Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression

Abstract

The contribution of peripheral immunity to autism spectrum disorders (ASDs) risk is debated and poorly understood. Some mothers of children with ASD have autoantibodies that react to fetal brain proteins, raising the possibility that a subset of ASD cases may be associated with a maternal antibody response during gestation. The mechanism by which the maternal immune system breaks tolerance has not been addressed. We hypothesized that the mechanism may involve decreased expression of the MET receptor tyrosine kinase, an ASD risk gene that also serves as a key negative regulator of immune responsiveness. In a sample of 365 mothers, including 202 mothers of children with ASD, the functional MET promoter variant rs1858830 C allele was strongly associated with the presence of an ASD-specific 37+73-kDa band pattern of maternal autoantibodies to fetal brain proteins (P=0.003). To determine the mechanism of this genetic association, we measured MET protein and cytokine production in freshly prepared peripheral blood mononuclear cells from 76 mothers of ASD and typically developing children. The MET rs1858830 C allele was significantly associated with MET protein expression (P=0.025). Moreover, decreased expression of the regulatory cytokine IL-10 was associated with both the MET gene C allele (P=0.001) and reduced MET protein levels (P=0.002). These results indicate genetic distinction among mothers who produce ASD-associated antibodies to fetal brain proteins, and suggest a potential mechanism for how a genetically determined decrease in MET protein production may lead to a reduction in immune regulation.

Myeloid dendritic cells frequencies are increased in children with autism spectrum disorder and associated with amygdala volume and repetitive behaviors

“…For example, MET signaling induces a tolerogenic phenotype in dendritic cells without affecting their antigen presenting capabilities (Okunishi et al, 2005; Rutella et al, 2006). We recently showed that the MET ‘C’ variant predisposes to innate immune cell activation and the loss of self-tolerance (Heuer et al, 2011). Individuals with a functional polymorphism in the promoter for MET, namely rs1858830 ‘C’ allele, carry a 2.25 fold increased relative risk for autism (Campbell et al, 2006).…”

Evidence supporting an altered immune response in ASD

“…A recent paper sheds insight into how the maternal immune system may lose tolerance which would allow it to produce antibodies against the fetal brain. The MET promoter variant rs1858839C allele was found to be significantly associated with the presence of ASD-associated maternal autoantibodies against fetal brain proteins [57]. MET receptor tyrosine kinase plays a role in negative regulation of the immune response and a disruption in this regulation could explain why there is a break in maternal tolerance to the fetus that leads to the production of autoantibodies.…”

The Role of the Immune System in Autism Spectrum Disorder

“…Recent estimates at this site suggest that the CC and CG alleles represent a 1.76 and 1.59 relative risk, respectively, over the GG allele (Campbell et al, 2008), with an odds ratio of 1.64 for the C variant (Jackson et al, 2009). This MET variant also appears connected to both an increase in 37/73 kDa maternal autoantibodies and a decrease in maternal IL-10, suggesting another mechanism through which MET may associate with ASD as a susceptibility factor (Heuer et al, 2011).…”