Objectives: To examine the functional consequences of MET rs1858830 genotype on immune function, and the association of the MET ‘C’ allele with the presence of maternal antibodies directed against fetal brain proteins.
Methods: Genotypes at the MET rs1858830 locus were determined by direct re-sequencing. Peripheral blood immune cells were isolated from patients, treated with exogenous HGF (MET receptor ligand), and then challenged with LPS (a strong inducer of inflammation). Inflammatory cytokines in resulting cell supernatants were analyzed by multiplex analysis, and the presence of the MET receptor protein was determined by ELISA. In addition, plasma from all mothers was analyzed by western blot for the presence of antibodies directed against specific fetal brain antigens. The presence of specific antibody reactivity patterns was then analyzed with respect to MET rs1858830 genotype.
Results: Mothers carrying the MET ‘C’ allele showed a significant decrease in the expression of the MET receptor protein in peripheral blood immune cells following activation. Further, the MET ‘C’ allele was associated with a significant increase in the level of the pro-inflammatory cytokine IL-12p40 and a decrease in the level of the anti-inflammatory cytokine IL-10 following LPS challenge. Finally, the MET ‘C’ allele was significantly associated with the presence of antibodies directed against fetal brain proteins at 37, 39, and 73 kDa.
Conclusions: These results suggest a potential mechanism for the ontogeny of antibodies directed against fetal brain in mothers of children with autism. Herein we describe a reduction in the amount of the regulatory MET receptor on immune cells in mothers carrying the MET ‘C’ allele. As a consequence these mothers exhibited a more pro-inflammatory phenotype when challenged with LPS indicating the potential for a defect in immune regulation in these mothers. Further, the association between the MET ‘C’ allele in mothers and the presence of potentially pathogenic anti-fetal brain antibodies suggests that the presence of the MET ‘C’ allele confers susceptibility towards the loss of self-tolerance through immune dysregulation.
See more of: Animal Models & Cell Biology
See more of: Biological Mechanisms