Maternal Cytokine Gene Regulation in the Pathogenesis of Autism

Background:   Activated cells of the immune system secrete cytokines that influence brain development and behavior.  Studies show that pro-inflammatory cytokines such as Interferon – gamma (IFN-gamma) and Tumor Necrosis Factor – alpha (TNF-alpha) are elevated in patients with autism spectrum disorders (ASD).  Genetic polymorphisms in the regulatory regions of cytokine genes have a positive or negative influence on the level of protein produced. Single nucleotide polymorphisms (SNP’s) in the promoter regions of cytokine genes including IFN-gamma, TNF-alpha, IL-1, IL-6 and IL-10 affect the level of transcription of the protein. Numerous studies have documented the dysregulation of cytokines as etiological factors in children with ASD, but there has been far less focus on the parents of autistic children. 

Objectives:   The aim of the study is to investigate the genetic polymorphisms in cytokine regulatory genes of mothers and correlate the presence of SNP’s in mothers and their autistic children. 

Methods:   Genomic DNA, from 46 paired specimens from mothers and their autistic children were obtained from the Autism Genetic Research Exchange (AGRE) database. Mothers were selected using the following criteria: a diagnosis of allergies and/or GI problems in their children; evidence of an overactive immune system. Seventeen regulatory SNPs from seven pro-inflammatory and anti-inflammatory cytokines were detected in a multiplex PCR, using the LifeCodes cytokine SNP assay (Tepnel/GenProbe).  The cytokines analyzed included TNF-alpha, IFN-gamma, TGF-beta, IL-1, L-6, IL-10 and IL-12. The SNPs were identified and detected by hybridization to beads on the Luminex bead array. Control samples were obtained from mothers who had neither autistic characteristics nor produced any offspring diagnosed with autism. 

Results:   Significant differences in the frequency of SNPs were observed between controls versus mothers and controls versus autistic children in the following pro-inflammatory cytokines: IFN-gamma, IL-1, IL-6, IL-12 and the anti-inflammatory cytokine, IL-10.  In contrast the TNF-alpha SNP was significantly increased only in mothers when compared to controls.  Overall, the pattern of SNPs detected in autistic children and their mothers favored a pro-inflammatory environment. 

Conclusions:   The results of this study suggest that both mothers and their autistic children exhibit cytokine immunogenetic profiles that trend towards a pro-inflammatory phenotype.