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.

Figure 1

Association of MET rs1858830 genotype with MET protein expression in peripheral blood mononuclear cells (PBMCs). MET protein expression was reduced 1.4-fold in mothers of genotype C/C (4.7±0.7 ng mg⁻¹ total protein) compared with mothers of genotype G/G (6.7±0.8 ng mg⁻¹ total protein) (P=0.030). MET protein expression was also decreased in mothers of genotype C/G compared with mothers of genotype G/G (P=0.025). There was no significant difference in MET protein expression between mothers of genotype C/C and C/G (P=0.463).

Figure 2

Correlation of both MET rs1858830 genotype (a) and MET protein levels (b) with IL-10 expression in peripheral blood mononuclear cells (PBMCs). (a) IL-10 protein is increased 1.8-fold in G/G genotype mothers (2295±321 ng mg⁻¹) compared with C/C genotype mothers (1267±192 ng mg⁻¹) (P=0.001). IL-10 protein is increased 1.6-fold in G/G genotype mothers compared with C/G genotype mothers (1429±165 ng mg⁻¹) (P=0.005). (b) Linear regression indicates highly significant correlation (r=0.401; P=0.003) between expression of MET protein and expression of IL-10 protein.

Figure 3

Proposed model of the mechanism by which maternal MET genotype predisposes, via immune dysregulation, toward neurodevelopmental alterations characteristic of ASD.