Browsing by Author "Miller, Derek"
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- ItemCellular immune responses in amniotic fluid of women with a sonographic short cervix(2020) Galaz, Jose; Romero, Roberto; Xu, Yi; Miller, Derek; Levenson, Dustyn; Para, Robert; Varrey, Aneesha; Hsu, Richard; Tong, Anna; Hassan, Sonia S.; Hsu, Chaur-Dong; Gomez-Lopez, NardhyObjectives: A sonographic short cervix is one of the strongest predictors of preterm delivery. However, the cellular immune composition of amniotic fluid in women with a short cervix has not yet been described. Herein, we determined cellular and soluble immune responses in amniotic fluid from pregnant women with a mid-trimester asymptomatic short cervix.
- ItemClinical 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
- ItemDefining a role for Interferon Epsilon in normal and complicated pregnancies(2022) Miller, Derek; Romero, Roberto; Kacerovsky, Marian; Musilova, Ivana; Galaz, Jose; Garcia-Flores, Valeria; Xu, Yi; Pusod, Errile; Demery-Poulos, Catherine; Gutierrez-Contreras, Pedro; Ning Liu, Tzu; Jung, Eunjung; Theis, Kevin R.; Coleman, Lanetta A.; Gomez-Lopez, NardhyInterferon epsilon (IFNe) is a recently described cytokine that is constitutively expressed in the female repro-ductive tract. However, the role of this hormonally regulated cytokine during human pregnancy is poorly un-derstood. Moreover, whether IFNe participates in host immune response against bacteria-driven intra-amniotic infection or cervical human papillomavirus infection during pregnancy is unknown. Herein, using a unique set of human samples derived from multiple study cohorts, we aimed to uncover the role of IFNe in normal and complicated pregnancies. We showed that IFNe is expressed in the myometrium, cervix, and chorioamniotic membranes, and may therefore represent a constitutive element of host defense mechanisms in these tissues during pregnancy. The expression of IFNe in the myometrium and cervix appeared greater in late gestation than in mid-pregnancy, but did not seem to be impacted by labor. Notably, concentrations of IFNe in amniotic fluid, but not cervical fluid, were increased in a subset of women undergoing spontaneous preterm labor with intra-amniotic infection, indicating that IFNe could participate in anti-microbial responses in the amniotic cavity. However, stimulation with Ureaplasma parvum and/or lipopolysaccharide did not enhance IFNE expression by amnion epithelial or cervical cells in vitro, implicating alternative sources of this cytokine during intra-amniotic or cervical infection, respectively. Collectively, our results represent the first characterization of IFNe expression by human reproductive and gestational tissues during normal pregnancy and suggest a role for this cytokine in intra-amniotic infection leading to preterm birth.
- ItemDifferential 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, NardhyBackground 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.
- ItemFetal 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, NardhyPreterm 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.
- ItemImmunosequencing and Profiling of T Cells at the Maternal-Fetal Interface of Women with Preterm Labor and Chronic Chorioamnionitis(2023) Miller, Derek; Romero, Roberto; Myers, Luke; Xu, Yi; Arenas-Hernández, Marcia; Galáz Alarcón, José Carlo; Soto, Cinque; Done, Bogdan; Quiroz, Angélica; Awonuga, Awoniyi O.; Bryant, David R.; Tarca, Adi L.; Gómez-Lopez, NardhyT cells are implicated in the pathophysiology of preterm labor and birth, the leading cause of neonatal morbidity and mortality worldwide. Specifically, maternal decidual T cells infiltrate the chorioamniotic membranes in chronic chorioamnionitis (CCA), a placental lesion considered to reflect maternal anti-fetal rejection, leading to preterm labor and birth. However, the phenotype and TCR repertoire of decidual T cells in women with preterm labor and CCA have not been investigated. In this study, we used phenotyping, TCR sequencing, and functional assays to elucidate the molecular characteristics and Ag specificity of T cells infiltrating the chorioamniotic membranes in women with CCA who underwent term or preterm labor. Phenotyping indicated distinct enrichment of human decidual effector memory T cell subsets in cases of preterm labor with CCA without altered regulatory T cell proportions. TCR sequencing revealed that the T cell repertoire of CCA is characterized by increased TCR richness and decreased clonal expansion in women with preterm labor. We identified 15 clones associated with CCA and compared these against established TCR databases, reporting that infiltrating T cells may possess specificity for maternal and fetal Ags, but not common viral Ags. Functional assays demonstrated that choriodecidual T cells can respond to maternal and fetal Ags. Collectively, our findings provide, to our knowledge, novel insight into the complex processes underlying chronic placental inflammation and further support a role for effector T cells in the mechanisms of disease for preterm labor and birth. Moreover, this work further strengthens the contribution of adaptive immunity to the syndromic nature of preterm labor and birth.
- ItemInnate 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, NardhyProblem: 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.
- ItemM2-polarized macrophages prevent preterm birth and improve neonatal survival and immunity(AMER ASSOC IMMUNOLOGISTS, 2024) Garcia-Flores, Valeria; Liu, Zhenjie; Romero, Roberto; Xu, Yi; Miller, Derek; Galaz Alarcón, José Carlo; Winters, Andrew; Farías Jofre, Marcelo Enrique; Theis, Kevin; Gomez-Lopez, NardhyPreterm birth (PTB), commonly preceded by preterm labor, is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm labor are associated with sterile intra-amniotic inflammation (SIAI), an inflammatory condition without detectable microorganisms. To date, no successful strategies to treat SIAI have been developed. Herein, we present mechanistic proof that treatment with M2-polarized macrophages (M2 MΦ) can effectively prevent PTB [(HMGB1, n = 28 vs. HMGB1+M2 MΦ, n = 29) (p<0.05)] and neonatal mortality [(HMGB1, n = 20 litters vs. HMGB1+M2 MΦ, n = 14 litters) (p<0.001)] induced by the ultrasound-guided intra-amniotic injection of the alarmin HMGB1 in mice. M2 MΦ halt the premature pathway of labor by infiltrating maternal and fetal compartments, where they inhibit NLRP3 inflammasome activation triggered by HMGB1. Furthermore, M2 MΦ dampen the HMGB1-induced inflammatory response in the amniotic cavity and fetal lung. Notably, neonates exposed to HMGB1 in utero display a reduced capacity to clear bacterial infection and gut microbiome dysbiosis, which are restored by M2 MΦ treatment [(HMGB1, n = 10 vs. HMGB1+ M2 MΦ, n = 10) (p<0.001 and p<0.01, respectively)]. Our findings provide cogent evidence that M2 MΦ can serve as a cellular strategy to mitigate PTB and decrease neonatal mortality.
- ItemPregnancy 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, NardhyProblem 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.
- ItemPregnancy-specific responses to COVID-19 revealed by high-throughput proteomics of human plasma(2023) Gomez-Lopez, Nardhy; Romero, Roberto; Escobar, Maria Fernanda; Carvajal, Javier Andres; Echavarria, Maria Paula; Albornoz, Ludwig L.; Nasner, Daniela; Miller, Derek; Gallo, Dahiana M.; Galaz, Jose; Arenas-Hernandez, Marcia; Bhatti, Gaurav; Done, Bogdan; Zambrano, Maria Andrea; Ramos, Isabella; Fernandez, Paula Andrea; Posada, Leandro; Chaiworapongsa, Tinnakorn; Jung, Eunjung; Garcia-Flores, Valeria; Suksai, Manaphat; Gotsch, Francesca; Bosco, Mariachiara; Than, Nandor Gabor; Tarca, Adi L.Gomez-Lopez et al. profile the plasma proteome of pregnant and non-pregnant COVID-19 patients and controls. Shared and pregnancy-specific proteomic changes are identified in COVID-19 patients compared to controls, with the proteome accurately identifying COVID-19 patients, even when asymptomatic.