-
International Journal of Laboratory... Oct 2021Abnormally activated complement system induces erythrolysis in a part of autoimmune hemolytic anemia (AIHA) patients. However, the alterations in serum complement levels...
INTRODUCTION
Abnormally activated complement system induces erythrolysis in a part of autoimmune hemolytic anemia (AIHA) patients. However, the alterations in serum complement levels in these patients are seldom reported. In this study, we aimed to evaluate the serum complement features of AIHA patients according to different clinical and laboratory characteristics and to find relationships between complement levels and hemolysis-associated laboratory indexes.
METHODS
A retrospective analysis of 146 AIHA patients was performed, and serum complement C3 and C4 levels were compared between control subjects and AIHA patients with different subtypes. Correlations of serum C3/C4 levels with titers of cold agglutinin test (CAT), direct antiglobulin test (DAT), and serological indexes were assessed. Spearman correlation analysis was performed to analyze the relationship between serum complement levels and other laboratory indexes.
RESULTS
Autoimmune hemolytic anemia patients showed reduced serum C3 levels, while serum C4 levels tended to be lower in DAT-positive AIHA patients but not in DAT-negative AIHA patients. Patients with warm AIHA secondary to connective tissue diseases and cold agglutinin disease/cold agglutinin syndrome had the lowest serum C3/C4 levels. Serum C4 levels were negatively correlated with CAT (P = .004) and DAT (anti-C3d) (P = .007) titers. In patients with positive CAT and/or DAT (anti-C3d) but negative DAT (anti-IgG), serum C3/C4 levels were negatively correlated with indirect bilirubin (P = .017 and =.026, respectively).
CONCLUSION
The study findings may be helpful in not only unraveling the mechanism underlying hemolysis in AIHA but also diagnosing AIHA and selecting targeted treatment strategies.
Topics: Adolescent; Adult; Aged; Anemia, Hemolytic, Autoimmune; Child; Complement C3; Complement C4; Coombs Test; Female; Hemolysis; Humans; Male; Middle Aged; Retrospective Studies; Young Adult
PubMed: 33459487
DOI: 10.1111/ijlh.13469 -
The Journal of Trauma and Acute Care... Nov 2022Complement activation after trauma promotes hemostasis but is associated with increased morbidity and mortality. However, the specific pathways and downstream mediators... (Randomized Controlled Trial)
Randomized Controlled Trial Observational Study
BACKGROUND
Complement activation after trauma promotes hemostasis but is associated with increased morbidity and mortality. However, the specific pathways and downstream mediators remain unclear. Recently, the anaphylatoxin C4a has been shown to bind to thrombin receptors. While plasma-based resuscitation has been shown to modify the endotheliopathy of trauma, it may provide complement zymogens that fuel ongoing inflammatory cascades. We sought to characterize the activation of complement after injury and the effect of fresh frozen plasma (FFP) on this inflammatory response. We hypothesized that trauma induces C4 activation, which is associated with worse outcomes and influenced by FFP resuscitation.
METHODS
Blood was collected from injured patients at a single level I trauma center enrolled in the Control of Major Bleeding after Trauma (COMBAT) randomized clinical trial. Proteomic analyses were performed through targeted liquid chromatography coupled with mass spectrometry. For the present observational study, concentrations of complement proteins were analyzed at multiple time points, compared between treatment groups, and correlated with outcomes.
RESULTS
C4 activation occurred over the first 6 hours postinjury with peak activation 6 to 24 hours. Tissue hypoperfusion, defined as base deficit >10 mEq/L, and requirement for massive transfusion were associated with greater C4 activation. C4 activation was associated with mortality, multiple organ failure, and longer ventilator requirement. In addition, temporal trends of C1q, factor B, and C3 by outcome groups support the prevailing theory of primary classical pathway activation with alternative pathway amplification. Resuscitation with FFP over the first 6 hours was associated with increased C4 activation at 12 and 24 hours.
CONCLUSION
C4 activation has an important inflammatory role postinjury, and FFP has the potential to augment this complement activation during resuscitation.
LEVEL OF EVIDENCE
Prognostic/epidemiological, level III.
Topics: Humans; Complement C4; Proteomics; Resuscitation; Plasma; Hemorrhage; Complement Activation
PubMed: 35610738
DOI: 10.1097/TA.0000000000003713 -
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 -
Diagnosis (Berlin, Germany) Jun 2018The circadian fluctuations in the blood levels of selected components of the complement system are ill-defined. Some authors found nadir serum levels of C4 and C3...
BACKGROUND
The circadian fluctuations in the blood levels of selected components of the complement system are ill-defined. Some authors found nadir serum levels of C4 and C3 components, together with C3a at nighttime, while others reported insomnia when pro-inflammatory components exhibited increased serum levels. In this study, we quantitatively estimate the morning and evening daytime serum levels of CH50, C4, C3, put into context with C-reactive protein (CRP), cortisol, parathyroid hormone (PTH) and 25(OH)vitamin D at 07:00 A.M. and at 07:00 P.M.
METHODS
Seven healthy adult women and 11 men who were voluntary participants agreed to a fasting venipuncture in the morning after having normally eaten through the day and in the evening. The C4 and C3 serum levels were measured on a Cobas (Roche Diagnostics, Switzerland) modular analyzer, CH50 was estimated using the COMPL300 enzyme-linked immunosorbent assay (ELISA) of Wieslab (Malmö, Sweden). CRP, 25(OH)vitamin D, PTH and cortisol concentrations were assessed with electro-chemiluminescence immunoassay (ECLIA) on the Roche Cobas 6000 platform; IgG was measured using nephelometry (Siemens, Germany).
RESULTS
With the exception of higher PTH levels in the evening [3.12-5.46, 95% confidence interval (CI)] compared to the morning (2.93-4.65, 95% CI), the mean and median values of C4, C3, CH50 as well as CRP, PTH and 25(OH)vitamin D fell within the established reference intervals. Cortisol levels were measured as an internal positive control for diurnal fluctuations (morning: 294-522 nmol/L, 95% CI; evening: 106-136 nmol/L, 95% CI).
CONCLUSIONS
The concentrations of the assessed complement components C4 and C3 as well as CH50 surrogate assay did not yield significantly different values between early morning and evening. This does not exclude their participation in the circadian metabolome; this pilot study with healthy participants suggests that patients with an autoimmune disease in remission can give their blood samples independently during daytime with or without fasting.
Topics: Adult; Aged; C-Reactive Protein; Circadian Rhythm; Complement C3; Complement C4; Complement Hemolytic Activity Assay; Female; Humans; Male; Middle Aged; Pilot Projects
PubMed: 29813028
DOI: 10.1515/dx-2018-0003 -
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 Endocrinology 2021Copy Number Variations (CNVs) account for a large proportion of human genome and are a primary contributor to human phenotypic variation, in addition to being the... (Review)
Review
Copy Number Variations (CNVs) account for a large proportion of human genome and are a primary contributor to human phenotypic variation, in addition to being the molecular basis of a wide spectrum of disease. Multiallelic CNVs represent a considerable fraction of large CNVs and are strictly related to segmental duplications according to their prevalent duplicate alleles. RCCX CNV is a complex, multiallelic and tandem CNV located in the major histocompatibility complex (MHC) class III region. RCCX structure is typically defined by the copy number of a DNA segment containing a series of genes - the serine/threonine kinase 19 (), the complement 4 (), the steroid 21-hydroxylase (), and the tenascin-X () - lie close to each other. In the Caucasian population, the most common RCCX haplotype (69%) consists of two segments containing the genes , with a telomere-to-centromere orientation. Nonallelic homologous recombination (NAHR) plays a key role into the RCCX genetic diversity: unequal crossover facilitates large structural rearrangements and copy number changes, whereas gene conversion mediates relatively short sequence transfers. The results of these events increased the RCCX genetic diversity and are responsible of specific human diseases. This review provides an overview on RCCX complexity pointing out the molecular bases of Congenital Adrenal Hyperplasia (CAH) due to CYP21A2 deficiency, CAH-X Syndrome and disorders related to CNV of complement component C4.
Topics: Adrenal Hyperplasia, Congenital; Complement C4; DNA Copy Number Variations; Genetic Variation; Humans; Nuclear Proteins; Protein Serine-Threonine Kinases; Pseudogenes; Steroid 21-Hydroxylase; Tenascin
PubMed: 34394006
DOI: 10.3389/fendo.2021.709758 -
International Immunopharmacology Sep 2023To explore the relationship between immunoglobulin A (IgA), complement C4, and liver fibrosis (L.F.) progression (LFP) in patients with chronic hepatitis B (CHB).
OBJECTIVE
To explore the relationship between immunoglobulin A (IgA), complement C4, and liver fibrosis (L.F.) progression (LFP) in patients with chronic hepatitis B (CHB).
METHODS
This is a retrospective cohort study of CHB patients who received liver biopsies. Relevant data, including demographics, clinical serum markers, and immunological results obtained during liver biopsies, were collected and analyzed to assess and verify the relationship between IgA, C4, and LFP.
RESULTS
This study included 1,938 CHB patients, of whom 132 received two liver biopsies (group 1). Thirty (22.7%) of these patients were diagnosed with LFP (increase in L.F. stage (Scheuer score F ≥ 1)). IgA (C-IgA) and C4 (C-C4) change values between the first and second biopsies were independent risk factors for LFP. IgA levels increased, and C4 levels decreased during the second liver puncture. The remaining 1,806 patients received one liver puncture (group 2). They were divided into the following subgroups: A (F ≤ 1), B (1 < F ≤ 3), and C (F > 3) to verify whether the same trend was observed by cross-sectional study. IgA levels were highest, and C4 levels were lowest in group C (IgA: C > B > A, p < 0.05; C4: C < B < A, p < 0.05).
CONCLUSIONS
The findings of this study suggest that serum IgA and C4 levels are independent risk factors for LFP that could serve as future targets for L.F. management and treatment.
Topics: Humans; Complement C4; Immunoglobulin A; Hepatitis B, Chronic; Retrospective Studies; Cross-Sectional Studies; Liver Cirrhosis; Liver; Biomarkers
PubMed: 37451022
DOI: 10.1016/j.intimp.2023.110604 -
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 -
Molecular Immunology Nov 2015Deficiencies in the classical pathway of complement activation have some common features but show also great differences. Deficiencies of each of the components (C1q,... (Review)
Review
Deficiencies in the classical pathway of complement activation have some common features but show also great differences. Deficiencies of each of the components (C1q, C1s, C1r, C4 and C2) imply increased susceptibility to bacterial infections. They are also associated with increased risk to develop systemic lupus erythematosus where deficiency of C1q is strongly associated to the disease while C4 less and C2 much less. Deficiency of C1q affects only activation of the classical pathway while deficiency of C4 and C2 also prevent activation of the lectin pathway. Bypass mechanisms may result in complement activation also in absence of C2 but not in absence of C1q or C4. The genes for C2 and C4 isotypes are closely located within the MHC class III region on chromosome 6p and the genes for the 3 C1q chains are on chromosome 1p. Deficiencies of C1q and of C4 show genetic heterogeneity while deficiency of C2 in the great majority of cases is caused by a specific deletion. The production of C4 and C2 is mainly by the hepatocytes in the liver while C1q is produced by monocytic bone marrow derived cells. This has implications for the possibility to treat the deficiency and hematopoietic stem cell transplantation has been tried in C1q deficiency.
Topics: Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 6; Complement C1q; Complement C2; Complement C4; Complement Pathway, Classical; Complement Pathway, Mannose-Binding Lectin; Gene Expression Regulation; Hepatocytes; Humans; Lupus Erythematosus, Systemic; Monocytes; Signal Transduction
PubMed: 26038300
DOI: 10.1016/j.molimm.2015.05.007 -
Clinical and Experimental Immunology Aug 2022The classical pathway of the complement cascade has been recognized as a key activation arm, partnering with the lectin activation arm and the alternative pathway to... (Review)
Review
The classical pathway of the complement cascade has been recognized as a key activation arm, partnering with the lectin activation arm and the alternative pathway to cleave C3 and initiate the assembly of the terminal components. While deficiencies of classical pathway components have been recognized since 1966, only recently have gain-of-function variants been described for some of these proteins. Loss-of-function variants in C1, C4, and C2 are most often associated with lupus and systemic infections with encapsulated bacteria. C3 deficiency varies slightly from this phenotypic class with membranoproliferative glomerulonephritis and infection as the dominant phenotypes. The gain-of-function variants recently described for C1r and C1s lead to periodontal Ehlers Danlos syndrome, a surprisingly structural phenotype. Gain-of-function in C3 and C2 are associated with endothelial manifestations including hemolytic uremic syndrome and vasculitis with C2 gain-of-function variants thus far having been reported in patients with a C3 glomerulopathy. This review will discuss the loss-of-function and gain-of-function phenotypes and place them within the larger context of complement deficiencies.
Topics: Complement Activation; Complement C4; Complement Pathway, Classical; Complement System Proteins
PubMed: 35648651
DOI: 10.1093/cei/uxac056