Browsing by Author "Done, Bogdan"

Now showing 1 - 8 of 8
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    A key role for NLRP3 signaling in preterm labor and birth driven by the alarmin S100B
    (2023) Galaz, Jose; Motomura, Kenichiro; Romero, Roberto; Liu, Zhenjie; Garcia-Flores, Valeria; Tao, Li; Xu, Yi; Done, Bogdan; Arenas-Hernandez, Marcia; Kanninen, Tomi; Farias-Jofre, Marcelo; Miller, Derek; Tarca, Adi L.; Gomez-Lopez, Nardhy
    Preterm birth remains the leading cause of neonatal morbidity and mortality worldwide. A substantial number of spontaneous preterm births occur in the context of sterile intra-amniotic inflammation, a condition that has been mechanistically proven to be triggered by alarmins. However, sterile intra-amniotic inflammation still lacks treatment. The NLRP3 inflammasome has been implicated in sterile intra-amniotic inflammation; yet, its underlying mechanisms, as well as the maternal and fetal contributions to this signaling pathway, are unclear. Herein, by utilizing a translational and clinically relevant model of alarmin-induced preterm labor and birth in Nlrp3-/- mice, we investigated the role of NLRP3 signaling by using imaging and molecular biology approaches. Nlrp3 deficiency abrogated preterm birth and the resulting neonatal mortality induced by the alarmin S100B by impeding the premature activation of the common pathway of labor as well as by dampening intra-amniotic and fetal inflammation. Moreover, Nlrp3 deficiency altered leukocyte infiltration and functionality in the uterus and decidua. Last, embryo transfer revealed that maternal and fetal Nlrp3 signaling contribute to alarmin-induced preterm birth and neonatal mortality, further strengthening the concept that both individuals participate in the complex process of preterm parturition. These findings provide novel insights into sterile intra-amniotic inflammation, a common etiology of preterm labor and birth, suggesting that the adverse perinatal outcomes resulting from prematurity can be prevented by targeting NLRP3 signaling.
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    Exhausted and Senescent T Cells at the Maternal-Fetal Interface in Preterm and Term Labor
    (2019) Slutsky, Rebecca; Romero, Roberto; Xu, Yi; Galaz, Jose; Miller, Derek; Done, Bogdan; Tarca, Adi L.; Gregor, Sabrina; Hassan, Sonia S.; Leng, Yaozhu; Gomez-Lopez, Nardhy
    Successful pregnancy requires a tightly-regulated equilibrium of immune cell interactions at the maternal-fetal interface (i.e., the decidual tissues), which plays a central role in the inflammatory process of labor. Most of the innate immune cells in this compartment have been well characterized; however, adaptive immune cells are still under investigation. Herein, we performed immunophenotyping of the decidua basalis and decidua parietalis to determine whether exhausted and senescent T cells are present at the maternal-fetal interface and whether the presence of pathological (i.e., preterm) or physiological (i.e., term) labor and/or placental inflammation alter such adaptive immune cells. In addition, decidual exhausted T cells were sorted to test their functional status. We found that (1) exhausted and senescent T cells were present at the maternal-fetal interface and predominantly expressed an effector memory phenotype, (2) exhausted CD4(+) T cells increased in the decidua parietalis as gestational age progressed, (3) exhausted CD4(+) and CD8(+) T cells decreased in the decidua basalis of women who underwent labor at term compared to those without labor, (4) exhausted CD4(+) T cells declined with the presence of placental inflammation in the decidua basalis of women with preterm labor, (5) exhausted CD8(+) T cells decreased with the presence of placental inflammation in the decidua basalis of women who underwent labor at term, (6) both senescent CD4(+) and CD8(+) T cells declined with the presence of placental inflammation in the decidua basalis of women who underwent preterm labor, and (7) decidual exhausted T cells produced IFN and TNF upon in vitro stimulation. Collectively, these findings indicate that exhausted and senescent T cells are present at the human maternal-fetal interface and undergo alterations in a subset of women either with labor at term or preterm labor and placental inflammation. Importantly, decidual T cell function can be restored upon stimulation.
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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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    Immunosequencing 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, Nardhy
    T 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.
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    Immunosequencing and Profiling of T Cells at the Maternal-Fetal Interface of Women with Preterm Labor and Chronic Chorioamnionitis
    (Springer, 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, Nardhy; CEDEUS (Chile)
    T 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.
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    Immunosequencing 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, Nardhy
    T 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.
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    Pregnancy-specific responses to COVID-19 are revealed by high-throughput proteomics of human plasma
    (2022) Gomez-Lopez, Nardhy; Romero, Roberto; Escobar, Maria; Carvajal, Javier; Echavarria, Maria; Albornoz, Ludwig; Nasner, Daniela; Miller, Derek; Gallo, Dahiana; Galaz Alarcón, José Carlo; Arenas-Hernandez, Marcia; Bhatti, Gaurav; Done, Bogdan; Zambrano, Maria; Ramos, Isabella; Fernandez, Paula; Posada, Leandro; Chaiworapongsa, Tinnakorn; Jung, Eunjung; Garcia-Flores, Valeria; Suksai, Manaphat; Gotsch, Francesca; Bosco, Mariachiara; Than, Nandor; Tarca, Adi
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    Pregnancy-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.