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Immunity Sep 2001Genetic predisposition plays a crucial role in susceptibility to systemic lupus erythematosus (SLE) in both human patients and animal models. Recent progress in... (Review)
Review
Genetic predisposition plays a crucial role in susceptibility to systemic lupus erythematosus (SLE) in both human patients and animal models. Recent progress in experimental systems and human linkage analysis is providing key insights into the genetic basis for susceptibility and elucidating the manner in which genetic interactions mediate severe disease pathogenesis. Genes in multiple pathways appear to participate in specific elements of the disease, and epistatic interactions among these genes play an important role in both aggravating and suppressing disease development.
Topics: Autoimmunity; Chromosome Mapping; Complement C4; Genetic Linkage; HLA Antigens; Humans; Lupus Erythematosus, Systemic; Receptors, IgG
PubMed: 11567630
DOI: 10.1016/s1074-7613(01)00201-1 -
Annals of the Rheumatic Diseases Feb 1989The metabolism of the complement proteins C3 and C4 was studied in patients with active and inactive systemic lupus erythematosus (SLE) using highly purified,...
The metabolism of the complement proteins C3 and C4 was studied in patients with active and inactive systemic lupus erythematosus (SLE) using highly purified, functionally active preparations. Nine patients with active and eight with inactive SLE were examined and 11 control subjects. There was a significant difference in the level of double stranded DNA antibodies, immune complexes, and serum C4 between the patients with active and inactive disease. Seven of 16 patients had detectable C4 null alleles and four had low serum concentrations of complement inhibitors. Each subject received approximately 370 kBq [125I]C4 and 93 kBq [131I]C3. Both patient groups showed significant C4 hypercatabolism compared with control subjects, but there was no difference between patients with active and inactive disease. The fractional catabolic rate (FCR) of C4 was comparable in subjects with and without detectable C4 null alleles. C4 production rate was significantly lower in patients with active SLE than in control subjects. There was significant C3 hypercatabolism for both patient groups, but C3 production was normal. An inverse correlation was observed between serum concentration and FCR. There was a highly significant correlation between C4 FCR and C3 FCR for control subjects + patients with inactive disease but not for those with active SLE combined with either controls or the inactive group. We conclude that complement hypercatabolism occurs in SLE irrespective of disease activity and that accelerated turnover does not account completely for the low C4 concentration observed in patients with active disease. This low concentration also results from impaired plasma production, which could reflect a high incidence of C4 null alleles or (inhibitory) factors associated with pathological complement activation, or both. Low C4 production could affect generation of the C3 converting enzyme C4b, 2b and thus influence proceeding complement activation.
Topics: Alleles; Antibodies, Antinuclear; Antigen-Antibody Complex; Complement C3; Complement C4; Complement Inactivator Proteins; DNA; Humans; Lupus Erythematosus, Systemic
PubMed: 2784659
DOI: 10.1136/ard.48.2.153 -
Proceedings of the National Academy of... Jan 1992The role of a viral gene product in evasion of the host immune response was investigated. The antibody-dependent complement-enhanced neutralization of vaccinia virus...
The role of a viral gene product in evasion of the host immune response was investigated. The antibody-dependent complement-enhanced neutralization of vaccinia virus infectivity was prevented by the culture medium from vaccinia virus-infected cells. The vaccinia virus complement-control protein (VCP) was identified as the secreted product of vaccinia virus gene C21L and has homology to a group of eukaryotic genes encoding regulators of complement activation. Thus, the culture medium from cells infected with a C21L deletion mutant was VCP deficient and had little or no effect on antibody-dependent complement-enhanced neutralization. In addition, the anticomplement effect was associated with the C21L-encoded protein partially purified from the medium of cells infected with wild-type virus. Antibody-dependent, complement-enhanced neutralization of vaccinia virus occurred with a complement source that was deficient in the classical pathway complement component C4 and required the alternative pathway complement factor B. Furthermore, the presence of VCP abrogated the complement-enhanced neutralization in C4-deficient serum. Together with previous hemolysis data, the present result suggests that VCP can inhibit both the classical and alternative pathways of complement activation. Skin lesions caused by the C21L deletion mutant were smaller than those caused by wild-type virus, demonstrating an important role for VCP in virulence. The C21L deletion mutant also was attenuated in C4-deficient guinea pigs, consistent with in vitro studies. Vaccinia virus appears to have acquired the ability to regulate the complement cascade for the purpose of evading the host immune response.
Topics: Animals; Antibodies, Viral; Complement C4; Complement Factor B; Complement Inactivator Proteins; Complement Pathway, Alternative; DNA Mutational Analysis; Guinea Pigs; Neutralization Tests; Vaccinia virus; Viral Proteins
PubMed: 1731333
DOI: 10.1073/pnas.89.2.628 -
International Journal of Oncology Feb 2023Long noncoding RNAs (lncRNAs) have a certain link to genomic stability (GS). However, the regulatory relationship of lncRNAs and GS has not been thoroughly investigated...
Long noncoding RNAs (lncRNAs) have a certain link to genomic stability (GS). However, the regulatory relationship of lncRNAs and GS has not been thoroughly investigated in hepatocellular carcinoma (HCC). In the present study, samples were retrieved from The Cancer Genome Atlas with somatic mutations and lncRNA expression data. Cox regression analysis was used to identify independent prognostic factors. The RNA levels were determined by reverse transcription‑quantitative PCR and protein levels were detected by western blot analysis. Cell Counting Kit‑8 and colony‑formation assays were used to assess cell viability. Cell migration was measured by wound‑healing and Transwell assays. Cell apoptosis and cell‑cycle progression were evaluated by flow cytometry. GS was detected by alkaline comet and chromosomal aberration assays. A xenograft model and lung metastasis model were used to assess the role of zinc finger protein, FOG family member 2 antisense 1 (ZFPM2‑AS1) in tumor growth . The molecular mechanisms underlying the biological functions of ZFPM2‑AS1 were investigated through bioinformatics prediction, RNA pull‑down and luciferase reporter assays. A total of 85 genomic instability‑related lncRNAs were identified and a prognostic model was developed. The prognostic model exhibited good predictive power (area under the receiver operating characteristic curve, 0.786). ZFPM2‑AS1 was significantly upregulated in tumor tissues (P<0.001) and it promoted DNA damage repair (P<0.01) and tumor progression and . Luciferase reporter assays demonstrated that miR‑3065‑5p was able to bind directly with ZFPM2‑AS1 and X‑ray repair cross complementing 4 (XRCC4). ZFPM2‑AS1 upregulated XRCC4 expression by acting as a sponge (P<0.001). In the present study, a prognostic model for HCC was developed and validated, and one lncRNA of its components was experimentally investigated. ZFPM2‑AS1 regulates XRCC4 by sponging miR‑3065‑5p to promote GS and HCC progression.
Topics: Humans; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Complement C4; DNA-Binding Proteins; Family; Gene Expression Regulation, Neoplastic; Genomic Instability; Liver Neoplasms; MicroRNAs; RNA, Long Noncoding; Zinc Fingers
PubMed: 36524359
DOI: 10.3892/ijo.2022.5467 -
The Journal of Biological Chemistry Mar 1994We have explored the template and factor requirements for transcription of the gene encoding the murine complement component C4, expressed predominantly but not... (Comparative Study)
Comparative Study
We have explored the template and factor requirements for transcription of the gene encoding the murine complement component C4, expressed predominantly but not exclusively in liver and mononuclear phagocytes. Competition experiments in transcription assays with liver nuclear extracts show that the regions upstream of the transcription initiation site are largely dispensable for obtaining basal levels of accurately initiated transcription. Activated transcription, however, depends on three upstream regulatory factors, two of which interact with target sites seemingly related to NF-1 (region -112/-87) and USF (region -85/-64), respectively. A third upstream regulatory factor has been detected by the surprising finding that double-stranded oligomers covering sequences proximal to the cap site (position -48 to -7) stimulate transcription from the C4 promoter specifically. Results of nucleotide deletions and site-directed mutations argue that the C4 initiator, that is, the most critical element for basal and accurate transcription of the gene, overlaps the cap site and extends into the transcribed sequences (-1 to +12). Immediately downstream of this region lies a last regulatory element (within the +5 to +43 boundaries) indispensable for high levels of transcription. These data assume wider interest because the C4 promoter does not contain TATA or CAAT boxes and does not feature any of the elements characteristic of the TATA-less genes so far reported.
Topics: Animals; Base Sequence; Cell Nucleus; Complement C4; Consensus Sequence; DNA; DNA Primers; Gene Expression Regulation; Kidney; Liver; Male; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Mutagenesis, Site-Directed; Polymerase Chain Reaction; Promoter Regions, Genetic; RNA Polymerase II; RNA Probes; Rats; Rats, Sprague-Dawley; Regulatory Sequences, Nucleic Acid; Sequence Deletion; Sequence Homology, Nucleic Acid; Spleen; Transcription, Genetic
PubMed: 8132550
DOI: No ID Found -
The EMBO Journal Oct 1985Molecular maps have been prepared of the HLA region on human chromosome 6 that includes the complement C4 and steroid 21-hydroxylase genes (21-OH), using DNA of...
Molecular maps have been prepared of the HLA region on human chromosome 6 that includes the complement C4 and steroid 21-hydroxylase genes (21-OH), using DNA of individuals deficient (QO) in either of the two forms C4A or C4B. In all, 18 haplotypes with C4A QO were examined by Southern analysis and two had deletions of 28-30 kb that included both the C4A and 21-OHA genes. Of six C4B QO haplotypes, one had a deletion that included both the C4B and 21-OHA genes. Thus, some of the C4 null alleles are due to deletion of the gene but the majority in this sample are not. Deletion occurred in two common haplotypes suggesting that in the population as a whole, C4A deficiency is due to deletion in about one-half the C4A QO haplotypes. As duplication of C4A or C4B genes does occur, the possibility that unequal cross-over could explain the C4 deletion was examined by preparing cosmid clones from the DNA of an individual typed C4A QO. A cloned genomic fragment containing the single C4B gene was isolated and found to be similar to the homologous region of a cosmid from a normal individual carrying a C4A gene. This suggests that if a cross-over has occurred it is in a region where the two genes are identical. The biological significance of the rather frequent occurrence in the population of haplotypes with C4A or C4B deletion together with the accompanying deletion of the 21-OHA gene is discussed.
Topics: Alleles; Chromosome Deletion; Chromosome Mapping; Cloning, Molecular; Complement C4; Complement C4a; Complement C4b; DNA Restriction Enzymes; Genes; Genetic Linkage; Genotype; Humans; Major Histocompatibility Complex; Steroid 21-Hydroxylase; Steroid Hydroxylases
PubMed: 2996881
DOI: 10.1002/j.1460-2075.1985.tb03969.x -
The Biochemical Journal Aug 1991
Review
Topics: Blood Coagulation; Carrier Proteins; Complement C4; Complement C4b; Complement Inactivator Proteins; Complement System Proteins; Glycoproteins; Humans; Protein Conformation; Protein S; Receptors, Complement
PubMed: 1831349
DOI: 10.1042/bj2770581 -
The Biochemical Journal Sep 1977The fourth component of complement, C4, was isolated from human serum in good yield, and in confirmation of previous reports was shown to be formed from three peptide...
The fourth component of complement, C4, was isolated from human serum in good yield, and in confirmation of previous reports was shown to be formed from three peptide chains, alpha, beta and gamma, with apparent mol.wts. 90 000, 80 000 and 30 000 respectively. Preparative methods are described for the isolation of the three peptide chains and their amino acid analyses reported. Component C4 contains 7.0% carbohydrate, alpha-chain 8.6% and the beta-chain 5.6%. The N-terminal amino acid sequences are given for 12 residues of the alpha-chain, eight of the beta-chain and 19 of the gamma-chain.
Topics: Amino Acid Sequence; Amino Acids; Carbohydrates; Complement C4; Electrophoresis, Polyacrylamide Gel; Humans; Peptides
PubMed: 921758
DOI: 10.1042/bj1650439 -
International Journal of... 2004Hypocomplementemia is an extremely complex phenomenon: we devoted our attention to its immunogenetic basis, particularly to the HLA haplotypes involved and to the study...
Hypocomplementemia is an extremely complex phenomenon: we devoted our attention to its immunogenetic basis, particularly to the HLA haplotypes involved and to the study of C4 polymorphic genes. With this in mind we analyzed a group of unrelated patients with hypocomplementemia and 15 families suffering from specific C4 deficiency. Firstly, we performed a population analysis in order to identify a statistically significant association: HLA-B35 and C4BQ0 alleles, in the total group of hypocomplementemic individuals, seem to be associated with the primary disease. Secondly, we defined HLA haplotypes clear-cut segregation in the hypocomplementemic families and we identified the most common HLA haplotypes carrying B35 and C4 null allele associated with this condition. With the aid of correspondence analysis and the Transmission Disequilibrium Test (TDT), we measured the strength of this association. In this work, mainly through family analysis, we envisaged a potentially interesting genomic trait, within HLA, close to B locus, that seems to be involved in hypocomplementemia itself and perhaps in hypocomplementemia-related disorders.
Topics: Algorithms; Alleles; Blotting, Western; Complement C4; Complement Factor B; Complement System Proteins; Densitometry; Electrophoresis, Polyacrylamide Gel; Family; Gene Frequency; Genetic Linkage; HLA Antigens; HLA-B35 Antigen; Haplotypes; Humans; Lod Score; Polymorphism, Genetic; Population
PubMed: 15461865
DOI: 10.1177/039463200401700311 -
PloS One 2014Non-tuberculous mycobacteria (NTM) are ubiquitous in the environment and they infect mainly persons with underlying pulmonary diseases but also previously healthy...
BACKGROUND
Non-tuberculous mycobacteria (NTM) are ubiquitous in the environment and they infect mainly persons with underlying pulmonary diseases but also previously healthy elderly women. Defects in host resistance that lead to pulmonary infections by NTM are relatively unknown. A few genetic defects have been associated with both pulmonary and disseminated mycobacterial infections. Rare disseminated NTM infections have been associated with genetic defects in T-cell mediated immunity and in cytokine signaling in families. We investigated whether there was an association between NTM infections and deficiencies of complement components C4A or C4B that are encoded by major histocompatibility complex (MHC).
METHODS
50 adult patients with a positive NTM culture with symptoms and findings of a NTM disease were recruited. Patients' clinical history was collected and symptoms and clinical findings were categorized according to 2007 diagnostic criteria of The American Thoracic Society (ATS). To investigate the deficiencies of complement, C4A and C4B gene copy numbers and phenotype frequencies of the C4 allotypes were analyzed. Unselected, healthy, 149 Finnish adults were used as controls.
RESULTS
NTM patients had more often C4 deficiencies (C4A or C4B) than controls (36/50 [72%] vs 83/149 [56%], OR = 2.05, 95%CI = 1.019-4.105, p = 0.042). C4 deficiencies for female NTM patients were more common than for controls (29/36 [81%] vs 55/100 [55%], OR = 3.39, 95% CI = 1.358-8.460, p = 0.007). C4 deficiences seemed not to be related to any specific underlying disease or C4 phenotype.
CONCLUSIONS
C4 deficiency may be a risk factor for NTM infection in especially elderly female patients.
Topics: Aged; Aged, 80 and over; Case-Control Studies; Complement C4; Disease Susceptibility; Female; Finland; Genotype; Humans; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Phenotype; Risk Factors
PubMed: 24638111
DOI: 10.1371/journal.pone.0091450