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Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond.

ABSTRACT: The complement cascade was identified over 100 years ago, yet investigation of its role in pregnancy remains an area of intense research. Complement inhibitors at the maternal-fetal interface prevent inappropriate complement activation to protect the fetus. However, this versatile proteolytic cascade also favorably influences numerous stages of pregnancy, including implantation, fetal development, and labor. Inappropriate complement activation in pregnancy can have adverse lifelong sequelae for both mother and child. This review summarizes the current understanding of complement activation during all stages of pregnancy. In addition, consequences of complement dysregulation during adverse pregnancy outcomes from miscarriage, preeclampsia, and pre-term birth are examined. Finally, future research directions into complement activation during pregnancy are considered.

SUBMITTER: Girardi G

PROVIDER: S-EPMC7411130 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond.

Girardi Guillermina G Lingo Joshua J JJ Fleming Sherry D SD Regal Jean F JF

Frontiers in immunology 20200731

The complement cascade was identified over 100 years ago, yet investigation of its role in pregnancy remains an area of intense research. Complement inhibitors at the maternal-fetal interface prevent inappropriate complement activation to protect the fetus. However, this versatile proteolytic cascade also favorably influences numerous stages of pregnancy, including implantation, fetal development, and labor. Inappropriate complement activation in pregnancy can have adverse lifelong sequelae for ...[more]

PMID: 32849586

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Project description:BackgroundVaginal microbiome and the local innate immune defense, including the complement system, contribute to anti- and proinflammatory homeostasis during pregnancy and parturition. The relationship between commensal vaginal bacteria and complement activation during pregnancy and delivery is not known.ObjectiveTo study the association of the cervicovaginal microbiota composition to activation and regulation of the complement system during pregnancy and labor.Study designWe recruited women during late pregnancy (weeks 41 + 5 to 42 + 0, n=48) and women in active labor (weeks 38 + 4 to 42 + 2, n=25). Mucosal swabs were taken from the external cervix and lateral fornix of the vagina. From the same sampling site, microbiota was analyzed with 16S RNA gene amplicon sequencing. A Western blot technique was used to detect complement C3, C4 and factor B activation and presence of complement inhibitors. For semiquantitative analysis, the bands of the electrophoresed proteins in gels were digitized on a flatbed photo scanner and staining intensities were analyzed using ImageJ/Fiji win-64 software. Patient data was collected from medical records and questionnaires.ResultsThe vaginal microbiota was Lactobacillus-dominant in most of the samples (n=60), L. iners and L. crispatus being the dominant species. L. gasseri and L. jensenii were found to be more abundant during pregnancy than active labor. L. jensenii abundance correlated with C4 activation during pregnancy but not in labor. Gardnerella vaginalis was associated with C4 activation both during pregnancy and labor. The amount of L. gasseri correlated with factor B activation during pregnancy but not during labor. Atopobium vaginae was more abundant during pregnancy than labor and correlated with C4 activation during labor and with factor B activation during pregnancy. Activation of the alternative pathway factor B was significantly stronger during pregnancy compared to labor. During labor complement activation may be inhibited by the abundant presence of factor H and FHL1.ConclusionsThese results indicate that bacterial composition of the vaginal microbiota could have a role in the local activation and regulation of complement-mediated inflammation during pregnancy. At the time of parturition complement activation appears to be more strictly regulated than during pregnancy.

Project description:BackgroundComplement factor H (CFH) has been found to be associated with insulin resistance. This study assessed the correlation between CFH and other clinical parameters, and determined whether CFH played a role in gestational diabetes mellitus (GDM) and adverse pregnancy outcomes.MethodsA total of 397 pregnant women were included for analysis in this nested case-control study. Clinical parameters and serum were collected within the 11-17th gestational age at the first prenatal visit. At 24-28 weeks of gestation, a 75 g oral glucose tolerance test was performed and subjects were divided into a GDM (n = 80) and a non-GDM control group (n = 317). The delivery data were also followed. The serum CFH level was assayed by ELISA.ResultsCFH was higher in GDM than in non-GDM controls (280.02 [58.60] vs. 264.20 [68.77]; P = 0.014). CFH level was moderately associated with pre-pregnancy body mass index (BMI), BMI and total triglycerides (TG), and slightly associated with gestational age, low density lipoprotein cholesterol (LDL-C), total cholesterol (TC) in GDM and non-GDM (all P < 0.05). Moreover, CFH level was moderately correlated with alkaline phosphatase (ALP) and slightly correlated with age, uric acid (UA) and total bilirubin (TB) in non-GDM (all P < 0.05). After adjustment for clinical confounding factors, BMI, TG, gestational age, ALP, TB, age and UA were independent risk factors for log10 CFH levels (all P < 0.05) in all subjects. In addition, overweight or obese pregnant women, women with hypertriglyceridemia and women in the second trimester had significantly higher CFH levels than normal weight and underweight group (P < 0.001), the non-hypertriglyceridemia group (P < 0.001) and women in the first trimester group (P < 0.05) in all pregnant women respectively. Following binary logistic regression, CFH was not independently associated with GDM and related pregnant outcomes.ConclusionsThe CFH in 11-17th weeks of gestation might be affected by many factors, including BMI, TG, gestational age, ALP, TB, age and UA. CFH was not an independent risk factor for GDM and avderse pregnancy outcomes.

Project description:Immune homeostasis of the intrauterine cavity is vital for pregnancy maintenance. At term or preterm, fetal and maternal tissue inflammation contributes to the onset of labor. Though multiple immune-modulating molecules are known, human leukocyte antigen (HLA)-G is unique to gestational tissues and contributes to maternal-fetal immune tolerance. Several reports on HLA-G's role exist; however, ambiguity exists regarding its functional contributions during pregnancy and parturition. To fill these knowledge gaps, a systematic review (SR) of the literature was conducted to better understand the expression, localization, function, and regulation of HLA-G during pregnancy and parturition. A SR of the literature on HLA-G expression and function reported in reproductive tissues during pregnancy, published between 1976-2020 in English, using three electronic databases (SCOPE, Medline, and ClinicalTrials.gov) was conducted. The selection of studies, data extraction, and quality assessment were performed in duplicate by two independent reviewers. Manuscripts were separated into three categories: (1) expression and localization of HLA-G, (2) regulators of HLA-G, and (3) the mechanistic roles of HAL-G. Data were extracted, analyzed, and summarized. The literature search yielded 2554 citations, 117 of which were selected for full-text evaluation, and 115 were included for the final review based on our inclusion/exclusion criteria. HLA-G expression and function were mostly studied in placental tissue and/or cells and peripheral blood immune cells, while only 13% of the studies reported data on amniotic fluid/cord blood and fetal membranes. Measurements of soluble and membranous HLA-G were determined mostly by RNA-based methods and protein by immunostaining, Western blot, or flow cytometric analyses. HLA-G was reported to regulate inflammation and inhibit immune-cell-mediated cytotoxicity and trophoblast invasion. Clinically, downregulation of HLA-G is reported to be associated with poor placentation in preeclampsia and immune cell infiltration during ascending infection. This SR identified several reports supporting the hypothesized role of immune regulation in gestational tissues during pregnancy. A lack of rigor and reproducibility in the experimental approaches and models in several reports make it difficult to fully elucidate the mechanisms of action of HLA-G in immune tolerance during pregnancy.

Dataset Information

Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond.

Publications

Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond.

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