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American Journal of Physiology. Lung... Aug 2021COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multisystem organ failure and viral sepsis characterized by respiratory failure, arrhythmias,...
COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multisystem organ failure and viral sepsis characterized by respiratory failure, arrhythmias, thromboembolic complications, and shock with high mortality. Autopsy and preclinical evidence implicate aberrant complement activation in endothelial injury and organ failure. Erythrocytes express complement receptors and are capable of binding immune complexes; therefore, we investigated complement activation in patients with COVID-19 using erythrocytes as a tool to diagnose complement activation. We discovered enhanced C3b and C4d deposition on erythrocytes in COVID-19 sepsis patients and non-COVID sepsis patients compared with healthy controls, supporting the role of complement in sepsis-associated organ injury. Our data suggest that erythrocytes may contribute to a precision medicine approach to sepsis and have diagnostic value in monitoring complement dysregulation in COVID-19-sepsis and non-COVID sepsis and identifying patients who may benefit from complement targeted therapies.
Topics: COVID-19; Complement Activation; Complement C3b; Complement C4b; Erythrocytes; Female; Humans; Male; Middle Aged; Peptide Fragments; Respiratory Insufficiency; SARS-CoV-2; Sepsis
PubMed: 34231390
DOI: 10.1152/ajplung.00231.2021 -
Indian Journal of Pathology &... 2021The aim of this study was to evaluate the immunohistochemical expression of C4d in native renal biopsies of proliferative glomerular diseases, complement pathways in...
INTRODUCTION
The aim of this study was to evaluate the immunohistochemical expression of C4d in native renal biopsies of proliferative glomerular diseases, complement pathways in these diseases, and assess the relationship of C4d with histological and clinicopathological parameters, other complement proteins, and immunoglobulin markers.
METHODS
This cross-sectional study was conducted during the year 2018-19 involving 107 native renal biopsies with histologically diagnosed cases of proliferative glomerular diseases. C4d immunohistochemical evaluation of renal tissue sections was performed using polyclonal antihuman C4d as the primary antibody. Patients were classified as positive and negative groups based on their glomerular C4d deposition.
RESULTS
The overall prevalence of C4d positivity was 80.4% in proliferative glomerular diseases ranging between 60.0% in C3 glomerulonephritis to 92.9% in membranoproliferative glomerulonephritis. Mixed capillary and mesangial deposition were noted in all cases of proliferative glomerulonephritis. Classical pathway was dominantly involved in all glomerular diseases except C3 glomerulonephritis and IgA nephropathy. Multivariate logistic regression analysis revealed that glomerular IgG staining (aOR: 5.86, 95% CI: 1.26-27.14) and IgM staining (aOR: 3.90, 95%CI: 1.07-14.18) were significantly associated with C4d positivity.
CONCLUSION
C4d staining along with immunoglobulin markers such as IgG and IgM and complement proteins can be useful in delineating different complement activation pathways in glomerular diseases and understanding the disease pathogenesis.
Topics: Adult; Biomarkers; Biopsy; Complement C4; Cross-Sectional Studies; Disease Progression; Female; Glomerulonephritis, Membranoproliferative; Humans; Immunohistochemistry; Kidney; Kidney Glomerulus; Male; Middle Aged; Retrospective Studies; Staining and Labeling
PubMed: 33433412
DOI: 10.4103/IJPM.IJPM_364_20 -
Health Science Reports Mar 2022SARS-CoV-2 infection has spread in each corner of the world. Many health systems have dealt with it intensively. The complement system is an instrumental component in...
PURPOSE
SARS-CoV-2 infection has spread in each corner of the world. Many health systems have dealt with it intensively. The complement system is an instrumental component in the inflammatory immune response and plays a role in the activation of blood coagulation. Our understanding of the pathophysiology of SARS-CoV-2 is still limited but is constantly expanding. This study aimed to determine changes in the complement system in intensive care unit (ICU) and non-ICU patients with COVID-19.
METHODS
In a cross-sectional study, plasma levels of C3, C4, and CH50 were determined in two groups of ICU and non-ICU patients with COVID-19 to understand the potential effects of SARS-CoV-2 on the innate immune system. The assays of C3 and C4 were conducted using turbidimetry method. The CH50 test was conducted using the functional method.
RESULTS
The present study revealed that the C3, C4, and CH50 plasma levels were 142.48 ± 30.38 mg/dL, 32.58 ± 8.78 mg/dL, and 61.74 ± 19.54%, respectively. These results indicate high levels of complement components C3 and C4 and complement function (CH50) in patients with COVID-19 than normal ranges. Plasma levels of C3, C4, and CH50 were higher in ICU patients than in non-ICU COVID-19 groups.
CONCLUSION
These results indicate that the innate immune system was activated in both ICU and non-ICU patients in response to SARS-CoV-2 infection. Further studies with a larger number of COVID-19 patients and additional testing of complement components (C3a and C5a) may reveal the role of COVID-19 infection in the activation of the complement system.
PubMed: 35224220
DOI: 10.1002/hsr2.519 -
Journal of Clinical Laboratory Analysis May 2020The prognostic role of complement C3 and C4 in peripheral blood in early stage of acute pancreatitis (AP) is unknown. In this study, we aimed to evaluate the prognostic...
OBJECTIVE
The prognostic role of complement C3 and C4 in peripheral blood in early stage of acute pancreatitis (AP) is unknown. In this study, we aimed to evaluate the prognostic value of C3 and C4 in early stage of AP.
METHODS
A total of 164 patients were enrolled in this study. The blood samples were collected within 24 hours after AP onset. We compared C3 and C4 levels in patients with different AP severity. The optimal cutoff value for them to predict severe AP (SAP) was determined by receiver operating characteristic (ROC) curve analysis.
RESULTS
The reduction of C3 and C4 levels was observed. For prediction of MSAP and SAP, the AUC of C3 and C4 levels was 0.695 (95% CI: 0.612-0.779) and 0.739 (95% CI: 0.657-0.821). The cutoff value of C3 and C4 levels was 0.705 and 0.145 g/L, with the sensitivity of 0.612 and 0.735, and the specificity of 0.735 and 0.710. For prediction of SAP, the AUC of C3 and C4 levels was 0.749 (95% CI: 0.607-0.891) and 0.766 (95% CI: 0.596-0.936). The cutoff value of C3 and C4 levels was 0.400 and 0.125 g/L, with the sensitivity of 0.859 and 0.767, and the specificity of 0.600 and 0.786.
CONCLUSIONS
A marked change of complement C3 and C4 was observed in peripheral blood of patients with AP, suggesting the participation of complement system in the early phase of AP. C3 and C4 levels were sensitive and accurate in judging the severity of AP.
Topics: Adult; Aged; Biomarkers; Complement C3; Complement C4; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Pancreatitis; ROC Curve
PubMed: 32187754
DOI: 10.1002/jcla.23205 -
Chinese Medical Journal Jul 2019Cryoglobulinemia often causes systemic vasculitis, thereby damaging to skin and internal organs including kidneys, even life-threatening. This review aimed to introduce... (Review)
Review
OBJECTIVE
Cryoglobulinemia often causes systemic vasculitis, thereby damaging to skin and internal organs including kidneys, even life-threatening. This review aimed to introduce the advances in understanding, detection, and treatment of this disease in recent years, with a particular concern to clinical practice.
DATA SOURCES
All the data in this review were from the English or Chinese literature in the PubMed and China National Knowledge Infrastructure databases as of March 2019.
STUDY SELECTION
This review selected important original articles, meaningful reviews, and some reports on cryoglobulinemia published in recent years and in history, as well as the guidelines for treatment of underlying diseases which lead to cryoglobulinemia.
RESULTS
Diagnosis of cryoglobulinemia relies on serum cryoglobulin test, in which to ensure that the blood sample temperature is not less than 37°C in the entire pre-analysis phase is the key to avoid false negative results. Cryoglobulinemic vasculitis (Cryo Vas), including cryoglobulinemic glomerulonephritis (Cryo GN), usually occurs in types II and III mixed cryoglobulinemia, and can also be seen in type I cryoglobulinemia caused by monoclonal IgG3 or IgG1. Skin purpura, positive serum rheumatoid factor, and decreased serum levels of C4 and C3 are important clues for prompting types II and III Cryo Vas. Renal biopsy is an important means for diagnosis of Cryo GN, while membranous proliferative GN is the most common pathological type of Cryo GN. In recent years, great advances have been made in the treatment of Cryo Vas and its underlying diseases, and this review has briefly introduced these advances.
CONCLUSIONS
Laboratory examinations of serum cryoglobulins urgently need standardization. The recent advances in the diagnosis and treatment of Cryo Vas and GN need to be popularized among the clinicians in related disciplines.
Topics: Animals; Complement C3; Complement C4; Cryoglobulinemia; Cryoglobulins; Glomerulonephritis; Humans; Vasculitis
PubMed: 31283654
DOI: 10.1097/CM9.0000000000000325 -
The British Journal of Ophthalmology Jun 2023To evaluate the association between serum levels of complement component (C) 3, C4 and C1q and visual field (VF) loss in patients with primary angle closure glaucoma...
Serum complement component 3, complement component 4 and complement component 1q levels predict progressive visual field loss in older women with primary angle closure glaucoma.
AIM
To evaluate the association between serum levels of complement component (C) 3, C4 and C1q and visual field (VF) loss in patients with primary angle closure glaucoma (PACG).
METHODS
In this prospective cohort study, a total of 308 patients with PACG were included. The patients were followed up every 6 months (at least 2 years), with clinical examination and VF testing. Based on their sex and age, the subjects were stratified into male and female subgroups, and by age at <60 and ≥60 years per subgroup.
RESULTS
One hundred twenty-three (39.94%) patients showed glaucoma VF progression. The serum levels of C3, C4 and C1q were significantly lower (p<0.05) in the progression group compared with the non-progression group in the ≥60 years female subgroup. In female patients with age ≥60 years, (1) lower levels of baseline C3 (HR=0.98, p<0.001), C4 (HR=0.96, p=0.01) and C1q levels (HR=0.99, p=0.003) were associated with a greater risk of VF progression; (2) patients with lower C3 levels had significantly (p<0.05) higher rates of VF loss progression, similar to those with lower C4 and lower C1q levels; and (3) the generalised additive model revealed a negative correlation between baseline C3 (p<0.001), C4 (p<0.001) and C1q (p<0.001) levels with the risk of VF progression. No statistical significance was observed in the male (<60 and ≥60 years) and female (<60 years) subgroups.
CONCLUSION
Decreased C3, C4 and C1q levels at baseline were significantly associated with a greater risk of VF loss progression only in older women with PACG.
Topics: Humans; Male; Female; Aged; Middle Aged; Visual Fields; Complement C1q; Complement C3; Glaucoma, Angle-Closure; Prospective Studies; Disease Progression; Retrospective Studies; Intraocular Pressure; Visual Field Tests; Vision Disorders
PubMed: 35017157
DOI: 10.1136/bjophthalmol-2021-320541 -
Clinical Proteomics Dec 2022Recurrent spontaneous abortion (RSA) is a common and complicated pregnancy-related disease that lacks a suitable biomarker to predict its recrudescence.
BACKGROUND
Recurrent spontaneous abortion (RSA) is a common and complicated pregnancy-related disease that lacks a suitable biomarker to predict its recrudescence.
METHODS
Tandem mass tag (TMT) analysis was conducted to obtain quantitative proteomic profiles in follicular fluid from patients with a history of RSA and from control group. ELISA validation of candidate differentially expressed proteins was conducted in a larger group of patients.
RESULTS
A total of 836 proteins were identified by TMT analysis; 51 were upregulated and 47 were downregulated in follicular fluid from cases of RSA versus control group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed several important pathways were enriched, involving a dysregulated immunoglobulin Fc receptor signaling pathway and overactivated complement cascade pathways. ELISA validated the differential expression of two proteins, histidine-rich globulin (HRG) and complement C4-B (C4B), which were downregulated and upregulated, respectively, in follicular fluid of patients with RSA. We performed receiver operating characteristic curve analysis of the ELISA results with the outcomes of current IVF cycles as classification variables. The area under the curve results for HRG alone, C4B alone and HRG-C4B combined were 0.785, 0.710 and 0.895, respectively.
CONCLUSIONS
TMT analysis identified 98 differentially expressed proteins in follicular fluid from patients with RSA, indicating follicle factors that act as early warning factors for the occurrence of RSA. Among them, HRG and C4B provide candidate markers to predict the clinical outcomes of IVF/ICSI cycles, and the potential for modeling an early detection system for RSA.
PubMed: 36528562
DOI: 10.1186/s12014-022-09383-9 -
Viruses Jan 2021Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One...
Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One anti-hexon neutralizing antibody, called 9C12, is known to activate the complement cascade, resulting in the deposition of complement component C4b on the capsid, and the neutralization of the virus. The mechanism of AdV neutralization by C4b is independent of downstream complement proteins and involves the blockage of the release of protein VI, which is required for viral escape from the endosome. To investigate the structural basis underlying how C4b blocks the uncoating of AdV, we built a model for the complex of human adenovirus type-5 (HAdV5) with 9C12, together with complement components C1 and C4b. This model positions C4b near the Arg-Gly-Asp (RGD) loops of the penton base. There are multiple amino acids in the RGD loop that might serve as covalent binding sites for the reactive thioester of C4b. Molecular dynamics simulations with a multimeric penton base and C4b indicated that stabilizing interactions may form between C4b and multiple RGD loops. We propose that C4b deposition on one RGD loop leads to the entanglement of C4b with additional RGD loops on the same penton base multimer and that this entanglement blocks AdV uncoating.
Topics: Adenoviridae; Antibodies, Neutralizing; Antibodies, Viral; Binding Sites; Capsid; Capsid Proteins; Complement C4; Humans; Immunoglobulin G; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Structure-Activity Relationship
PubMed: 33467558
DOI: 10.3390/v13010111 -
Arthritis & Rheumatology (Hoboken, N.J.) Aug 2022Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to...
OBJECTIVE
Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (SS), or myositis.
METHODS
Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls.
RESULTS
A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals' capacity to deposit C4b on immune complexes.
CONCLUSION
We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.
Topics: Autoantibodies; Complement C4; Complement C4b; DNA Copy Number Variations; Humans; Lupus Erythematosus, Systemic; Myositis; Risk Factors
PubMed: 35315244
DOI: 10.1002/art.42122 -
Frontiers in Genetics 2021Schizophrenia is a common neuropsychiatric disorder with complex pathophysiology. Recent reports suggested that complement system alterations contributed to pathological...
Schizophrenia is a common neuropsychiatric disorder with complex pathophysiology. Recent reports suggested that complement system alterations contributed to pathological synapse elimination that was associated with psychiatric symptoms in schizophrenia. Complement component 3 (C3) and complement component 4 (C4) play central roles in complement cascades. In this study, we compared peripheral C3 and C4 protein levels between first-episode psychosis (FEP) and healthy control (HC). Then we explored whether single nucleotide polymorphisms (SNPs) at C3 or C4 genes affect peripheral C3 or C4 protein levels. In total, 181 FEPs and 204 HCs were recruited after providing written informed consent. We measured serum C3 and C4 protein levels using turbidimetric inhibition immunoassay and genotyped C3 and C4 polymorphisms using the Sequenom MassArray genotyping. Our results showed that three SNPs were nominally associated with schizophrenia (rs11569562/C3: A > G, = 0.048; rs2277983/C3: A > G, = 0.040; rs149898426/C4: G > A, = 0.012); one haplotype was nominally associated with schizophrenia, constructed by rs11569562-rs2277983-rs1389623 (GGG, = 0.048); FEP had higher serum C3 and C4 (both < 0.001) levels than HC; rs1389623 polymorphisms were associated with elevated C3 levels in our meta-analysis (standard mean difference, 0.50; 95% confidence interval, 0.30 to 0.71); the FEP with CG genotype of rs149898426 had higher C4 levels than that with GG genotypes ( = 0.005). Overall, these findings indicated that complement system altered in FEP and rs149898426 of C4 gene represented a genetic risk marker for schizophrenia likely through mediating complement system. Further studies with larger sample sizes needs to be validated.
PubMed: 34306006
DOI: 10.3389/fgene.2021.647246