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HLA Jan 2024The complement component 4 gene loci, composed of the C4A and C4B genes and located on chromosome 6, encodes for complement component 4 (C4) proteins, a key intermediate...
The complement component 4 gene loci, composed of the C4A and C4B genes and located on chromosome 6, encodes for complement component 4 (C4) proteins, 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. C4A and C4B gene loci exhibit copy number variation, with each composite gene varying between 0 and 5 copies per haplotype. C4A and C4B genes also vary in size depending on the presence of the human endogenous retrovirus (HERV) in intron 9, denoted by C4(L) for long-form and C4(S) for short-form, which affects expression and is found in both C4A and C4B. 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. C4A and C4B 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 C4A and C4B 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 C4A and C4B sequences from short-read sequencing data, named C4Investigator. Using paired-end targeted or whole genome sequence data as input, C4Investigator determines the overall gene copy numbers, as well as C4A, C4B, C4(Rodger), C4(Ch), C4(L), and C4(S). Additionally, C4Ivestigator reports the full overall C4A and C4B aligned sequence, enabling nucleotide level analysis. To demonstrate the utility of this workflow we have analyzed C4A and C4B variation in the 1000 Genomes Project Data set, showing that these genes are highly poly-allelic with many variants that have the potential to impact C4 protein function.
Topics: Humans; DNA Copy Number Variations; Complement C4b; Alleles; Complement C4; Genomics; Sequence Analysis; Epitopes
PubMed: 37899688
DOI: 10.1111/tan.15273 -
The Journal of Biological Chemistry May 1987The major histocompatibility complex-linked human complement C4 genes are highly homologous in primary structure but give rise to products which differ in... (Comparative Study)
Comparative Study
The major histocompatibility complex-linked human complement C4 genes are highly homologous in primary structure but give rise to products which differ in complement-activating function. In order to examine the synthesis, function, and regulation of these two genes independently, cloned C4A and C4B genes were transfected into mouse fibroblast L-cells. In the stable transfected cell lines, C4A and C4B are synthesized, undergo a complex series of post-translational modifications, and each functions appropriately in activation of the classical complement pathway. A marked difference in the kinetics of complement component C1-mediated cleavage of the C4A- and C4B-alpha chains was demonstrated in the transfectants and may contribute to the differences in the intrinsic functional activity of the two C4 isotypes. In contrast to the expression of other complement genes which are affected during the hepatic "acute phase response" (factor B, C3), the expression of C4 was not regulated by interleukin-1 or tumor necrosis factor. Interferon-gamma, however, mediated a dose- and time-dependent increase in the expression of the C4 genes. Moreover, interferon had a significantly greater and longer-lasting effect on the synthesis of C4A than that of C4B. Differences in the expression and regulation of these two genes provide insight into the control of complement activation during inflammation.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line; Complement C4; Complement C4a; Complement C4b; DNA, Recombinant; Fibroblasts; Gene Expression Regulation; Humans; Interferon-gamma; L Cells; Liver Neoplasms; Mice; Protein Processing, Post-Translational; Transfection
PubMed: 3034887
DOI: No ID Found -
Biochemia Medica Oct 2019Reference intervals (RIs) for complement assays in EDTA plasma samples have not previously been published. The objectives of the present study were to validate and/or...
INTRODUCTION
Reference intervals (RIs) for complement assays in EDTA plasma samples have not previously been published. The objectives of the present study were to validate and/or determine RIs for classical pathway (CP50) activity and C3c, C4 and C1 inhibitor protein (C1INH) assays and to assess the need for age-specific RIs in EDTA plasma.
MATERIALS AND METHODS
We retrospectively evaluated a cohort of 387 patients attending our university hospital and known to be free of complement-modifying diseases. The need for age partitioning was assessed and RIs were calculated according to the CLSI protocol.
RESULTS
No need for age partitioning was evidenced for CP50 activity, C3c and C4 concentrations and RIs (90% CI) were calculated from the pooled data: 35.4 (33.1-37.2) to 76.3 (73.7-83.6) U/mL for CP50 activity, 0.80 (0.75-0.87) to 1.64 (1.59-1.72) g/L for C3c, and 0.12 (0.10-0.14) to 0.38 (0.36-0.40) g/L for C4. Our results highlight a positive association between age and C1INH concentrations. We derived 3 age partitions (6 months to 30 years, 30-50 and > 50 years) and the related RIs: 0.20 (0.18-0.21) to 0.38 (0.36-0.40) g/L, 0.22 (0.20-0.24) to 0.39 (0.36-0.41) g/L and 0.25 (0.22-0.27) to 0.41 (0.40-0.43) g/L, respectively).
CONCLUSIONS
The newly determined RIs for CP50 activity were higher than those provided by the manufacturer for EDTA plasma samples, whereas those for C3c and C4 RIs were similar to the values provided for serum samples. The C1INH concentration and activity were found to be associated with age and age-specific RIs are mandatory for this analyte.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Complement C1 Inhibitor Protein; Complement C3c; Complement C4; Female; Humans; Male; Middle Aged; Reference Values; Retrospective Studies; Young Adult
PubMed: 31624460
DOI: 10.11613/BM.2019.030707 -
Kidney International Dec 1986Monoclonal antibodies reactive against the complement C4A and C4B isotypic components were used in an immunoperoxidase technique for the histological study of normal...
Monoclonal antibodies reactive against the complement C4A and C4B isotypic components were used in an immunoperoxidase technique for the histological study of normal human renal tissue. Prominent staining with both antibodies was seen in the mesangial areas of all normal kidney sections investigated. Occasional staining of arteriolar walls of the same tissues, however, was also observed. In contrast, no mesangial staining was seen using monoclonal antibodies reactive against other 'early' complement components, such as C1q and C3. Specificity of the glomerular staining with the anti-C4 reagents was demonstrated in two patients possessing only the C4A serum component but lacking genetically the C4B locus products. As would be predicted, glomerular staining with the anti-C4A reagent, but not anti-C4B, was clearly demonstrable. It is concluded that both isotypes of complement C4 are present in normal human glomeruli and thus might be operative for normal mesangial function.
Topics: Antibodies, Monoclonal; Antibody Specificity; Binding, Competitive; Collodion; Complement C4; Complement C4a; Complement C4b; Electrophoresis, Polyacrylamide Gel; Glomerular Mesangium; Humans; Immunoenzyme Techniques; Immunoglobulin Isotypes; Kidney; Kidney Glomerulus
PubMed: 3546915
DOI: 10.1038/ki.1986.275 -
Frontiers in Immunology 2021Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports...
Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports suggest that TA-TMA is caused by complement activation by complement-related genetic variants; however, this needs to be verified, especially in adults. Here, we performed a nested case-control study of allo-HSCT-treated adults at a single center. Fifteen TA-TMA patients and 15 non-TA-TMA patients, matched according to the propensity score, were enrolled. Based on a previous report showing an association between complement-related genes and development of TA-TMA, we first sequenced these 17 genes. Both cohorts harbored several genetic variants with rare allele frequencies; however, there was no difference in the percentage of patients in the TA-TMA and non-TA-TMA groups with the rare variants, or in the average number of rare variants per patient. Second, we measured plasma concentrations of complement proteins. Notably, levels of Ba protein on Day 7 following allo-HSCT were abnormally and significantly higher in TA-TMA than in non-TA-TMA cases, suggesting that complement activation the alternative pathway contributes to TA-TMA. All other parameters, including soluble C5b-9, on Day 7 were similar between the groups. The levels of C3, C4, CH50, and complement factors H and I in the TA-TMA group after Day 28 were significantly lower than those in the non-TA-TMA group. Complement-related genetic variants did not predict TA-TMA development. By contrast, abnormally high levels of Ba on Day 7 did predict development of TA-TMA and non-relapse mortality. Thus, Ba levels on Day 7 after allo-HSCT are a sensitive and prognostic biomarker of TA-TMA.
Topics: Adult; Aged; Biomarkers; Complement C4; Complement Pathway, Alternative; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Predictive Value of Tests; Retrospective Studies; Risk Assessment; Risk Factors; Thrombotic Microangiopathies; Time Factors; Transplantation, Homologous; Treatment Outcome; Up-Regulation
PubMed: 34326846
DOI: 10.3389/fimmu.2021.695037 -
European Journal of Immunology Sep 2002Mice lacking the classical complement component C4 (C4(-/-)) were evaluated for autoreactivity because classical complement deficiencies are major risk factors for human... (Comparative Study)
Comparative Study
Mice lacking the classical complement component C4 (C4(-/-)) were evaluated for autoreactivity because classical complement deficiencies are major risk factors for human systemic lupus erythematosus (SLE). Naive, 6-month-old C4(-/-) mice have significantly more IgM anti-double-strand DNA antibodies than C4(+/+) controls. By 9 months, IgG anti-dsDNA antibodies are increased and this spontaneous autoreactivity is evident across a mixture of genetic backgrounds. C4(+/-) heterozygous mice also develop autoantibodies, reminiscent of the high incidence of partial C4 deficiency observed in human SLE. Kidneys of C4(-/-) mice have glomerular immune complexes, but progressive renal disease is not apparent in unmanipulated animals. Nonetheless, splenic B cells from C4(-/-) and not C4(+/+) mice as young as 3 months can be triggered to secrete IgM anti-dsDNA antibodies in vitro, before autoantibody titers are significantly elevated in vivo. These findings suggest that C4 normally helps prevent early stages of autoimmune disease and that C4 deficiency predisposes to abnormal regulation of autoreactive B cells.
Topics: Animals; Antibodies, Antinuclear; Antibody Specificity; Antigen-Antibody Complex; B-Lymphocytes; Cells, Cultured; Complement C4; Crosses, Genetic; DNA; Female; Immunoglobulin G; Immunoglobulin M; Kidney; Kidney Glomerulus; Lipopolysaccharides; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Specific Pathogen-Free Organisms
PubMed: 12207352
DOI: 10.1002/1521-4141(200209)32:9<2672::AID-IMMU2672>3.0.CO;2-X -
Oxidative Medicine and Cellular... 2022Prostatitis is a common disease of the male genitourinary system, which seriously disturbs the physical and mental health of male patients. It is related to many factors...
OBJECTIVE
Prostatitis is a common disease of the male genitourinary system, which seriously disturbs the physical and mental health of male patients. It is related to many factors such as living habits, age, and race, but the etiology has not been fully elucidated. This study investigated whether there is a causal relationship between clinical biochemical indicators (i.e., intermediate phenotype) and prostatitis through Mendelian randomization. The subjects of the study were prostatitis patients and related SNPs in the Guangxi Fangchenggang health examination cohort.
METHODS
According to the requirements of Mendelian randomization (MR), the single nucleotide polymorphisms (SNPs) related to prostatitis patients and 29 common SNPs related to clinical biochemical indicators were analyzed by linkage disequilibrium, and the calculated SNPs were selected. Finally, the related SNPs were analyzed by Mendelian randomization method.
RESULTS
15 biochemical indicators such as complement C4, FOL, CRP, HCY, and estradiol have shared chronic prostatitis SNP sites, and five qualified SNPs were finally screened for complement C4. Finally, complement C4 was obtained by Mendelian randomization method ( = 0.039), which was statistically significant. The other 28 clinical endophenotypes were all negative.
CONCLUSION
The results show that there was a causal relationship between complement C4 and prostatitis, and the more consistent SNP is rs2075799.
Topics: China; Complement C4; Endophenotypes; Humans; Male; Mendelian Randomization Analysis; Prostatitis
PubMed: 36071874
DOI: 10.1155/2022/4560609 -
Proceedings of the National Academy of... Jan 1985A comparison of the sequence of the subunit of human alpha 2-macroglobulin (alpha 2M; 1451 amino acid residues) with that of murine complement component pro-C3 (1639... (Comparative Study)
Comparative Study
A comparison of the sequence of the subunit of human alpha 2-macroglobulin (alpha 2M; 1451 amino acid residues) with that of murine complement component pro-C3 (1639 amino acid residues) reveals eight extended regions of sequence similarity. These regions contain between 19% and 31% identically placed residues and account for 75% and 67%, respectively, of the polypeptide chains of alpha 2M and pro-C3. Published sequence data for complement component C4 show that segments of this protein match well with corresponding stretches in alpha 2M and pro-C3. It is proposed that alpha 2M, C3 and C4, which all contain a unique activatable beta-cysteinyl-gamma-glutamyl thiol ester, have a common evolutionary origin and are homologous proteins. Several larger regions of low sequence similarity indicate the presence of structural domains in each of these proteins that specifically modify an underlying common gross structure. The quartets of basic residues in pro-C3 and pro-C4, at which cleavage takes place to produce the mature subunits of these proteins, and most of the residues forming the anaphylatoxin peptides of C3 and C4 (C3a and C4a) are absent in alpha 2M. In addition, C3 and C4 contain large portions, which extend beyond the COOH terminus of alpha 2M.
Topics: Amino Acid Sequence; Biological Evolution; Complement C3; Complement C4; Humans; Protein Precursors; alpha-Macroglobulins
PubMed: 2578664
DOI: 10.1073/pnas.82.1.9 -
Molecular Biology Reports Dec 2023MicroRNA and cell-free DNA have shown significant correlations with several autoimmune disorders including systemic lupus erythematosus (SLE). SLE has been associated...
BACKGROUND
MicroRNA and cell-free DNA have shown significant correlations with several autoimmune disorders including systemic lupus erythematosus (SLE). SLE has been associated with challenges in determining its activity, so that the need for biomarkers contributing to assessing its activity is emerging. The current study investigated miRNA-21, miRNA-146a and plasma cf-DNA in determination of SLE activity, in addition their association with clinical data including complement factor 3 (C3), complement factor(C4), anti-dsDNA, and other disease activity indices.
METHODS AND RESULTS
Eighty subjects divided into; twenty active patients (with SLE-DAI2K score of 16-18) twenty inactive patients (with SLE-DAI2K score of 1-3), and forty healthy control participants) were included in this study. Serum miR-21, miR-146a, and plasma cf-DNA were quantified by real time PCR and their correlation with clinical data was statistically analyzed. The results demonstrated that active cases have significant upregulation of serum miRNA-21 and plasma cf-DNA. Moreover, miR-21 showed a negative, significant pertaining to C3, C4 and was positively related to Systemic Lupus Erythematosus Disease Activity Index 2 K score (SLE-DAI Index2K score) and Systemic-Lupus-Erythematosus-Disease Activity-Index 2 K activity (SLE-DAI 2 K activity). Also, Active group miRNA-146a was negatively, significantly correlated with C3, as well as a positive significant relationship with SLE-DAI2K score and SLEDAI 2 K activity, in addition to anti DNA Autoantibodies. Furthermore, miR-21 and cf-DNA demonstrated a differential value through Receiver Operating Characteristic (ROC) curve's study.
CONCLUSIONS
the present study illustrated miR-21, miR-146a, and cf-DNA relationship with SLE clinical data. In addition to their potential value in SLE diagnosis, and activity determination.
Topics: Humans; Biomarkers; Cell-Free Nucleic Acids; Complement C3; Complement C4; DNA; Lupus Erythematosus, Systemic; MicroRNAs
PubMed: 37904010
DOI: 10.1007/s11033-023-08845-z -
Gut Nov 1982Serum levels of the complement proteins C3, C4, C1 inhibitor (C1 INH), factor I (C3b inactivator) and factor H (BIH) and plasma levels of cleavage products of C3 (C3c)...
Serum levels of the complement proteins C3, C4, C1 inhibitor (C1 INH), factor I (C3b inactivator) and factor H (BIH) and plasma levels of cleavage products of C3 (C3c) and factor B were measured in 26 patients with acute pancreatitis. Breakdown of C3 occurred in 19 patients, as shown by a reduction in C3 level and the presence of C3c. C4 levels, however, did not fall and factor B breakdown products were not detected, thus suggesting that enzymatic cleavage of C3 occurred without significant involvement of either the early classical pathway or the alternative pathway. C1 INH and factor H both showed increases, presumably reflecting an acute phase response. Factor I showed an initial fall followed by a rise. There was no correlation between the presence or extent of C3 breakdown and the clinical condition of the patients. It is concluded that C3 cleavage in pancreatitis probably results from tryptic activity and that the measurement of complement components has no part to play in the management of the disease.
Topics: Acute Disease; Complement Activation; Complement C3; Complement C4; Complement Factor B; Complement Inactivator Proteins; Enzyme Precursors; Humans; Pancreatitis; Time Factors
PubMed: 6922819
DOI: 10.1136/gut.23.11.944