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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 -
International Journal of Rheumatic... Feb 2015Lupus nephritis (LN) has significant impact on the outcome of patients with systemic lupus erythematosus (SLE). In the absence of any new breakthrough for management of... (Review)
Review
Lupus nephritis (LN) has significant impact on the outcome of patients with systemic lupus erythematosus (SLE). In the absence of any new breakthrough for management of LN over the last few years, using existing treatment modalities in a more effective manner is the mainstay of improving outcomes. For effectively using the drugs, disease activity needs to be assessed accurately and more objectively, which is not possible with present clinical assessment tools. Biomarkers help in accurate assessment of disease activity and enable the physician to individualize the therapy. Conventional disease activity markers have limitations which need to be addressed and research in the area of biomarker discovery in LN has immensely expanded over the last two decades as evident by the literature. Moreover, biomarkers for LN should be different from the markers of overall disease activity as LN requires significant immunosuppression, unlike other non-renal manifestations of SLE. Newly discovered biomarkers exhibit qualities pertaining to different aspects of disease activity and damage. In this review, we discuss the established as well as new biomarkers of SLE in the light of their role in LN diagnosis, follow-up, prediction of renal flare and correlation with renal histology findings.
Topics: Acute-Phase Proteins; Biomarkers; Chemokines; Complement C3; Complement C4; Cytokine TWEAK; Cytokines; Disease Progression; Female; Humans; Kidney Function Tests; Lipocalin-2; Lipocalins; Lupus Nephritis; Male; Predictive Value of Tests; Proto-Oncogene Proteins; Sensitivity and Specificity; Severity of Illness Index; Tumor Necrosis Factors
PubMed: 25884459
DOI: 10.1111/1756-185X.12602 -
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 -
Free Radical Biology & Medicine Feb 2024Dysregulated cell death machinery and an excessive inflammatory response in Coxsackievirus B3(CVB3)-infected myocarditis are hallmarks of an abnormal host response....
BACKGROUND
Dysregulated cell death machinery and an excessive inflammatory response in Coxsackievirus B3(CVB3)-infected myocarditis are hallmarks of an abnormal host response. Complement C4 and C3 are considered the central components of the classical activation pathway and often participate in the response process in the early stages of virus infection.
METHODS
In our study, we constructed a mouse model of CVB3-related viral myocarditis via intraperitoneal injection of Fer-1 and detected myocarditis and ferroptosis markers in the mouse myocardium. Then, we performed co-IP and protein mass spectrometry analyses to explore which components interact with the ferroptosis gene transferrin receptor (TFRC). Finally, functional experiments were conducted to verify the role of complement components in regulating ferroptosis in CVB3 infection.
RESULTS
It showed that the ferroptosis inhibitor Fer-1 could alleviate the inflammation in viral myocarditis as well as ferroptosis. Mechanistically, during CVB3 infection, the key factor TFRC was activated and inhibited by Fer-1. Fer-1 effectively prevented the consumption of complement C3 and overload of the complement product C4b. Interestingly, we found that TFRC directly interacts with complement C4, leading to an increase in the product of C4b and a decrease in the downstream complement C3. Functional experiments have also confirmed that regulating the complement C4/C3 pathway can effectively rescue cell ferroptosis caused by CVB3 infection.
CONCLUSIONS
In this study, we found that ferroptosis occurs through crosstalk with complement C4 in viral myocarditis through interaction with TFRC and that regulating the complement C4/C3 pathway may rescue ferroptosis in CVB3-infected cardiomyocytes.
Topics: Animals; Mice; Myocarditis; Complement C3; Ferroptosis; Coxsackievirus Infections; Enterovirus B, Human; Myocardium; Immunologic Factors; Virus Diseases; Complement C4; Receptors, Transferrin
PubMed: 38169212
DOI: 10.1016/j.freeradbiomed.2023.12.038 -
Kidney International Oct 2018Certain kidney diseases are associated with complement activation although a renal triggering factor has not been identified. Here we demonstrated that renin, a...
Certain kidney diseases are associated with complement activation although a renal triggering factor has not been identified. Here we demonstrated that renin, a kidney-specific enzyme, cleaves C3 into C3b and C3a, in a manner identical to the C3 convertase. Cleavage was specifically blocked by the renin inhibitor aliskiren. Renin-mediated C3 cleavage and its inhibition by aliskiren also occurred in serum. Generation of C3 cleavage products was demonstrated by immunoblotting, detecting the cleavage product C3b, by N-terminal sequencing of the cleavage product, and by ELISA for C3a release. Functional assays showed mast cell chemotaxis towards the cleavage product C3a and release of factor Ba when the cleavage product C3b was combined with factor B and factor D. The renin-mediated C3 cleavage product bound to factor B. In the presence of aliskiren this did not occur, and less C3 deposited on renin-producing cells. The effect of aliskiren was studied in three patients with dense deposit disease and this demonstrated decreased systemic and renal complement activation (increased C3, decreased C3a and C5a, decreased renal C3 and C5b-9 deposition and/or decreased glomerular basement membrane thickness) over a follow-up period of four to seven years. Thus, renin can trigger complement activation, an effect inhibited by aliskiren. Since renin concentrations are higher in renal tissue than systemically, this may explain the renal propensity of complement-mediated disease in the presence of complement mutations or auto-antibodies.
Topics: Amides; Chemotaxis; Child; Complement Activation; Complement C3; Complement C3a; Complement C3b; Complement C4; Complement C5a; Complement C5b; Complement Factor B; Complement Factor D; Female; Fumarates; Glomerular Basement Membrane; Glomerulonephritis, Membranoproliferative; Humans; Mast Cells; Renin
PubMed: 29884545
DOI: 10.1016/j.kint.2018.04.004 -
Schizophrenia Research Aug 2021Schizophrenia is a complex brain disorder with genetic and environmental factors contributing to its etiology. Complement C4 genes are schizophrenia susceptibility loci...
Schizophrenia is a complex brain disorder with genetic and environmental factors contributing to its etiology. Complement C4 genes are schizophrenia susceptibility loci and are activated in response to infections and gut microbiome imbalances. We hypothesize that C4 genetic susceptibility predisposes individuals to neuropathological effects from pathogen exposures or a microbiome in dysbiosis. In 214 individuals with schizophrenia and 123 non-psychiatric controls, we examined C4 gene copy number and haplotype groups for associations with schizophrenia and microbial plasma biomarkers. C4A copy number and haplotypes containing HERV-K insertions (C4A-long; C4AL-C4AL) conferred elevated odds ratios for schizophrenia diagnoses (OR 1.58-2.56, p < 0.0001), while C4B-short (C4BS) haplogroups conferred decreased odds (OR 0.43, p < 0.0001). Haplogroup-microbe combinations showed extensive associations with schizophrenia including C4AL with Candida albicans IgG (OR 2.16, p < 0.0005), C4AL-C4BL with cytomegalovirus (CMV) IgG (OR 1.79, p < 0.008), C4BS with lipopolysaccharide-binding protein (LBP) (OR 1.18, p < 0.0001), and C4AL-C4AL with Toxoplasma gondii IgG (OR = 17.67, p < 0.0001). In controls, only one haplogroup-microbe combination was significant: C4BS with CMV IgG (OR 0.52, p < 0.02). In schizophrenia only, LBP and CMV IgG levels were inversely correlated with C4A and C4S copy numbers, respectively (R = 0.13-0.16, p < 0.0001). C4 haplogroups were associated with altered scores of cognitive functioning in both cases and controls and with psychiatric symptom scores in schizophrenia. Our findings link complement C4 genes with a susceptibility to infections and a dysbiotic microbiome in schizophrenia. These results support immune system mechanisms by which gene-environmental interactions may be operative in schizophrenia.
Topics: Biomarkers; Complement C4; Complement C4a; Gene-Environment Interaction; Humans; Schizophrenia
PubMed: 33632634
DOI: 10.1016/j.schres.2021.02.001 -
Immunobiology Nov 2019Alex Law and Paul Levine recall their work to establish the covalent bond between C3 and target surfaces. It started with a naive experiment by analyzing the membrane... (Review)
Review
Alex Law and Paul Levine recall their work to establish the covalent bond between C3 and target surfaces. It started with a naive experiment by analyzing the membrane polypeptides of sheep erythrocytes bound with I-labelled C3. They found complexes with molecular weight higher than the individual C3 polypeptides. These complexes survived all conditions designed to disrupt non-covalent interactions. They then showed that the bond was an ester, with an active acyl group on C3 which reacted with a hydroxyl group on the acceptor molecule. With the discovery of an internal thioester by Jim Prahl, Jamila Janatova, Brian Tack and their colleagues, it became clear that the reaction was by an acyl transfer from the thioester of C3 to the target hydroxyl group. Later on they showed that C4 also bound covalently to target molecules. By establishing a fluid phase system to study the kinetics of the binding reactions of C3 and C4, Alex was able to continue the work in the MRC Immunochemistry Unit in Oxford from 1981, to eventually determine the chemical mechanism of the binding reaction. In order to give some sense of reality, this article is written as a narrative from Alex, who did the experiments. Both Alex and Paul are retired. Pauls lives on Martha's Vineyard where he writes occasional articles on science for one of the Island's newspapers. Alex lives in Hong Kong and tries to make some sense of the local politics.
Topics: Animals; Complement C3; Complement C4; History, 20th Century; Humans; Protein Binding
PubMed: 31445811
DOI: 10.1016/j.imbio.2019.08.003 -
Medical Microbiology and Immunology Feb 2021Chlamydia trachomatis (C. trachomatis) is the leading cause of sexually transmitted bacterial infections worldwide, with over 120 million annual cases. C. trachomatis...
Chlamydia trachomatis (C. trachomatis) is the leading cause of sexually transmitted bacterial infections worldwide, with over 120 million annual cases. C. trachomatis infections are associated with severe reproductive complications in women such as extrauterine pregnancy and tubal infertility. The infections are often long lasting, associated with immunopathology, and fail to elicit protective immunity which makes recurrent infections common. The immunological mechanisms involved in C. trachomatis infections are only partially understood. Murine infection models suggest that the complement system plays a significant role in both protective immunity and immunopathology during primary Chlamydia infections. However, only limited structural and mechanistic evidence exists on complement-mediated immunity against C. trachomatis. To expand our current knowledge on this topic, we analyzed global complement deposition on C. trachomatis using comprehensive in-depth mass spectrometry-based proteomics. We show that factor B, properdin, and C4b bind to C. trachomatis demonstrating that C. trachomatis-induced complement activation proceeds through at least two activation pathways. Complement activation leads to cleavage and deposition of C3 and C5 activation products, causing initiation of the terminal complement pathway and deposition of C5b, C6, C7, C8, C9 on C. trachomatis. Interestingly, using immunoelectron microscopy, we show that C5b-9 deposition occurred sporadically and only in rare cases formed complete lytic terminal complexes, possibly caused by the presence of the negative regulators vitronectin and clusterin. Finally, cleavage analysis of C3 demonstrated that deposited C3b is degraded to the opsonins iC3b and C3dg and that this complement opsonization facilitates C. trachomatis binding to human B-cells.
Topics: Chlamydia trachomatis; Complement Activation; Complement C4; Complement C4b; Complement Factor B; Complement System Proteins; Humans; Protein Binding; Proteomics; Serum
PubMed: 33206237
DOI: 10.1007/s00430-020-00695-x -
Frontiers in Immunology 2021Human complement C4 is one of the most diverse but heritable effectors for humoral immunity. To help understand the roles of C4 in the defense and pathogenesis of...
Human complement C4 is one of the most diverse but heritable effectors for humoral immunity. To help understand the roles of C4 in the defense and pathogenesis of autoimmune and inflammatory diseases, we determined the bases of polymorphisms including the frequent genetic deficiency of C4A and/or C4B isotypes. We demonstrated the diversities of C4A and C4B proteins and their gene copy number variations (CNVs) in healthy subjects and patients with autoimmune disease, such as type 1 diabetes, systemic lupus erythematosus (SLE) and encephalitis. We identified subjects with (a) the fastest migrating C4B allotype, B7, or (b) a deficiency of C4B protein caused by genetic mutation in addition to gene copy-number variation. Those variants and mutants were characterized, sequenced and specific techniques for detection developed. Novel findings were made in four case series. First, the amino acid sequence determinant for C4B7 was likely the R729Q variation at the anaphylatoxin-like region. Second, in healthy White subject MS630, a C-nucleotide deletion at codon-755 led to frameshift mutations in his single gene, which was a private mutation. Third, in European family E94 with multiplex lupus-related mortality and low serum C4 levels, the culprit was a recurrent haplotype with and that segregated with two defective genes and identical mutations at the donor splice site of intron-28. Fourth, in East-Asian subject E133P with anti-NMDA receptor encephalitis, the gene had a mutation that changed tryptophan-660 to a stop-codon (W660x), which was present in a haplotype with and . The W660x mutation is recurrent among East-Asians with a frequency of 1.5% but not detectable among patients with SLE. A meticulous annotation of sequences revealed clusters of variations proximal to sites for protein processing, activation and inactivation, and binding of interacting molecules.
Topics: Autoimmune Diseases; Case-Control Studies; Complement C4a; Complement C4b; DNA Copy Number Variations; Female; Gene Dosage; Gene Frequency; Genetic Predisposition to Disease; Humans; Immunity, Humoral; Male; Mutation; Phenotype
PubMed: 34764957
DOI: 10.3389/fimmu.2021.739430