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NPJ Genomic Medicine Oct 2022Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with...
Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.
PubMed: 36198672
DOI: 10.1038/s41525-022-00327-8 -
Developmental Neuroscience 2023Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment....
Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system-derived neuroinflammation, synapse pruning, and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced, or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal, inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n = 335) and/or in nonpsychiatric comparison subjects (NCs; n = 233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-reactive protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F = 20.74, p < 0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants, plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff = 0.39, CI = 0.01-0.77, R2 = 0.18, p < 0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index, race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR-NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F = 5.16, p < 0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 requires replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia.
Topics: Humans; Complement C4; Schizophrenia; Inflammation; Biomarkers; Immunoglobulin G
PubMed: 37734326
DOI: 10.1159/000534185 -
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 -
Frontiers in Immunology 2022It is generally believed that complement system is strongly associated with the risk of nonalcoholic fatty liver disease (NAFLD). However, complement system contains a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
It is generally believed that complement system is strongly associated with the risk of nonalcoholic fatty liver disease (NAFLD). However, complement system contains a variety of complement components, and the relationship between complement components and the risk and severity of NAFLD is inconsistent. The aim of this meta-analysis was to evaluate the association of complement components with the risk and severity of NAFLD.
METHODS
We searched PubMed, Embase, Cochrane Library, Google Scholar, Scopus, and ZhiWang Chinese databases from inception to May 2022 for observational studies reporting the risk of NAFLD with complement components. Random-effects meta-analysis was used to obtain pooled estimates of the effect due to heterogeneity.
RESULTS
We identified 18 studies with a total of 18560 included subjects. According to recent studies, levels of complement component 3 (C3) (mean difference (MD): 0.43, 95% confidence interval (CI) 0.26-0.60), complement component 4 (C4) (MD: 0.04, 95% CI 0.02-0.07), complement component 5(C5) (MD: 34.03, 95% CI 30.80-37.27), complement factor B (CFB) (MD: 0.22, 95% CI 0.13-0.31) and acylation stimulating protein (ASP) (standard mean difference (SMD): 5.17, 95% CI 2.57-7.77) in patients with NAFLD were significantly higher than those in the control group. However, no statistical significance was obtained in complement factor D (CFD) levels between NAFLD and non-NAFLD (MD=156.51, 95% CI -59.38-372.40). Moreover, the levels of C3, C5, CFB, and ASP in patients with moderate and severe NAFLD were significantly higher than those in patients with mild NAFLD. Except for C4 and CFD, the included studies did not explore the changes in the severity of NAFLD according to the concentration of C4 and CFD.
CONCLUSIONS
This meta-analysis demonstrates that an increase in complement components including C3, C5, CFB, and ASP is associated with an increased risk and severity of NAFLD, indicating that they may be good biomarkers and targets for the diagnosis and treatment of NAFLD.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO [https://www.crd.york.ac.uk/PROSPERO/], identifier CRD42022348650.
Topics: Humans; Biomarkers; Complement Factor B; Immunologic Factors; Non-alcoholic Fatty Liver Disease
PubMed: 36569882
DOI: 10.3389/fimmu.2022.1054159 -
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 -
Research and Practice in Thrombosis and... Feb 2023A State of the Art lecture titled "Etiology and Outcomes of Thrombotic Microangiopathies in Pregnancy" was presented at the International Society on Thrombosis and...
A State of the Art lecture titled "Etiology and Outcomes of Thrombotic Microangiopathies in Pregnancy" was presented at the International Society on Thrombosis and Haemostasis Congress in 2022. First, it is important to understand changes in laboratory parameters in normal pregnancy, including complement levels, specifically the increase in C3, C4, C3a, and C4a throughout pregnancy. Complement is critical in normal pregnancy for implantation and for placental development. Complement-mediated hemolytic uremic syndrome (CM-HUS) and thrombotic thrombocytopenic purpura (TTP) can present anytime from the first trimester to the postpartum period. In comparison, Thrombotic microangiopathies specific to pregnancy, such as preeclampsia (PET) or hemolysis, elevated liver enzymes, and low platelets (HELLP), present from the second trimester. C5b-9 deposition (following terminal complement pathway activation) is demonstrated in CM-HUS cases, and in HELLP and few PET cases. PET can also be confirmed and related to severity using soluble fms-like tyrosine kinase-1/placental growth factor ratios. Diagnosis of CM-HUS and TTP in pregnancy can be further complicated by clinical overlap at presentation with PET or occasionally HELLP. Management is aided by ADAMTS-13 analysis to confirm or exclude TTP. Treatment of CM-HUS, in conjunction with supportive care, is complement inhibitor therapy (eculizumab or ravulizumab). Acute TTP requires standard therapy, but caplacizumab should be avoided. Confirmation of congenital or immune subtypes informs care in subsequent pregnancies. Finally, we summarize relevant new data on this topic presented during the 2022 International Society on Thrombosis and Haemostasis Congress.
PubMed: 37063764
DOI: 10.1016/j.rpth.2023.100084 -
Frontiers in Immunology 2020Complement, a part of the innate arm of the immune system, is integral to the frontline defense of the host against innumerable pathogens, which includes RNA viruses.... (Review)
Review
Complement, a part of the innate arm of the immune system, is integral to the frontline defense of the host against innumerable pathogens, which includes RNA viruses. Among the major groups of viruses, RNA viruses contribute significantly to the global mortality and morbidity index associated with viral infection. Despite multiple routes of entry adopted by these viruses, facing complement is inevitable. The initial interaction with complement and the nature of this interaction play an important role in determining host resistance versus susceptibility to the viral infection. Many RNA viruses are potent activators of complement, often resulting in virus neutralization. Yet, another facet of virus-induced activation is the exacerbation in pathogenesis contributing to the overall morbidity. The severity in disease and death associated with RNA virus infections shows a tip in the scale favoring viruses. Growing evidence suggest that like their DNA counterparts, RNA viruses have co-evolved to master ingenious strategies to remarkably restrict complement. Modulation of host genes involved in antiviral responses contributed prominently to the adoption of unique strategies to keep complement at bay, which included either down regulation of activation components (C3, C4) or up regulation of complement regulatory proteins. All this hints at a possible "hijacking" of the cross-talk mechanism of the host immune system. Enveloped RNA viruses have a selective advantage of not only modulating the host responses but also recruiting membrane-associated regulators of complement activation (RCAs). This review aims to highlight the significant progress in the understanding of RNA virus-complement interactions.
Topics: Adaptive Immunity; Animals; Complement Activation; Complement System Proteins; Evolution, Molecular; Gene Expression Regulation, Viral; Host-Pathogen Interactions; Humans; Immunity, Innate; RNA Virus Infections; RNA Viruses; Severity of Illness Index
PubMed: 33133089
DOI: 10.3389/fimmu.2020.573583 -
Autoimmunity Reviews Dec 2023Complement levels have been proposed as candidate biomarkers of disease activity and obstetric risk in systemic lupus erythematosus (SLE) pregnancies, but their... (Meta-Analysis)
Meta-Analysis Review
Complement levels during the first trimester predict disease flare and adverse pregnancy outcomes in systemic lupus erythematosus: A network meta-analysis on 532 pregnancies.
BACKGROUND
Complement levels have been proposed as candidate biomarkers of disease activity and obstetric risk in systemic lupus erythematosus (SLE) pregnancies, but their reliability has been questioned due to the physiologic fluctuations of complement during gestation. Thus, this network meta-analysis aimed at assessing the clinical significance of complement fluctuations in lupus pregnant women.
METHODS
Corresponding authors of 19 studies meeting inclusion criteria were invited to contribute with additional data including C3 and C4 levels [before pregnancy, at conception, in every trimester (T) and 3 months after delivery]; data were pooled together in a network meta-analysis.
RESULTS
A total of 532 lupus women from four studies were included in the analysis. In SLE women, C3 and C4 increased progressively during gestation: levels remained stable during T1 and peaked in T2 to decrease in T3. Patients with previous lupus nephritis (LN) and those who experienced flares during pregnancy had significantly lower mean levels of C3 and C4 at all timepoints. The lowest levels of complement were observed, particularly during T1, in patients with LN and gestational flare. Both reduction and the lack of increase of C3 and C4 levels at T1 versus conception were associated with gestational flares, particularly in LN patients. Pregnancies with flare had a statistically significant higher rate of maternal and fetal complications(60% versus 50.3%; p = 0.03).
CONCLUSIONS
Low complement levels, particularly in T1, were associated with a higher frequency of gestational flare. Either reduction or smaller increase of C3 and/or C4 levels, even within normal range, might predict flares especially in early gestation.
Topics: Humans; Female; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, First; Network Meta-Analysis; Reproducibility of Results; Symptom Flare Up; Pregnancy Complications; Lupus Erythematosus, Systemic; Lupus Nephritis; Complement System Proteins; Retrospective Studies
PubMed: 37852515
DOI: 10.1016/j.autrev.2023.103467 -
Neurology(R) Neuroimmunology &... Jan 2022To determine the role of complement in the disease pathology of multifocal motor neuropathy (MMN), we investigated complement activation, and inhibition, on binding of...
BACKGROUND AND OBJECTIVES
To determine the role of complement in the disease pathology of multifocal motor neuropathy (MMN), we investigated complement activation, and inhibition, on binding of MMN patient-derived immunoglobulin M (IgM) antibodies in an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model for MMN.
METHODS
iPSC-derived MNs were characterized for the expression of complement receptors and membrane-bound regulators, for the binding of circulating IgM anti-GM1 from patients with MMN, and for subsequent fixation of C4 and C3 on incubation with fresh serum. The potency of ARGX-117, a novel inhibitory monoclonal antibody targeting C2, to inhibit fixation of complement was assessed.
RESULTS
iPSC-derived MNs moderately express the complement regulatory proteins CD46 and CD55 and strongly expressed CD59. Furthermore, MNs express C3aR, C5aR, and complement receptor 1. IgM anti-GM1 antibodies in serum from patients with MMN bind to MNs and induce C3 and C4 fixation on incubation with fresh serum. ARGX-117 inhibits complement activation downstream of C4 induced by patient-derived anti-GM1 antibodies bound to MNs.
DISCUSSION
Binding of IgM antibodies from patients with MMN to iPSC-derived MNs induces complement activation. By expressing complement regulatory proteins, particularly CD59, MNs are protected against complement-mediated lysis. Yet, because of expressing C3aR, the function of these cells may be affected by complement activation upstream of membrane attack complex formation. ARGX-117 inhibits complement activation upstream of C3 in this disease model for MMN and therefore represents an intervention strategy to prevent harmful effects of complement in MMN.
Topics: Antibodies, Monoclonal, Humanized; Cells, Cultured; Complement Activation; Complement C2; Humans; Immunoglobulin M; Induced Pluripotent Stem Cells; Motor Neurons; Polyneuropathies
PubMed: 34759020
DOI: 10.1212/NXI.0000000000001107