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Chemosphere Mar 2022Exposure to metals and metalloids is widely related with human health, and could affect the function of immune system. The complement system links innate and adaptive...
Exposure to metals and metalloids is widely related with human health, and could affect the function of immune system. The complement system links innate and adaptive immunity, and is critically involved in the pathogenesis of inflammatory and immune diseases. The third and fourth components of complement (C3, C4) play key roles in the complement system. However, few studies have examined the relations between multiple metals and complement levels. In this study, based on a total of 2977 participants from the Dongfeng-Tongji cohort, China, we investigated 17 plasma metals and serum C3, C4 levels, and calculated C3/C4-associated genetic risk scores (GRSs) using established single nucleotide polymorphisms. We further explored the potential gene-metal interactions on C3 and C4. After multivariable adjustment, an increment of 10-standard deviation increase in natural log-transformed exposure concentrations of plasma copper was associated with 0.549 (0.489, 0.608) (FDR <0.0001), and 1.146 (0.999, 1.294) (FDR <0.0001) higher natural log-transformed serum C3 and C4 levels, respectively. While each increment of 10-standard deviation of natural log-transformed zinc was associated with a difference of 0.083 (0.024, 0.143) (FDR = 0.049) and 0.007 (-0.138, 0.152) (FDR = 0.935) in log-transformed C3 and C4 levels, respectively. Participants with higher GRS had higher C3 and C4 levels. Furthermore, we found a significant interaction between arsenic exposure and C3-GRS in relation to C3 level (P = 0.0096). Our results suggested that plasma arsenic would modify the association between C3 genetic predisposition and serum C3 level. We provide new insight into metals exposure on the human immune system. These findings require replication in future research.
Topics: Complement C3; Humans; Metalloids; Metals; Risk Factors; Serum
PubMed: 34752839
DOI: 10.1016/j.chemosphere.2021.132801 -
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 -
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 -
Journal of Veterinary Internal Medicine 2024High concentrations of complement factors are presented in serum of animal epilepsy models and human patients with epilepsy.
BACKGROUND
High concentrations of complement factors are presented in serum of animal epilepsy models and human patients with epilepsy.
OBJECTIVES
To determine whether complement dysregulation occurs in dogs with idiopathic epilepsy (IE).
ANIMALS
The study included 49 dogs with IE subgrouped into treatment (n = 19), and nontreatment (n = 30), and 29 healthy dogs.
METHODS
In this case-control study, the serum concentrations of the third (C3) and fourth (C4) components of the complement system were measured using a canine-specific ELISA kit.
RESULTS
Serum C3 and C4 concentrations were significantly higher in dogs with IE (C3, median; 4.901 [IQR; 3.915-6.673] mg/mL, P < .001; C4, 0.327 [0.134-0.557] mg/mL, P = .03) than in healthy control dogs (C3, 3.550 [3.075-4.191] mg/mL; C4, 0.267 [0.131-0.427] mg/mL). No significant differences were observed in serum C3 and C4 concentrations between dogs in the treatment (C3, median; 4.894 [IQR; 4.192-5.715] mg/mL; C4, 0.427 [0.143-0.586] mg/mL) and nontreatment groups (C3, 5.051 [3.702-7.132] mg/mL; C4, 0.258 [0.130-0.489] mg/mL). Dogs with a seizure frequency >3 times/month had significantly higher serum C3 (6.461 [4.695-8.735] mg/mL; P < .01) and C4 (0.451 [0.163-0.675] mg/mL; P = .01) concentrations than those with a seizure frequency ≤3 times/month (C3, 3.859 [3.464-5.142] mg/mL; C4, 0.161 [0.100-0.325] mg/mL).
CONCLUSIONS AND CLINICAL IMPORTANCE
Dysregulation of classical complement pathway was identified in IE dogs. Serum C3 and C4 concentrations could be diagnostic biomarkers for IE in dogs with higher seizure frequency.
Topics: Humans; Dogs; Animals; Complement C3; Complement C4; Case-Control Studies; Epilepsy; Seizures; Dog Diseases
PubMed: 38329151
DOI: 10.1111/jvim.17008 -
Frontiers in Cellular Neuroscience 2023Complement system plays an important role in the immune defense against pathogens; however, recent studies demonstrated an important role of complement subunits C1q, C4,...
Complement C4-deficient mice have a high mortality rate during PTZ-induced epileptic seizures, which correlates with cognitive problems and the deficiency in the expression of Egr1 and other immediate early genes.
Complement system plays an important role in the immune defense against pathogens; however, recent studies demonstrated an important role of complement subunits C1q, C4, and C3 in normal functions of the central nervous system (CNS) such as non-functional synapse elimination (synapse pruning), and during various neurologic pathologies. Humans have two forms of C4 protein encoded by C4A and C4B genes that share 99.5% homology, while mice have only one C4B gene that is functionally active in the complement cascade. Overexpression of the human C4A gene was shown to contribute to the development of schizophrenia by mediating extensive synapse pruning through the activation C1q-C4-C3 pathway, while C4B deficiency or low levels of C4B expression were shown to relate to the development of schizophrenia and autism spectrum disorders possibly via other mechanisms not related to synapse elimination. To investigate the potential role of C4B in neuronal functions not related to synapse pruning, we compared wildtype (WT) mice with C3- and C4B- deficient animals for their susceptibility to pentylenetetrazole (PTZ)- induced epileptic seizures. We found that C4B (but not C3)-deficient mice were highly susceptible to convulsant and subconvulsant doses of PTZ when compared to WT controls. Further gene expression analysis revealed that in contrast to WT or C3-deficient animals, C4B-deficient mice failed to upregulate expressions of multiple immediate early genes (IEGs) Egrs1-4, c-Fos, c-Jus, FosB, Npas4, and Nur77 during epileptic seizures. Moreover, C4B-deficient mice had low levels of baseline expression of Egr1 on mRNA and protein levels, which was correlated with the cognitive problems of these animals. C4-deficient animals also failed to upregulate several genes downstream of IEGs such as BDNF and pro-inflammatory cytokines IL-1β, IL-6, and TNF. Taken together, our study demonstrates a new role of C4B in the regulation of expression of IEGs and their downstream targets during CNS insults such as epileptic seizures.
PubMed: 37234916
DOI: 10.3389/fncel.2023.1170031 -
Ocular Immunology and Inflammation Apr 2024To study the role of the complement system's C3 and C4 fractions in the pathogenesis of different types of uveitis.
PURPOSE
To study the role of the complement system's C3 and C4 fractions in the pathogenesis of different types of uveitis.
METHODS
A prospective case-control study. 118 patients were enrolled. The control group comprised 60 patients who were otherwise healthy people undergoing cataract or pterygium surgery, whereas the uveitis patients group consisted of 58 people. The levels of C3 and C4 fractions in the blood and in the aqueous humor for both groups were evaluated and compared.
RESULTS
No statistically significant differences were found in the levels of the C3 and C4 fractions in the blood between the groups. However, a statistically significant difference was observed in the levels of C3 and C4 in the aqueous humor between the case and control groups, as C3 and C4 fractions were not detected in the control group. The analysis of the mean gradient between the C4 levels in the blood samples and in the aqueous samples did not reveal a statistically significant difference between the case and control groups. However, upon performing an analogous mean gradient analysis of C3 levels, a statistically significant elevation in the value of the mean gradient was observed in the case group as compared to the control group.
CONCLUSION
Our findings are in line with our initial hypothesis, that the complement system's C3 and C4 fractions may have a role in the pathogenesis of uveitis.
PubMed: 38588040
DOI: 10.1080/09273948.2024.2337838 -
Glomerular endothelial activation, C4d deposits and microangiopathy in immunoglobulin A nephropathy.Nephrology, Dialysis, Transplantation :... Mar 2021Immunoglobulin A nephropathy (IgAN) is considered as mesangiopathy since it initiates in the mesangium; however, other glomerular components are involved and the... (Review)
Review
Immunoglobulin A nephropathy (IgAN) is considered as mesangiopathy since it initiates in the mesangium; however, other glomerular components are involved and the glomerular capillary wall offers the first contact to circulating macromolecular IgA1. Acute and active forms of IgAN are associated with endocapillary hypercellularity and vascular damage of various degrees, in severe cases with microangiopathy (MA) without or with thrombosis [thrombotic microangiopathy (TMA)]. Vascular damage activates complement and coagulation cascades. A defective complement regulation has recently been detected in active and progressive cases of IgAN. C4d deposits in renal biopsies have been found to be an early risk factor. These observations have raised interest in manifestation of MA and TMA in progressive cases of IgAN. MA-TMA lesions have been found in various percentages (2-53%) of patients with IgAN according to patients' selection and pathology definition of TMA. The association with hypertension (HTN) was so strong that it led to the hypothesis that MA/TMA in IgAN was a mere consequence of severe HTN. Old and new clinical and experimental data indicate that in IgAN the interaction of the glomerular capillary wall with immune reactants and complement uncontrolled activation leading to C4b deposits favours the development of MA-TMA, which plays a role in progression and renal function decline. The central role of complement activation is relevant also for the new therapeutic interventions offered by the pharma.
Topics: Complement Activation; Complement C4b; Glomerulonephritis, IGA; Humans; Kidney Glomerulus; Thrombotic Microangiopathies; Vascular Diseases
PubMed: 31755918
DOI: 10.1093/ndt/gfz241