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Lupus Nov 2019Prognosis of pregnancies in women with antiphospholipid syndrome has dramatically improved over the past two decades using conventional treatment with low molecular...
Prognosis of pregnancies in women with antiphospholipid syndrome has dramatically improved over the past two decades using conventional treatment with low molecular weight heparin and low-dose aspirin. However, despite this regimen, 10-15% of antiphospholipid syndrome patients experience pregnancy losses. Several studies have been performed in order to identify risk factors predictive of complications. Thrombosis has been generally accepted as the key pathogenetic mechanism underlying pregnancy morbidity. However, the thrombogenic state alone is not able to explain all the different mechanisms leading to pregnancy failure. In fact, emerging evidence shows that complement pathway could play an important role in mediating clinical events in antiphospholipid syndrome. However, the exact mechanism through which complement mediates antiphospholipid syndrome complications remains unknown. Low complement levels (C3 and C4) are associated with poor pregnancy outcome in women with antiphospholipid syndrome in different studies. Hypocomplementemia could be indicated as an early predictor of adverse pregnancy outcome, available at the beginning of pregnancy for starting, if necessary, additional treatment to conventional therapy. However, future studies need to better understand the impact of low complement level on antiphospholipid syndrome pregnancy outcome.
Topics: Anticoagulants; Antiphospholipid Syndrome; Complement Activation; Complement C3; Complement C4; Female; Humans; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prognosis; Risk Factors; Thrombosis
PubMed: 31623520
DOI: 10.1177/0961203319882507 -
Clinical Journal of the American... Nov 2021Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan-Meier method.
RESULTS
Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2-15 (median, 9; interquartile range, 7-11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; 0.05). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on the initial biopsy specimen.
CONCLUSIONS
Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.
Topics: Adolescent; Autoantibodies; Child; Child, Preschool; Complement C3; Complement C3b; Complement C4; Complement Factor B; Complement Factor H; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Glomerulonephritis, Membranoproliferative; Graft Survival; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Male; Phenotype; Prognosis; Proportional Hazards Models; Prospective Studies; Recurrence; Registries; Risk Factors
PubMed: 34551983
DOI: 10.2215/CJN.00320121 -
Frontiers in Immunology 2022Vaginal microbiome and the local innate immune defense, including the complement system, contribute to anti- and proinflammatory homeostasis during pregnancy and...
BACKGROUND
Vaginal 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.
OBJECTIVE
To study the association of the cervicovaginal microbiota composition to activation and regulation of the complement system during pregnancy and labor.
STUDY DESIGN
We 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.
RESULTS
The vaginal microbiota was -dominant in most of the samples (n=60), and being the dominant species. and were found to be more abundant during pregnancy than active labor. abundance correlated with C4 activation during pregnancy but not in labor. was associated with C4 activation both during pregnancy and labor. The amount of correlated with factor B activation during pregnancy but not during labor. 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.
CONCLUSIONS
These 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.
Topics: Bacteria; Complement Activation; Complement Factor B; Female; Gardnerella vaginalis; Humans; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Microbiota; Muscle Proteins; Parturition; Pregnancy; Vagina
PubMed: 35958597
DOI: 10.3389/fimmu.2022.925630 -
Journal of Immunology (Baltimore, Md. :... Nov 2023C4b-binding protein (C4BP) is a fluid-phase complement inhibitor that prevents uncontrolled activation of the classical and lectin complement pathways. As a complement... (Review)
Review
C4b-binding protein (C4BP) is a fluid-phase complement inhibitor that prevents uncontrolled activation of the classical and lectin complement pathways. As a complement inhibitor, C4BP also promotes apoptotic cell death and is hijacked by microbes and tumors for complement evasion. Although initially characterized for its role in complement inhibition, there is an emerging recognition that C4BP functions in a complement-independent manner to promote cell survival, protect against autoimmune damage, and modulate the virulence of microbial pathogens. In this Brief Review, we summarize the structure and functions of human C4BP, with a special focus on activities that extend beyond the canonical role of C4BP in complement inhibition.
Topics: Humans; Complement C4b-Binding Protein; Complement System Proteins; Complement Inactivating Agents; Complement Pathway, Mannose-Binding Lectin; Virulence; Protein Binding; Complement C4b
PubMed: 37931209
DOI: 10.4049/jimmunol.2300333 -
Nature Jun 2020Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus...
Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men, whereas schizophrenia affects men with greater frequency and severity relative to women. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
Topics: Adult; Alleles; Complement C3; Complement C4; Female; Genetic Predisposition to Disease; HLA Antigens; Haplotypes; Humans; Lupus Erythematosus, Systemic; Major Histocompatibility Complex; Male; Middle Aged; Sex Characteristics; Sjogren's Syndrome; Young Adult
PubMed: 32499649
DOI: 10.1038/s41586-020-2277-x -
Journal of Neuroimmunology Feb 2022Immune system dysregulation may be involved in schizophrenia, but biomarker studies have thus far reported inconsistent findings. The relationship of plasma levels of...
Immune system dysregulation may be involved in schizophrenia, but biomarker studies have thus far reported inconsistent findings. The relationship of plasma levels of complement markers C3 and C4, with schizophrenia, sociodemographic and clinico-psychological factors were here studied in 183 patients and 212 controls. C3 and C4 levels were significantly higher in the patients and in subjects with elevated C-reactive protein (CRP), and positively correlated with body mass index (BMI) (p < 0.05). Schizophrenia, BMI, and CRP were significant predictors for C3 and C4 levels in multivariate analyses (p < 0.001). In conclusion, complements C3 and C4 are potential peripheral biomarkers in schizophrenia.
Topics: Adult; Biomarkers; Body Mass Index; C-Reactive Protein; Complement C3; Complement C4; Female; Humans; Male; Middle Aged; Schizophrenia
PubMed: 34990981
DOI: 10.1016/j.jneuroim.2021.577793 -
Molecular Psychiatry Jan 2020The complement system is a set of immune proteins involved in first-line defense against pathogens and removal of waste materials. Recent evidence has implicated the... (Review)
Review
The complement system is a set of immune proteins involved in first-line defense against pathogens and removal of waste materials. Recent evidence has implicated the complement cascade in diseases involving the central nervous system, including schizophrenia. Here, we provide an up-to-date narrative review and critique of the literature on the relationship between schizophrenia and complement gene polymorphisms, gene expression, protein concentration, and pathway activity. A literature search identified 23 new studies since the first review on this topic in 2008. Overall complement pathway activity appears to be elevated in schizophrenia. Recent studies have identified complement component 4 (C4) and CUB and Sushi Multiple Domains 1 (CSMD1) as potential genetic markers of schizophrenia. In particular, there is some evidence of higher rates of C4B/C4S deficiency, reduced peripheral C4B concentration, and elevated brain C4A mRNA expression in schizophrenia patients compared to controls. To better elucidate the additive effects of multiple complement genotypes, we also conducted gene- and gene-set analysis through MAGMA which supported the role of Human Leukocyte Antigen class (HLA) III genes and, to a lesser extent, CSMD1 in schizophrenia; however, the HLA-schizophrenia association was likely driven by the C4 gene. Lastly, we identified several limitations of the literature on the complement system and schizophrenia, including: small sample sizes, inconsistent methodologies, limited measurements of neural concentrations of complement proteins, little exploration of the link between complement and schizophrenia phenotype, and lack of studies exploring schizophrenia treatment response. Overall, recent findings highlight complement components-in particular, C4 and CSMD1-as potential novel drug targets in schizophrenia. Given the growing availability of complement-targeted therapies, future clinical studies evaluating their efficacy in schizophrenia hold the potential to accelerate treatment advances.
Topics: Complement C4; Complement C4a; Complement C4b; Complement System Proteins; Gene Expression; Gene Expression Regulation; Genotype; HLA Antigens; Humans; Polymorphism, Genetic; Schizophrenia
PubMed: 31439935
DOI: 10.1038/s41380-019-0479-0 -
Frontiers in Endocrinology 2021Early diagnosis and therapy of papillary thyroid carcinoma (PTC) is essential for reducing recurrence and improving the long-term survival. In this study, we aimed to...
BACKGROUND
Early diagnosis and therapy of papillary thyroid carcinoma (PTC) is essential for reducing recurrence and improving the long-term survival. In this study, we aimed to investigate the proteome profile of plasma and screen unique proteins which could be used as a biomarker for predicting PTC.
METHODS
Serum samples were collected from 29 PTC patients and 29 nodular goiter (NG) patients. Five PTC serum samples and five NG serum samples were selected for proteome profiles by proteomics. Eight proteins in PTC and NG serum samples were selected for confirmation by enzyme-linked immunosorbent assay analysis. Receiver operating characteristic curves was used to evaluate the diagnostic value of potential biomarkers.
RESULTS
Complement C4-A (C4A) and plasminogen (PLG) were significantly lower in serum samples of PTC patients compared with NG patients. C4A was observed to have excellent diagnostic accuracy for PTC, with a sensitivity of 91.67% and specificity of 83.33%. The diagnostic value of PLG for PTC was demonstrated by a sensitivity at 87.50% and specificity at 75.00%. The AUC for C4A and PLG was 0.97 ± 0.02 and 0.89 ± 0.05.
CONCLUSION
C4A and PLG appeared to be excellent potential biomarkers for the prediction of PTC.
Topics: Adult; Biomarkers, Tumor; Complement C4a; Female; Humans; Male; Middle Aged; Plasminogen; Proteomics; Sensitivity and Specificity; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 34803909
DOI: 10.3389/fendo.2021.737638 -
Journal of Neuroimmunology Nov 2021While complement-dependent cytotoxicity (CDC) is a known effector mechanism in aquaporin-4-immunoglobulin (Ig)G-positive (AQP4-IgG+) neuromyelitis optica spectrum... (Comparative Study)
Comparative Study
While complement-dependent cytotoxicity (CDC) is a known effector mechanism in aquaporin-4-immunoglobulin (Ig)G-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD), the role of CDC in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is less clear. We determined complement C3 and C4 plasma concentrations in patients with clinically stable AQP4-IgG+ NMOSD (n = 16), MOGAD (n = 15), early multiple sclerosis (MS, n = 19) and in healthy controls (HC, n = 18). C4 was lower in AQP4-IgG+ NMOSD than in MOGAD, MS and HC (p < 0.05, pairwise comparisons). C3 was lower in AQP4-IgG+ NMOSD than in MS (p = 0.034). These findings suggest subtle complement consumption in clinically stable AQP4-IgG+ NMOSD, but not in MOGAD.
Topics: Adult; Aquaporin 4; Autoantibodies; Complement Activation; Complement C3; Complement C4; Cytotoxicity, Immunologic; Demyelinating Autoimmune Diseases, CNS; Female; Humans; Immunoglobulin G; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Myelin-Oligodendrocyte Glycoprotein; Neuromyelitis Optica; Prospective Studies
PubMed: 34464830
DOI: 10.1016/j.jneuroim.2021.577699 -
American Journal of Obstetrics and... Feb 2022The complement system is critical to human health owing to its central role in host defense and innate immunity. During pregnancy, the complement system must be... (Review)
Review
The complement system is critical to human health owing to its central role in host defense and innate immunity. During pregnancy, the complement system must be appropriately regulated to allow for immunologic tolerance to the developing fetus and placenta. Although some degree of complement activation can be seen in normal pregnancy, the fetus seems to be protected in part through the placental expression of complement regulatory proteins, which inhibit complement activation at different steps along the complement activation cascade. In women who develop preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome, there is a shift toward increased complement activation and decreased complement regulation. There is an increase in placental deposition of C5b-9, which is the terminal effector of classical, lectin, and alternative complement pathways. C5b-9 deposition stimulates trophoblasts to secrete soluble fms-like tyrosine kinase-1, which sequesters vascular endothelial growth factor and placental growth factor. Pathogenic mutations or deletions in complement regulatory genes, which predispose to increased complement activation, have been detected in women with preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Before the disease, biomarkers of alternative complement pathway activation are increased; during active disease, biomarkers of terminal complement pathway activation are increased. Urinary excretion of C5b-9 is associated with preeclampsia with severe features and distinguishes it from other hypertensive disorders of pregnancy. Taken together, existing data link preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome with increased activation of the terminal complement pathway that, in some cases, may be influenced by genetic alterations in complement regulators. These findings suggest that the inhibition of the terminal complement pathway, possibly through C5 blockade, may be an effective strategy to treat preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome, but this strategy warrants further evaluation in clinical trials.
Topics: Antibodies, Monoclonal, Humanized; Biomarkers; Complement Activation; Complement Inactivating Agents; Complement System Proteins; Female; HELLP Syndrome; Humans; Mutation; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Vascular Endothelial Growth Factor Receptor-1
PubMed: 32986992
DOI: 10.1016/j.ajog.2020.09.038