Change in Mononuclear Leukocyte Responsiveness in Midpregnancy and Subsequent Preterm Birth
Columbia University, New York, New York, United StatesObstetrics and Gynecology (Impact Factor: 5.18). 04/2013; 121(4):805-811. DOI: 10.1097/AOG.0b013e3182878a80
OBJECTIVE:: To estimate the associations of change in immune response with preterm delivery, omega-3 supplementation, and fish diet. METHODS:: This was an ancillary study to a randomized trial of omega-3 fatty acid supplementation for the prevention of recurrent preterm birth. In vitro maternal peripheral blood mononuclear leukocyte production of the anti-inflammatory cytokine, interleukin-10, and the proinflammatory cytokine, tumor necrosis factor-α, in response to stimulation with lipopolysaccharide, was measured at 16-22 weeks of gestation (baseline) and again at 25-28 weeks of gestation (follow-up) among women with prior spontaneous preterm birth. Changes in concentrations from baseline to follow-up ([INCREMENT]) were compared separately among groups defined by gestational age category at delivery, fish diet history, and omega-3 compared with placebo treatment assignment with Kruskal-Wallis tests. RESULTS:: Interleukin-10 [INCREMENT] differed by gestational age category among 292 women with paired assays. Concentrations increased less in women delivering between 35 and 36 6/7 weeks of gestation (48.9 pg/mL) compared with women delivering at term (159.3 pg/mL) and decreased by 65.2 pg/mL in women delivering before 35 weeks of gestation (P=.01). Tumor necrosis factor-α Δ also differed by gestational age category among 319 women, but the pattern was inconsistent. Those delivering between 35 and 36 6/7 weeks of gestation exhibited decreased concentrations of tumor necrosis factor-α at follow-up compared with baseline (-356.0 pg/mL); concentrations increased among women delivering before 35 weeks of gestation and those delivering at term, 132.1 and 86.9 pg/mL (P=.03). Interleukin-10 Δ and tumor necrosis factor-α Δ were unaffected by either omega-3 supplementation or fish diet. CONCLUSION:: Recurrent preterm birth was associated with decreased peripheral blood mononuclear leukocyte production of interleukin-10 in response to a stimulus during the second trimester. CLINICAL TRIAL REGISTRATION:: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00135902. LEVEL OF EVIDENCE:: II.
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ABSTRACT: ProblemPrevious studies have investigated the utility of inflammation markers as predictors of preterm birth, but none have compared trends in levels between uncomplicated and preterm pregnancy.Method of studyWe explored longitudinal changes in plasma cytokines, including IL-1β, IL-6, IL-10, and TNF-α, as well as C-reactive protein in pregnant women from a nested case–control study.ResultsIL-6 was associated with increased odds of spontaneous preterm birth, defined by presentation of spontaneous preterm labor and/or preterm premature rupture of the membranes. Associations were strongest later in pregnancy. IL-10 was associated with increased odds of placentally mediated preterm birth, defined by presentation with preeclampsia or intrauterine growth restriction, and odds ratios were also highest near the end of pregnancy.Conclusion Maternal inflammation markers were associated with increased risk of preterm birth, and relationships differed by etiology of preterm delivery and gestational age at sample collection.American Journal Of Reproductive Immunology 05/2014; 72(3). DOI:10.1111/aji.12265 · 2.44 Impact Factor
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ABSTRACT: Single-cell technologies have immense potential to shed light on molecular and biological processes that drive human diseases. Mass cytometry (or Cytometry by Time Of Flight mass spectrometry, CyTOF) has already been employed in clinical studies to comprehensively survey patients' circulating immune system. As interest in the "bedside" application of mass cytometry is growing, the delineation of relevant methodological issues is called for. This report uses a newly generated dataset to discuss important methodological considerations when mass cytometry is implemented in a clinical study. Specifically, the use of whole blood samples versus peripheral blood mononuclear cells (PBMCs), design of mass-tagged antibody panels, technical and analytical implications of sample barcoding, and application of traditional and unsupervised approaches to analyze high-dimensional mass cytometry datasets are discussed. A mass cytometry assay was implemented in a cross-sectional study of 19 women with a history of term or preterm birth to determine whether immune traits in peripheral blood differentiate the two groups in the absence of pregnancy. Twenty-seven phenotypic and 11 intracellular markers were simultaneously analyzed in whole blood samples stimulated with lipopolysaccharide (LPS at 0, 0.1, 1, 10, and 100 ng mL-1) to examine dose-dependent signaling responses within the toll-like receptor 4 (TLR4) pathway. Complementary analyses, grounded in traditional or unsupervised gating strategies of immune cell subsets, indicated that the prpS6 and pMAPKAPK2 responses in classical monocytes are accentuated in women with a history of preterm birth (FDR<1%). The results suggest that women predisposed to preterm birth may be prone to mount an exacerbated TLR4 response during the course of pregnancy. This important hypothesis-generating finding points to the power of single-cell mass cytometry to detect biologically important differences in a relatively small patient cohort.Cytometry Part A 07/2015; 87(9). DOI:10.1002/cyto.a.22720 · 2.93 Impact Factor
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