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Journal of Innate Immunity 2015Activation of complement leads to generation of the 3 anaphylatoxins C3a, C4a, and C5a. Although all 3 peptides are structurally similar, only C3a and C5a share a... (Review)
Review
Activation of complement leads to generation of the 3 anaphylatoxins C3a, C4a, and C5a. Although all 3 peptides are structurally similar, only C3a and C5a share a similar functional profile that includes the classic inflammatory activities and, more recently, developmental homing and regenerative properties among others. In contrast, the functional profile of C4a is questionable in most cases owing to contamination of C4a preparations with physiologically relevant levels of C3a and/or C5a. Combined with the absence of an identified C4a receptor and the inability of C4a to signal through the C3a and C5a receptors, it is clear that C4a should not be included in the family of complement anaphylatoxins.
Topics: Complement Activation; Complement C3; Complement C4a; Complement C5a; Humans; Inflammation; Terminology as Topic
PubMed: 25659340
DOI: 10.1159/000371423 -
Molecular Psychiatry Nov 2017The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene-environment interactions (GEI). Genetic and environmental risk factors are being... (Review)
Review
The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene-environment interactions (GEI). Genetic and environmental risk factors are being identified with increasing frequency, yet their very number vastly increases the scope of possible GEI, making it difficult to identify them with certainty. Accumulating evidence suggests a dysregulated complement pathway among the pathogenic processes of schizophrenia. The complement pathway mediates innate and acquired immunity, and its activation drives the removal of damaged cells, autoantigens and environmentally derived antigens. Abnormalities in complement functions occur in many infectious and autoimmune disorders that have been linked to schizophrenia. Many older reports indicate altered serum complement activity in schizophrenia, though the data are inconclusive. Compellingly, recent genome-wide association studies suggest repeat polymorphisms incorporating the complement 4A (C4A) and 4B (C4B) genes as risk factors for schizophrenia. The C4A/C4B genetic associations have re-ignited interest not only in inflammation-related models for schizophrenia pathogenesis, but also in neurodevelopmental theories, because rodent models indicate a role for complement proteins in synaptic pruning and neurodevelopment. Thus, the complement system could be used as one of the 'staging posts' for a variety of focused studies of schizophrenia pathogenesis. They include GEI studies of the C4A/C4B repeat polymorphisms in relation to inflammation-related or infectious processes, animal model studies and tests of hypotheses linked to autoimmune diseases that can co-segregate with schizophrenia. If they can be replicated, such studies would vastly improve our understanding of pathogenic processes in schizophrenia through GEI analyses and open new avenues for therapy.
Topics: Animals; Brain; Complement Activation; Complement C4a; Complement C4b; Complement Pathway, Classical; Gene-Environment Interaction; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Polymorphism, Genetic; Schizophrenia
PubMed: 28761078
DOI: 10.1038/mp.2017.151 -
Molecular Immunology Dec 2014The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. In this review we describe recently published... (Review)
Review
The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. In this review we describe recently published results in which a B cell receptor-knock-in mouse strain specific for nucleolar self-antigens was bred with mice deficient in complement C4 and discuss the implications for the lupus field. Absence of C4 leads to a breakdown in the elimination of autoreactive B cell clones at the transitional stage. This is characterized by a relative increase in their response to a range of stimuli, entrance into follicles and a greater propensity to form self-reactive germinal centers. In this review, a model is proposed in which, in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells and follicular dendritic cells, resulting in secretion of Type I interferon. This allows for the maturation and activation of self-reactive B cell clones leading to increased spontaneous formation of germinal centers and subsequent generation of autoantibodies.
Topics: Animals; Autoantibodies; B-Lymphocytes; Complement C4; Dendritic Cells, Follicular; Germinal Center; Humans
PubMed: 24636642
DOI: 10.1016/j.molimm.2014.02.010 -
Journal of Nephrology Jan 2023The activation of the complement system contributes essentially to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. We here...
BACKGROUND
The activation of the complement system contributes essentially to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. We here aimed to directly compare levels of C3 and C4 for outcome prediction in ANCA-associated renal vasculitis.
METHODS
Serum levels of complement components C3 and C4 were directly compared in association with clinical and outcome data in a retrospective cohort of ANCA-associated renal vasculitis.
RESULTS
As compared to poor outcome prediction by low levels of complement C3 (p = 0.0093), low levels of complement C4 did not associate with early requirement of kidney replacement therapy (KRT) or death (p = 0.2396). In the subgroup that experienced KRT or death, low C3 levels identified 11/14 (78.6%, p = 0.0071) and C4 levels 9/14 (64.3%, p = 0.1786) cases. Interestingly, 2/14 (14.3%) patients that experienced KRT or death had isolated C4 lowering, and combining low C3 and/or C4 levels identified 13/14 (92.3%, p < 0.0001) cases in this subgroup. Non-superiority to predict poor outcome by low C3 and/or C4 as compared to C3 alone in the total cohort was attributed to 4/24 (16.7%) patients with isolated C4 lowering in the subgroup that did not experience KRT or death.
CONCLUSION
While low levels of complement C3 were superior in predicting poor outcome in ANCA-associated renal vasculitis, a minor fraction with poor outcome had isolated C4 lowering not captured by serum C3 measurements. Therefore, detailed knowledge of distinct complement components contributing to kidney injury could be of relevance to improve current strategies targeting the complement system in ANCA-associated renal vasculitis.
Topics: Humans; Antibodies, Antineutrophil Cytoplasmic; Complement C3; Retrospective Studies; Kidney; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Complement C4
PubMed: 35962865
DOI: 10.1007/s40620-022-01414-w -
Frontiers in Immunology 2022Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody (MOG-IgG) associated disease (MOGAD) are autoimmune inflammatory... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVE
Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody (MOG-IgG) associated disease (MOGAD) are autoimmune inflammatory demyelinating diseases of the central nervous system (CNS). As the clinical features of NMOSD are similar to MOGAD, diagnostic confusion exists between the two diseases. To better discriminate NMOSD from MOGAD, we investigated whether the plasma levels of complement 3 (C3) and complement 4 (C4) are different in NMOSD and MOGAD during the acute attacks of the diseases. We sought to determine whether C3 or C4 has an influence on the features of NMOSD.
METHODS
In this observational study, data from 73 aquaporin-4 antibodies (AQP4-IgG) positive NMOSD patients and 22 MOG-IgG positive MOGAD patients were collected retrospectively. Demographics, clinical characteristics, plasma parameters, and cerebrospinal fluid (CSF) findings will be analyzed for comparability between the two groups. Immunoglobulin-G (IgG) and albumin were measured in both plasma and CSF. Plasma levels of C3 and C4 were measured and compared between the NMOSD, MOGAD, and 42 healthy controls (HC). The correlations between plasma C3, C4, and NMOSD clinical parameters were analyzed.
RESULTS
The ages of onset were later in the AQP4-IgG positive NMOSD group and females predominated, which differed from the MOGAD group, whose ages were younger and with a slight male preponderance. The AQP4-IgG positive NMOSD patients presented with the clinical symptoms of optic neuritis (ON) and transverse myelitis (TM), whereas encephalitis symptoms were more prevalent in MOGAD patients. CSF analysis shows that slight but not significantly higher white cell count (WCC) and protein were observed in the MOGAD group than in the AQP4-IgG positive NMOSD group. The plasma levels of IgG in MOGAD patients are significantly lower ( = 0.027) than in NMOSD patients. On the contrary, the plasma levels of albumin in MOGAD were higher than in NMOSD, which reached statistical significance ( = 0.039). Both the plasma C3 and C4 levels in the NMOSD group were significantly lower than in MOGAD and HC. The receiver operating characteristic (ROC) curve of the prediction model comprises C3 and C4 to distinguish NMOSD from MOGAD [area under the curve (AUC): 0.731, 0.645], which are considered to have discriminatory values. The results of Spearman's analysis revealed that there was a significant positive correlation between the plasma C3 and the CSF WCC (r = 0.383, = 0.040). There was an inverse correlation between plasma C4 and plasma IgG (r = -0.244, = 0.038). Plasma C3 or C4 was significantly positively correlated with CSF albumin and Q-Alb, which is considered a measure of blood-brain barrier (BBB) disruption.
CONCLUSION
During the acute phase of NMOSD and MOGAD, plasma C3 and C4 may become potential biomarkers for distinguishing the two diseases and reflecting the NMOSD BBB damage.
Topics: Albumins; Aquaporin 4; Biomarkers; Blood-Brain Barrier; Cell Movement; Complement C3; Complement C4; Female; Humans; Immunoglobulin G; Male; Myelin-Oligodendrocyte Glycoprotein; Neuromyelitis Optica; Retrospective Studies
PubMed: 35898513
DOI: 10.3389/fimmu.2022.853891 -
Frontiers in Psychiatry 2022To investigate the changes in immunity and clinical infection events among patients with chronic insomnia.
PURPOSE
To investigate the changes in immunity and clinical infection events among patients with chronic insomnia.
MATERIALS AND METHODS
Forty-two patients with chronic insomnia (age = 64.44 ± 10.53) and 47 normal controls (age = 67.08 ± 7.822) were selected to determine differences in data, such as complete blood counts (CBCs), biochemical indices, lymphocyte subsets, immunoglobulin (Ig), complement C3 and C4 and interleukin-6 (IL-6), as well as to compare the incidence of clinical infection between the two groups.
RESULTS
There were significant differences in erythrocyte, hemoglobin, hematocrit, albumin, globulin, creatinine, IgG, IgG/IgM ratio, CD4 T-lymphocytes, CD19-lymphocytes, CD4/CD8 ratio, platelet/lymphocyte ratio, CD19/CD3 ratio, and clinical infection events between the chronic insomnia group and the control group ( < 0.05). There was no significant difference in neutrophil, lymphocyte, monocyte, and platelet counts; lymphocyte subsets CD8 T and CD56; platelet-to-lymphocyte ratio (PLR); neutrophil-to-lymphocyte ratio (NLR); complement C3; complement C4; IgM; IgA; and IL-6 between the experimental group and their controls ( > 0.05). The systolic and diastolic blood pressures of the chronic insomnia group did not vary widely from those of the controls ( > 0.05).
CONCLUSION
Patients with chronic insomnia have immunological abnormalities, characterized by a higher incidence of clinical infection.
PubMed: 36329922
DOI: 10.3389/fpsyt.2022.1034405 -
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 -
International Journal of Molecular... Jun 2021Acute kidney injury (AKI) is a common and severe complication of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) causing progressive chronic... (Comparative Study)
Comparative Study
UNLABELLED
Acute kidney injury (AKI) is a common and severe complication of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) causing progressive chronic kidney disease (CKD), end-stage renal disease (ESRD) or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN), a common manifestation of glomerular injury in AAV. However, there is growing evidence that activation of the complement pathway contributes to the pathogenesis and progression of AAV. We here aimed to compare glomerular and tubulointerstitial lesions in ANCA GN and extrarenal manifestation of AAV in association with levels of circulating complement components C3c and C4.
METHODS
Plasma levels of C3c and C4 in a total number of 53 kidney biopsies with ANCA GN were retrospectively included between 2015 and 2020. Glomerular and tubulointerstitial lesions were evaluated according to established scoring systems for ANCA GN and analogous to the Banff classification.
RESULTS
We here show that circulating levels of C3c and C4 in ANCA GN were comparable to the majority of other renal pathologies. Furthermore, hypocomplementemia was only detectable in a minor subset of ANCA GN and not correlated with renal or extrarenal AAV manifestations. However, low levels of circulating C3c correlated with AKI severity in ANCA GN independent of systemic disease activity or extrarenal AAV manifestation. By systematic scoring of glomerular and tubulointerstitial lesions, we provide evidence that low levels of circulating C3c and C4 correlated with vasculitis manifestations to distinct renal compartments in ANCA GN.
CONCLUSIONS
We here expand our current knowledge about distinct complement components in association with vasculitis manifestations to different renal compartments in ANCA GN. While low levels of C4 correlated with glomerulitis, our observation that low levels of circulating complement component C3c is associated with interstitial vasculitis manifestation reflected by intimal arteritis implicates that C3c contributes to tubulointerstitial injury in ANCA GN.
Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Complement C3c; Complement C4; Female; Glomerulonephritis; Humans; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Retrospective Studies
PubMed: 34205415
DOI: 10.3390/ijms22126588 -
Frontiers in Immunology 2021Activation of the complement system has been observed in coronavirus disease 19 (COVID-19). We conducted a systematic review and meta-analysis with meta-regression to... (Meta-Analysis)
Meta-Analysis
Activation of the complement system has been observed in coronavirus disease 19 (COVID-19). We conducted a systematic review and meta-analysis with meta-regression to investigate possible differences in the serum concentrations of two routinely measured complement components, C3 and C4, in COVID-19 patients with different severity and survival status. We searched PubMed, Web of Science and Scopus, between January 2020 and February 2021, for studies reporting serum complement C3 and C4, measures of COVID-19 severity, and survival. Eligibility criteria were a) reporting continuous data on serum C3 and C4 concentrations in COVID-19 patients, -b) investigating COVID-19 patients with different disease severity and/or survival status, c) adult patients, d) English language, e) ≥10 patients, and f) full-text available. Using a random-effects model, standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated to evaluate differences in serum C3 and C4 concentrations between COVID-19 patients with low vs. high severity or survivor vs. non-survivor status. Risk of bias was assessed using the Newcastle-Ottawa scale whereas publication bias was assessed with the Begg's and Egger's tests. Certainty of evidence was assessed using GRADE. Nineteen studies in 3,764 COVID-19 patients were included in the meta-analysis. Both C3 and C4 concentrations were significantly lower in patients with high disease severity or non-survivor status than patients with low severity or survivor status (C3 SMD=-0.40, 95% CI -0.60 to -0.21, p<0.001; C4 SMD=-0.29, 95% CI -0.49 to -0.09, p=0.005; moderate certainty of evidence). Extreme between-study heterogeneity was observed (C3, I = 82.1%; C4, I = 84.4%). Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and direction of the effect size was not modified. There was no publication bias. In meta-regression, the SMD of C3 was significantly associated with white blood cell count, C-reactive protein (CRP), and pro-thrombin time, whereas the SMD of C4 was significantly associated with CRP, pro-thrombin time, D-dimer, and albumin. In conclusion, lower concentrations of C3 and C4, indicating complement activation, were significantly associated with higher COVID-19 severity and mortality. C3 and C4 might be useful to predict adverse clinical consequences in these patients. PROSPERO, Registration number: CRD42021239634.
Topics: Biomarkers; COVID-19; Complement Activation; Complement C3; Complement C4; Humans; SARS-CoV-2; Severity of Illness Index
PubMed: 34163491
DOI: 10.3389/fimmu.2021.696085 -
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