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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 Immunology 2022A proportion of patients with immunogloblin G (IgG) 4-related disease (IgG4-RD) have hypocomplementemia. We aimed to identify characteristics of such patients.
BACKGROUND
A proportion of patients with immunogloblin G (IgG) 4-related disease (IgG4-RD) have hypocomplementemia. We aimed to identify characteristics of such patients.
METHODS
We analyzed the demographic and clinical data and complement levels of 85 patients with IgG4-RD. We defined hypocomplementemia as serum C3 and/or C4 levels below the lower limit of normal at diagnosis. We also compared the characteristics of patients with and without IgG4-RD.
RESULTS
Thirty-two (38%) patients had hypocomplementemia at diagnosis. Patients with hypocomplementemia had more lymph node (p < 0.01), lung (p < 0.01), and kidney (p = 0.02) involvement and a higher IgG4-RD responder index than those without (p = 0.05). Additionally, patients with hypocomplementemia had significantly higher IgG (p < 0.01), IgG4 (p < 0.01), and soluble interleukin 2-receptor (sIL-2R) (p < 0.01) levels and total IgG minus IgG4 (p < 0.01). C3 and C4 levels negatively correlated with IgG, IgG4, and sIL-2R levels, total IgG minus IgG4, and number of IgG4-RD responder index: a measure of the disease activity in IgG4-RD. Patients with hypocomplementemia at diagnosis had a significantly higher frequency of relapse (p = 0.024), as determined using the log-rank test. A multivariate logistic regression analysis showed the presence of hypocomplementemia was independently associated with relapse (OR, 6.842; 95% confidence interval [95%CI], 1.684-27.79; p = 0.007).
CONCLUSIONS
Patients with IgG4-RD with hypocomplementemia have a more active clinical phenotype, suggesting contributions of the complement system in the pathophysiology of IgG4-RD.
Topics: Complement System Proteins; Hematologic Diseases; Humans; Immune System Diseases; Immunoglobulin G; Immunoglobulin G4-Related Disease; Receptors, Interleukin-2; Recurrence
PubMed: 35296071
DOI: 10.3389/fimmu.2022.828122 -
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 -
Frontiers in Immunology 2022The role of the complement system in antibody-mediated rejection (ABMR) is insufficiently understood. We aimed to investigate the role of local and systemic complement...
BACKGROUND
The role of the complement system in antibody-mediated rejection (ABMR) is insufficiently understood. We aimed to investigate the role of local and systemic complement activation in active (aABMR). We quantified complement activation markers, C3, C3d, and C5b-9 in plasma of aABMR, and acute T-cell mediated rejection (aTCMR), and non-rejection kidney transplant recipients. Intra-renal complement markers were analyzed as C4d, C3d, C5b-9, and CD59 deposition. We examined complement activation and CD59 expression on renal endothelial cells upon incubation with human leukocyte antigen antibodies.
METHODS
We included 50 kidney transplant recipients, who we histopathologically classified as aABMR (n=17), aTCMR (n=18), and non-rejection patients (n=15).
RESULTS
Complement activation in plasma did not differ across groups. C3d and C4d deposition were discriminative for aABMR diagnosis. Particularly, C3d deposition was stronger in glomerular (P<0,01), and peritubular capillaries (P<0,05) comparing aABMR to aTCMR rejection and non-rejection biopsies. In contrast to C3d, C5b-9 was only mildly expressed across all groups. For C5b-9, no significant difference between aABMR and non-rejection biopsies regarding peritubular and glomerular C5b-9 deposition was evident. We replicated these findings using renal endothelial cells and found complement pathway activation with C4d and C3d, but without terminal C5b-9 deposition. Complement regulator CD59 was variably present in biopsies and constitutively expressed on renal endothelial cells .
CONCLUSION
Our results indicate that terminal complement might only play a minor role in late aABMR, possibly indicating the need to re-evaluate the applicability of terminal complement inhibitors as treatment for aABMR.
Topics: Antibodies; Complement C4b; Complement Membrane Attack Complex; Complement System Proteins; Endothelial Cells; Female; Graft Rejection; Humans; Kidney; Kidney Diseases; Male
PubMed: 35493506
DOI: 10.3389/fimmu.2022.845301 -
Frontiers in Endocrinology 2023We aimed to explore the association between serum complements and kidney function of diabetic kidney disease (DKD) in Chinese patients.
OBJECTIVE
We aimed to explore the association between serum complements and kidney function of diabetic kidney disease (DKD) in Chinese patients.
METHODS
This is a retrospective study involving 2,441 participants. DKD was diagnosed according to the Kidney Disease: Improving Global Outcomes (KDIGO) categories. Participants were classified as stages G1-G5 by KDIGO glomerular filtration rate (GFR) categories. Effect sizes are expressed as odds ratio (OR) with 95% confidence interval (CI).
RESULTS
After balancing age, gender, systolic blood pressure (SBP), hemoglobin A1c (HbA1C), serum triglyceride (TG), and urinary albumin-to-creatinine ratio (UACR) between the G2-G5 and control groups, per 0.1 g/L increment in serum complement C3 was significantly associated with a 27.8% reduced risk of DKD at G5 stage (OR, 95% CI, P: 0.722, 0.616-0.847, <0.001) relative to the G1 stage. Conversely, per 0.1 g/L increment in serum complement C4 was associated with an 83.0-177.6% increased risk of G2-G5 stage (P<0.001). Serum complement C1q was not statistically significant compared to controls at all stages prior to or after propensity score matching.
CONCLUSIONS
Our results indicate that high concentrations of serum C4 were associated with the significantly elevated risk of kidney function deterioration across all stages, and reduced serum C3 levels with an increased risk of DKD stage G5.
Topics: Humans; Diabetic Nephropathies; Retrospective Studies; Kidney; Kidney Function Tests; Glomerular Filtration Rate; Diabetes Mellitus
PubMed: 38047115
DOI: 10.3389/fendo.2023.1195966 -
BioRxiv : the Preprint Server For... Jul 2023The complement component 4 gene locus, composed of the and genes and located on chromosome 6, encodes for C4 protein, a key intermediate in the classical and lectin...
The complement component 4 gene locus, composed of the and genes and located on chromosome 6, encodes for C4 protein, a key intermediate in the classical and lectin pathways of the complement system. The complement system is an important modulator of immune system activity and is also involved in the clearance of immune complexes and cellular debris. The gene locus exhibits copy number variation, with each composite gene varying between 0-5 copies per haplotype, genes also vary in size depending on the presence of the HERV retrovirus in intron 9, denoted by for long-form and for short-form, which modulates expression and is found in both and . Additionally, human blood group antigens Rodgers and Chido are located on the C4 protein, with the Rodger epitope generally found on C4A protein, and the Chido epitope generally found on C4B protein. copy number variation has been implicated in numerous autoimmune and pathogenic diseases. Despite the central role of C4 in immune function and regulation, high-throughput genomic sequence analysis of variants has been impeded by the high degree of sequence similarity and complex genetic variation exhibited by these genes. To investigate C4 variation using genomic sequencing data, we have developed a novel bioinformatic pipeline for comprehensive, high-throughput characterization of human sequence from short-read sequencing data, named C4Investigator. Using paired-end targeted or whole genome sequence data as input, C4Investigator determines gene copy number for overall and , additionally, C4Ivestigator reports the full overall aligned sequence, enabling nucleotide level analysis of . To demonstrate the utility of this workflow we have analyzed variation in the 1000 Genomes Project Dataset, showing that the genes are highly poly-allelic with many variants that have the potential to impact C4 protein function.
PubMed: 37503256
DOI: 10.1101/2023.07.18.549551 -
Frontiers in Immunology 2016The complement system plays an important role in the innate and acquired immune response against pathogens. It consists of more than 30 proteins found in soluble form or... (Review)
Review
The complement system plays an important role in the innate and acquired immune response against pathogens. It consists of more than 30 proteins found in soluble form or attached to cell membranes. Most complement proteins circulate in inactive forms and can be sequentially activated by the classical, alternative, or lectin pathways. Biological functions, such as opsonization, removal of apoptotic cells, adjuvant function, activation of B lymphocytes, degranulation of mast cells and basophils, and solubilization and clearance of immune complex and cell lysis, are dependent on complement activation. Although the activation of the complement system is important to avoid infections, it also can contribute to the inflammatory response triggered by immune complex deposition in tissues in autoimmune diseases. Paradoxically, the deficiency of early complement proteins from the classical pathway (CP) is strongly associated with development of systemic lupus erythematous (SLE) - mainly C1q deficiency (93%) and C4 deficiency (75%). The aim of this review is to focus on the deficiencies of early components of the CP (C1q, C1r, C1s, C4, and C2) proteins in SLE patients.
PubMed: 26941740
DOI: 10.3389/fimmu.2016.00055 -
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 -
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 -
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