ABSTRACT
Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.
Subject(s)
Acetates/blood , Fetus/immunology , Pre-Eclampsia/immunology , Prenatal Exposure Delayed Effects/immunology , T-Lymphocytes, Regulatory/immunology , Acetates/administration & dosage , Acetates/immunology , Acetates/metabolism , Adult , Animals , Animals, Newborn , Case-Control Studies , Child Development , Child, Preschool , Dietary Supplements , Female , Fetus/cytology , Fetus/diagnostic imaging , Gastrointestinal Microbiome/immunology , Germ-Free Life/immunology , Humans , Immune Tolerance/immunology , Infant , Infant, Newborn , Longitudinal Studies , Maternal-Fetal Exchange/immunology , Mice , Organ Size/immunology , Pre-Eclampsia/blood , Pre-Eclampsia/diagnosis , Pregnancy , Prenatal Exposure Delayed Effects/pathology , Prenatal Exposure Delayed Effects/prevention & control , Prospective Studies , Thymus Gland/cytology , Thymus Gland/diagnostic imaging , Thymus Gland/growth & development , Thymus Gland/immunology , Transcription Factors/immunology , Transcription Factors/metabolism , Ultrasonography, Prenatal , Young Adult , AIRE ProteinABSTRACT
We derived an automated algorithm for accurately measuring the thalamic diameter from 2-D fetal ultrasound (US) brain images. The algorithm overcomes the inherent limitations of the US image modality: nonuniform density; missing boundaries; and strong speckle noise. We introduced a "guitar" structure that represents the negative space surrounding the thalamic regions. The guitar acts as a landmark for deriving the widest points of the thalamus even when its boundaries are not identifiable. We augmented a generalized level-set framework with a shape prior and constraints derived from statistical shape models of the guitars; this framework was used to segment US images and measure the thalamic diameter. Our segmentation method achieved a higher mean Dice similarity coefficient, Hausdorff distance, specificity, and reduced contour leakage when compared to other well-established methods. The automatic thalamic diameter measurement had an interobserver variability of -0.56 ± 2.29 mm compared to manual measurement by an expert sonographer. Our method was capable of automatically estimating the thalamic diameter, with the measurement accuracy on par with clinical assessment. Our method can be used as part of computer-assisted screening tools that automatically measure the biometrics of the fetal thalamus; these biometrics are linked to neurodevelopmental outcomes.