Browsing by Author "Miller, Derek"

Now showing 1 - 6 of 6
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    Clinical chorioamnionitis at term IX : in vivo evidence of intra-amniotic inflammasome activation
    (2019) Gomez-López, Nardhy; Romero, Roberto; Maymon, Ely; Kusanovic, Juan Pedro; Panaitescu, Bogdan; Miller, Derek; Pacora, Percy; Tarca, Adi L.; Motomura, Kenichiro; Erez, Offer; Jung, Eunjung J.; Hassan, Sonia S.; Hsu, Chaur Dong
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    Differential immunophenotype of circulating monocytes from pregnant women in response to viral ligands
    (2023) Farías Jofré, Marcelo Enrique; Romero, Roberto; Xu, Yi; Levenson, Dustyn; Tao, Li; Kanninen, Tomi; Galaz, Jose; Arenas-Hernandez, Marcia; Liu, Zhenjie; Miller, Derek; Bhatti, Gaurav; Seyerle, Megan; Tarca, Adi L.; Gomez-Lopez, Nardhy
    Background Viral infections during pregnancy can have deleterious effects on mothers and their offspring. Monocytes participate in the maternal host defense against invading viruses; however, whether pregnancy alters monocyte responses is still under investigation. Herein, we undertook a comprehensive in vitro study of peripheral monocytes to characterize the differences in phenotype and interferon release driven by viral ligands between pregnant and non-pregnant women. Methods Peripheral blood was collected from third-trimester pregnant (n = 20) or non-pregnant (n = 20, controls) women. Peripheral blood mononuclear cells were isolated and exposed to R848 (TLR7/TLR8 agonist), Gardiquimod (TLR7 agonist), Poly(I:C) (HMW) VacciGrade™ (TLR3 agonist), Poly(I:C) (HMW) LyoVec™ (RIG-I/MDA-5 agonist), or ODN2216 (TLR9 agonist) for 24 h. Cells and supernatants were collected for monocyte phenotyping and immunoassays to detect specific interferons, respectively. Results The proportions of classical (CD14hiCD16−), intermediate (CD14hiCD16+), non-classical (CD14loCD16+), and CD14loCD16− monocytes were differentially affected between pregnant and non-pregnant women in response to TLR3 stimulation. The proportions of pregnancy-derived monocytes expressing adhesion molecules (Basigin and PSGL-1) or the chemokine receptors CCR5 and CCR2 were diminished in response to TLR7/TLR8 stimulation, while the proportions of CCR5− monocytes were increased. Such differences were found to be primarily driven by TLR8 signaling, rather than TLR7. Moreover, the proportions of monocytes expressing the chemokine receptor CXCR1 were increased during pregnancy in response to poly(I:C) stimulation through TLR3, but not RIG-I/MDA-5. By contrast, pregnancy-specific changes in the monocyte response to TLR9 stimulation were not observed. Notably, the soluble interferon response to viral stimulation by mononuclear cells was not diminished in pregnancy. Conclusions Our data provide insight into the differential responsiveness of pregnancy-derived monocytes to ssRNA and dsRNA, mainly driven by TLR8 and membrane-bound TLR3, which may help to explain the increased susceptibility of pregnant women to adverse outcomes resulting from viral infection as observed during recent and historic pandemics.
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    Fetal and maternal NLRP3 signaling is required for preterm labor and birth
    (AMER SOC CLINICAL INVESTIGATION INC, 2022) Motomura, Kenichiro; Romero, Roberto; Galaz, Jose; Tao, Li; Garcia-Flores, Valeria; Xu, Yi; Done, Bogdan; Arenas-Hernandez, Marcia; Miller, Derek; Gutierrez-Contreras, Pedro; Farias-Jofre, Marcelo; Aras, Siddhesh; Grossman, Lawrence, I; Tarca, Adi L.; Gomez-Lopez, Nardhy
    Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. One of every 4 preterm neonates is born to a mother with intra-amniotic inflammation driven by invading bacteria. However, the molecular mechanisms underlying this hostile immune response remain unclear. Here, we used a translationally relevant model of preterm birth in Nlrp3-deficient and-sufficient pregnant mice to identify what we believe is a previously unknown dual role for the NLRP3 pathway in the fetal and maternal signaling required for the premature onset of the labor cascade leading to fetal injury and neonatal death. Specifically, the NLRP3 sensor molecule and/or inflammasome is essential for triggering intra-amniotic and decidual inflammation, fetal membrane activation, uterine contractility, and cervical dilation. NLRP3 also regulates the functional status of neutrophils and macrophages in the uterus and decidua, without altering their influx, as well as maternal systemic inflammation. Finally, both embryo transfer experimentation and heterozygous mating systems provided mechanistic evidence showing that NLRP3 signaling in both the fetus and the mother is required for the premature activation of the labor cascade. These data provide insights into the mechanisms of fetal-maternal dialog in the syndrome of preterm labor and indicate that targeting the NLRP3 pathway could prevent adverse perinatal outcomes.
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    Innate lymphoid cells at the human maternal-fetal interface in spontaneous preterm labor
    (WILEY, 2018) Xu, Yi; Romero, Roberto; Miller, Derek; Silva, Pablo; Panaitescu, Bogdan; Theis, Kevin R.; Arif, Afrah; Hassan, Sonia S.; Gomez Lopez, Nardhy
    Problem: Pathological inflammation is causally linked to preterm labor and birth, the leading cause of neonatal morbidity and mortality worldwide. Our aims were to investigate whether (i) the newly described family of innate lymphoid cells (ILCs) was present at the human maternal-fetal interface and (ii) ILC inflammatory subsets were associated with the pathological process of preterm labor.
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    Pregnancy imparts distinct systemic adaptive immune function
    (WILEY, 2022) Demery-Poulos, Catherine; Romero, Roberto; Xu, Yi; Arenas-Hernandez, Marcia; Miller, Derek; Tao, Li; Galaz, Jose; Farias-Jofre, Marcelo; Bhatti, Gaurav; Garcia-Flores, Valeria; Seyerle, Megan; Tarca, Adi L.; Gomez-Lopez, Nardhy
    Problem Pregnancy represents a state of systemic immune activation that is primarily driven by alterations in circulating innate immune cells. Recent studies have suggested that cellular adaptive immune components, T cells and B cells, also undergo changes throughout gestation. However, the phenotypes and functions of such adaptive immune cells are poorly understood. Herein, we utilized high-dimensional flow cytometry and functional assays to characterize T-cell and B-cell responses in pregnant and non-pregnant women. Methods Peripheral blood mononuclear cells from pregnant (n = 20) and non-pregnant (n = 25) women were used for phenotyping of T-cell and B-cell subsets. T-cell proliferation and B-cell activation were assessed by flow cytometry after in vitro stimulation, and lymphocyte cytotoxicity was evaluated by using a cell-based assay. Statistical comparisons were performed with linear mixed-effects models. Results Pregnancy was associated with modestly enhanced basal activation of peripheral CD4(+) T cells. Both CD4(+) and CD8(+) T cells from pregnant women showed increased activation-induced proliferation; yet, a reduced proportion of these cells expressed activation markers compared to non-pregnant women. There were no differences in peripheral lymphocyte cytotoxicity between study groups. A greater proportion of B cells from pregnant women displayed memory-like and activated phenotypes, and such cells exhibited higher activation following stimulation. Conclusion Maternal circulating T cells and B cells display distinct responses during pregnancy. The former may reflect the unique capacity of T cells to respond to potential threats without undergoing aberrant activation, thereby preventing systemic inflammatory responses that can lead to adverse perinatal consequences.
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    The immunophenotype of amniotic fluid leukocytes in normal and complicated pregnancies
    (WILEY, 2018) Gomez Lopez, Nardhy; Romero, Roberto; Xu, Yi; Miller, Derek; Leng, Yaozhu; Panaitescu, Bogdan; Silva, Pablo; Faro, Jonathan; Alhousseini, Ali; Gill, Navleen; Hassan, Sonia S.; Hsu, Chaur Dong
    ProblemThe immune cellular composition of amniotic fluid is poorly understood. Herein, we determined: 1) the immunophenotype of amniotic fluid immune cells during the second and third trimester in the absence of intra-amniotic infection/inflammation; 2) whether amniotic fluid T cells and ILCs display different phenotypical characteristics to that of peripheral cells; and 3) whether the amniotic fluid immune cells are altered in women with intra-amniotic infection/inflammation.