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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.

SUBMITTER: Heuer L

PROVIDER: S-EPMC3309488 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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

Heuer L L Braunschweig D D Ashwood P P Van de Water J J Campbell D B DB

Translational psychiatry 20111018

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 rece ...[more]

PMID: 22833194

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Project description:Several groups have described the presence of fetal brain-reactive maternal autoantibodies in the plasma of some mothers whose children have autism spectrum disorder (ASD). We previously identified seven autoantigens targeted by these maternal autoantibodies, each of which is expressed at significant levels in the developing brain and has demonstrated roles in typical neurodevelopment. To further understand the binding repertoire of the maternal autoantibodies, as well as the presence of any meaningful differences with respect to the recognition and binding of these ASD-specific autoantibodies to each of these neuronal autoantigens, we utilized overlapping peptide microarrays incubated with maternal plasma samples obtained from the Childhood Autism Risk from Genetics and Environment (CHARGE) Study. In an effort to identify the most commonly recognized (immunodominant) epitope sequences targeted by maternal autoantibodies for each of the seven ASD-specific autoantigens, arrays were screened with plasma from mothers with children across diagnostic groups (ASD and typically developing (TD)) that were positive for at least one antigen by western blot (N = 67) or negative control mothers unreactive to any of the autoantigens (N = 18). Of the 63 peptides identified with the discovery microarrays, at least one immunodominant peptide was successfully identified for each of the seven antigenic proteins using subsequent selective screening microarrays. Furthermore, while limited by our relatively small sample size, there were peptides that were distinctly recognized by autoantibodies relative to diagnosis For example, reactivity was observed exclusively in mothers of children of ASD towards several peptides, including the LDH-B peptides DCIIIVVSNPVDILT (9.1% ASD vs. 0% TD; odds ratio (95% CI) = 6.644 (0.355-124.384)) and PVAEEEATVPNNKIT (5.5% ASD vs. 0% TD; odds ratio (95% CI) = 4.067 (0.203-81.403)).These results suggest that there are differences in the binding repertoire between the antigen positive ASD and TD maternal samples. Further, the autoantibodies in plasma from mothers of children with ASD bound to a more diverse set of peptides, and there were specific peptide binding combinations observed only in this group. Future studies are underway to determine the critical amino acids necessary for autoantibody binding, which will be essential in developing a potential therapeutic strategy for maternal autoantibody related (MAR) ASD.

Project description:ImportancePrenatal maternal stress is increasingly associated with adverse outcomes in pregnant women and their offspring. However, the association between maternal stress and human fetal brain growth and metabolism is unknown.ObjectiveTo identify the association between prenatal maternal psychological distress and fetal brain growth, cortical maturation, and biochemical development using advanced 3-dimensional volumetric magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS).Design, setting, and participantsThis cohort study prospectively recruited pregnant women from low-risk obstetric clinics in Washington, DC, from January 1, 2016, to April 17, 2019. Participants were healthy volunteers with a normal prenatal medical history, no chronic or pregnancy-induced physical or mental illnesses, and normal results on fetal ultrasonography and biometry studies. Fetal brain MRI studies were performed at 2 time points between 24 and 40 weeks' gestation.ExposuresPrenatal maternal stress, anxiety, and depression.Main outcomes and measuresVolumes of fetal total brain, cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and hippocampus were measured from 3-dimensional reconstructed T2-weighted MRI scans. Cortical folding measurements included local gyrification index, sulcal depth, and curvedness. Fetal brain N-acetylaspartate, creatine, and choline levels were quantified using 1H-MRS. Maternal stress, depression, and anxiety were measured with the Perceived Stress Scale (PSS), Edinburgh Postnatal Depression Scale (EPDS), Spielberger State Anxiety Inventory (SSAI), and Spielberger Trait Anxiety Inventory (STAI).ResultsA total of 193 MRI studies were performed in 119 pregnant women (67 [56%] carrying male fetuses and 52 [44%], female fetuses; maternal mean [SD] age, 34.46 [5.95] years) between 24 and 40 gestational weeks. All women were high school graduates, 99 (83%) were college graduates, and 100 (84%) reported professional employment. Thirty-two women (27%) had positive scores for stress, 31 (26%) for anxiety, and 13 (11%) for depression. Maternal trait anxiety was associated with smaller fetal left hippocampal volume (STAI score: -0.002 cm3; 95% CI, -0.003 to -0.0008 cm3; P = .004). Maternal anxiety and stress were associated with increased fetal cortical gyrification in the frontal lobe (β for SSAI score: 0.004 [95% CI, 0.001-0.006; P = .002]; β for STAI score: 0.004 [95% CI, 0.002-0.006; P < .001]; β for PSS score: 0.005 [95% CI, 0.001-0.008; P = .005]) and temporal lobe (β for SSAI score: 0.004 [95% CI, 0.001-0.007; P = .004]; β for STAI score: 0.004 [95% CI, 0.0008-0.006; P = .01]). Elevated maternal depression was associated with decreased creatine (EPDS score: -0.04; 95% CI, -0.06 to -0.02; P = .005) and choline (EPDS score: -0.03; 95% CI, -0.05 to -0.01; P = .02) levels in the fetal brain.Conclusions and relevanceThis study found that the prevalence of maternal psychological distress in healthy, well-educated, and employed pregnant women was high, underappreciated, and associated with impaired fetal brain biochemistry and hippocampal growth as well as accelerated cortical folding. These findings appear to support the need for routine mental health surveillance for all pregnant women and targeted interventions in women with elevated psychological distress.

Dataset Information

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

Publications

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

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