses in children with FXS exhibit a skew towards a T_H2 cytokine profile when compared with controls. These findings support previous observations of T_H2 cytokines profiles in the plasma of children with FXS. Further evaluation of T_H2 cytokine profiles in FXS is warranted to delineate immune alteration in FXS with and without the occurrence of ASD in this disorder.