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PubMed1982

Phagocytosis of C3b-coated sheep red blood cells by guinea-pig macrophages in the absence of antibody.

C1 was passively attached to tannic-acid-treated SRBC in the absence of antibody. EC1,4,2,3 were prepared by the stepwise reaction of EC1 with C4, C2, and C3. Contamination with IgM or IgG antibodies of the complement components used could not be detected by immunochemical methods; furthermore, possibly contaminating traces of antibody were removed by careful absorption of all preparations with erythrocytes. The C3b-opsonized SRBC were ingested by unstimulated guinea-pig peritoneal macrophages and PMN leukocytes. Addition of purified IgM to the C3b-opsonized SRBC did not substantially enhance particle uptake. It is concluded that C3b alone can act as an opsonin and triggers phagocytosis in the absence of antibody.

Animals↗
PubMed1992

Sperm age, sex ratio, and hyperhaploidy frequency in mice.

Physiologically aged and unaged sperm from each of 12 sexually mature B6SJLF1/J mice were used to fertilize oocytes from females of the same strain, with each male serving as its own control. Male genomes in 323 and 307 first-cleavage metaphases obtained by in vivo and in vitro fertilization, respectively, were analyzed cytogenetically, using C-banding for detection of the Y chromosome. The sex (X:Y) ratio among all zygotes resulting from in vivo fertilization was 1.18; in zygotes resulting from in vivo fertilization by aged (14-d mating intervals) sperm, however, the ratio was 1.53, which differed significantly (chi 2 = 6.72, P less than 0.01) from the theoretical value of 1.00. Comparison of the sex ratio in zygotes resulting from in vivo fertilization by unaged sperm (3-d mating intervals), 0.94, with that in zygotes resulting from fertilization by aged sperm (using a 2 x 2 contingency table) showed a significant (chi c2 = 4.19, P less than 0.05) relationship between sex ratio and sperm age. In vitro neither the combined nor the individual 3- and 14-d data deviated significantly from the expected sex ratio of 1.00. The frequency of sperm-derived hyperhaploidy did not differ significantly between the in vivo (3.4%) and in vitro (5.9%) populations, but did between unaged (2.5%) and aged (6.8%) sperm (chi c2 = 5.74, P less than 0.01). All hyperhaploid zygotes had a complement of n + 1 chromosomes, except the 14-d in vitro group, where complements of n + 2 and n + 3 chromosomes were seen. Sperm-derived polyploidy, which was observed only in the in vitro group, was independent of sperm age and occurred in 6.8% of the zygotes. These data provide support for the sperm-aging hypothesis and indicate, for the first time, an influence of sperm aging in the male genital tract on the X:Y ratio of conceptuses resulting from natural matings of chromosomally normal males.

Animals↗
PubMed1994

Expression of the components and regulatory proteins of the classical pathway of complement in normal and diseased synovium.

We studied the synthesis of the classical pathway complement components in synovial membrane. Ribonucleic acid was extracted from the synovial membranes of patients with rheumatoid arthritis (RA) or osteoarthritis (OA), as well as from normal synovial membrane. Northern blot and dot blot analysis showed that the mRNAs for all classical pathway complement components (C1qA chain, C1qB chain, C1qC chain, C1r, C1s, C4 and C2) and the fluid-phase regulatory components (C1-inhibitor, C4-bp and factor I) were present in all three types of synovial membrane. Thus, all the components of the classical pathway were expressed in normal and diseased synovium. In an attempt to determine which components were synthesised by each cell type, monocytes (mononuclear phagocytes), human umbilical vein endothelial cells (HUVEC), synovial membrane fibroblasts (from normal, OA and RA synovial membrane) and peripheral blood lymphocytes were cultured in vitro and secretion rates of individual components were measured and total cellular RNA was analysed by Northern blotting. Monocytes secreted C1q, C1r, C1s, C4, C2, C1-inhibitor and C4-bp but not factor I. Fibroblasts secreted C1r, C1s, C2, C3, C1-inhibitor and factor I but not C1q, C4 or C4-bp. HUVEC secreted C1s, C2, C1-inhibitor and factor I but not C1q, C1r, C4 or C4-bp. Lymphocytes did not secrete any of these components. In three instances mRNA was detected in the absence of secreted protein: mRNAs for the C1qA and C1qC chains were detected in HUVEC, whereas the mRNA for the C1qB chain was not, and C4 mRNA was detected in both fibroblasts and HUVEC.(ABSTRACT TRUNCATED AT 250 WORDS)

Arthritis, Rheumatoid↗
PubMed1986

Binding of C-reactive protein to nucleated cells leads to complement activation without cytolysis.

C-reactive protein (CRP) is an acute-phase reactant that is found bound to cells at sites of inflammation. We have passively sensitized HEp-2 cells for CRP binding and examined the effect of this treatment on complement activation and cell lysis. When cells were treated with protamine sulfate and CRP and were incubated with normal human serum in a 4-hr 51Cr-release assay, no significant lysis was noted. In contrast, HEp-2 cells treated with antibody and normal human serum were lysed. The consumption of complement components in normal human serum after incubation with cells treated with protamine and CRP was measured by hemolytic assays. CRP-treated cells consumed over 80% of C1, C4, and C2 and about 40% of C3 present. No significant consumption of C5 through C9 components was observed. Cells treated with antibody and complement showed consumption of C1 through C9. Cells were also sensitized for CRP binding by using diazophenylphosphocholine. This treatment also led to CRP binding and activation of the early classical pathway (C1, C4, C2, and to a lesser extent C3). The components of the membrane attack complex (C5 through C9) were not activated. Both a mouse monoclonal IgM and a human IgG antibody to phosphocholine activated the entire classical pathway. These results indicate that CRP activation of the classical complement pathway is restricted to the early part of the pathway. In the absence of activation of the membrane attack complex, complement-mediated cell lysis cannot occur.

Animals↗
PubMed1990

Inherited complement deficiency states: implications for immunity and immunological disease.

The study of complement deficiency states and their influence on immune function has generated new insights and still provides a challenge to continued investigation. The association of classical pathway deficiencies (C1, C4, C2 or C3) with immunological diseases such as SLE and glomerulonephritis has contributed to current knowledge concerning complement-dependent immune complex handling and elimination. Susceptibility to systemic infection with encapsulated bacteria is encountered in most forms of inherited complement deficiency. Recurrent neisserial infection is the only clinical manifestation clearly associated with defects of the membranolytic sequence C5-C9, while deficiency of properdin, a component of the alternative activation pathway, appears to predispose to nonrecurrent meningococcal disease. Inherited complement deficiency is rare, but the perspective is widened by the more common occurence of acquired defects in immunological diseases, and the apparent requirement for efficient complement recruitment in host defense. Another aspect is the possibility that complement deficiency might alleviate or prevent inflammatory symptoms. Notably, complement deficiency has not been reported in classical rheumatoid arthritis. Considerations of this kind would be refuted or modified by findings of complement deficiency in single patients.

Animals↗
PubMed1996

Differential expression of complement components in human fetal and adult kidneys.

Various studies have shown that complement components are synthesized by renal cells and that mRNA for a number of complement components is detectable in renal tissue. The present study shows that complement proteins are present both in fetal and adult human kidneys. The localization of the complement components was compared with the localization of other proteins for which specific expression in defined renal cell types is known from the literature. In adult human kidneys C3, factor B and factor H were detected in the mesangial area by immunohistochemistry, whereas C2 and C4 were present in the proximal tubuli. In fetal kidneys C3 and factor B were expressed in glomeruli of kidneys of 11 weeks of gestation. In kidneys of 13 to 19 weeks of gestation no staining for C3 was found in the glomerulus, whereas for factor B glomerular staining was found in all fetal kidneys examined. Factor B was also detected in fetal tubuli and in the interstitium. Factor H was expressed in fetal tubuli starting at 13 weeks of gestation. For both C3 and C2 weak tubular staining was found in all fetal kidneys investigated. C4 could not be detected in any of the fetal kidneys. While not all the complement proteins investigated were detectable by immunohistochemistry, by RT-PCR analysis, mRNA expression for C3, factor B, factor H, C2 and C4 was found in all adult and fetal renal tissue. The finding of mRNA for the complement components in the fetal and the adult kidneys indicates that local synthesis of complement occurs both in the adult and in the fetal kidney. Next to the in situ expression of complement components in fetal kidneys the synthesis of complement proteins in vitro by fetal renal cells was investigated. Four different primary mesangial cell lines were shown to synthesize all complement proteins investigated. Although a specific role for complement during the development of the kidney is not known, it is possible that certain complement components may play a role during renal differentiation.

Adult↗
PubMed1982

Antibody and complement in the stimulation of neutrophil chemiluminescence by Neisseria meningitidis: studies in a patient with complete deficiency of C7.

When an eight-year-old boy with a syndrome compatible with disseminated neisseria infection was found to lack C7, studies on the role of antibody and complement in the interaction of polymorphonuclear leukocytes (PMNLs) and Neisseria were initiated with use of a luminol-enhanced chemiluminescence assay. The chemiluminescent response to opsonized Neisseria meningitidis was markedly lower than the response to opsonized zymosan or Streptococcus pneumoniae but was similar to that obtained with Haemophilus influenzae type b. IgG antibody to N. meningitidis was shown to enhance the chemiluminescent response. The chemiluminescent response of PMNLs to N. meningitidis was normal when the bacteria were incubated with sera deficient in C5, C6, or C7 but was absent in serum lacking C2. Thus, both antibody and the early-acting proteins of the classical complement pathway appear to be essential for maximal stimulation of PMNL oxidative metabolism by N. meningitidis, although the late-acting components of complement are not.

Animals↗
PubMed1987

Orientation and molecular map position of the complement genes in the mouse MHC.

Over the past few years six gene clusters have been isolated from the major histocompatibility complex (MHC) of the BALB/c mouse encompassing a total of 1600 kb of DNA and 48 genes. The molecular distances between these gene clusters and the orientation of four of the six clusters on chromosome 17 is not known. Here we use pulse-field gradient gels and Southern blot hybridization to establish large-scale genomic restriction maps covering several hundreds of kb surrounding the three gene clusters located in the K, I, S, and D regions of the MHC. Comparison of the maps orients the complement gene clusters in the S region with the 21-OHB gene pointing towards the K end and the C2 gene pointing towards the D end of the MHC. The distances between the E alpha and 21-OHB genes is 430 kb and between the C2 and TNF-alpha genes at least 420 kb.

Animals↗
PubMed1994

Effect of cytokines on the secretion of the fifth and eighth complement components by HepG2 cells.

Liver cells can be induced by interleukin-1, tumor necrosis factor and interleukin-6 to secrete higher amounts of complement components. Information, so far available only for the early components, indicates that these cytokines exhibit different effects on various complement proteins. For instance, they promote the biosynthesis of C3 and B but have no effect on that of C4 and C2. These observations led us to evaluate the ability of interleukin-1, tumor necrosis factor and interleukin-6 to modulate the secretion of the late complement components by HepG2 cells, a human hepatoma-derived cell line known to produce several complement proteins. The amount of complement components in the culture supernatant was evaluated by a sensitive enzyme-linked immunosorbent assay revealing picogram levels of these proteins. The HepG2 cells were found to secrete a substantial amount of C3 (approximately 1 microgram/10(6) cells), easily detectable C5 (approximately 150 ng/10(6) cells) and C8 (approximately 10 ng/10(6) cells) and a low amount of C6 (approximately 0.5 ng/10(6) cells), whereas the levels of both C7 and C9 could not be measured. The addition of interleukin-1, tumor necrosis factor and interleukin-6 to the cell culture resulted in an enhanced secretion of C8, whereas that of C5 was only marginally increased. None of these cytokines had a clear effect on the secretion of C6 nor induced the production of C7 and C9.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Hepatocellular↗
PubMed1987

Human C3b/C4b receptor (CR1). Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristics of C3/C4 binding proteins.

10 overlapping CR1 cDNA clones that span 5.5 kb were isolated from a tonsillar library and sequenced in whole or in part. A single long open reading frame beginning at the 5' end of the clones and extending 4.7 kb downstream to a stop codon was identified. This sequence represents approximately 80% of the estimated 6 kb of coding sequence for the F allotype of CR1. Three tandem, direct, long homologous repeats (LHRs) of 450 amino acids were identified. Analysis of the sequences of tryptic peptides provided evidence for a fourth LHR in the F allotype of CR1. Amino acid identity between the LHRs ranged from 70% between the first and third repeats to 99% between the NH2-terminal 250 amino acids of the first and second repeats. Each LHR comprises seven short consensus repeats (SCRs) of 60-70 amino acids that resemble the SCRs of other C3/C4 binding proteins, such as complement receptor type 2, factors B and H, C4 binding protein, and C2. Two additional SCRs join the LHRs to a single membrane-spanning domain of 25 amino acids; thus, the F allotype of CR1 probably contains at least 30 SCRs, 23 of which have been sequenced. Each SCR is predicted to form a triple loop structure in which the four conserved half-cystines form disulfide linkages. The linear alignment of 30 SCRs as a semi-rigid structure would extend 1,140A from the plasma membrane and might facilitate the interaction of CR1 with C3b and C4b located within the interstices of immune complexes and microbial cell walls. The COOH-terminal cytoplasmic domain of 43 residues contains a six-amino-acid sequence that is homologous to the sequence in the epidermal growth factor receptor that is phosphorylated by protein kinase C.

Amino Acid Sequence↗
PubMed2005

Oxiagin from the Naja oxiana cobra venom is the first reprolysin inhibiting the classical pathway of complement.

A basic glycoprotein oxiagin with molecular mass of 49.8 kDa was isolated from the venom of Central Asian cobra Naja oxiana. Partial amino acid sequence determination has shown that oxiagin belongs to reprolysins, a subfamily of animal metalloproteinases possessing a characteristic multidomain structure. Oxiagin was found to inhibit the classical pathway of the complement system. A study of the oxiagin influence on the different stages of the classical pathway showed that it inhibited the formation of C3-convertase. To achieve it, oxiagin binds to IgG on the surface of sheep erythrocytes sensitized with rabbit antibodies, thus, preventing the interaction of component C2 (without its inactivation) with immobilized C4b. IC50 for the inhibiton of classical pathway of complement system by oxiagin is 80 nM, while it does not affect the alternative pathway at concentrations up to 1.2 microM. Oxiagin possessed hemagglutinating activity towards sheep and rabbit erythrocytes, and this activity as well as the complement inhibition by oxiagin were suppressed by D-galactose. Oxiagin is the first representative of snake venom reprolysins that inhibits the complement system, utilizing non-proteolytic inhibiting strategy.

Amino Acid Sequence↗
PubMed1986

In vitro inhibition of the classical pathway of human complement by a natural microbial product, colistin sulphate.

Colistin sulphate was found to be an inhibitor of the classical pathway of the complement system. The main sites of inhibition were the interaction of EAC14 with C2 and EAC142 with C3. It also inhibited EAC14 formation from EA and C2-deficient serum, EAC1-7 formation from EAC1-3, C5, C6 and C7 and the interaction of EAC1-7 with C8 and C9, though less efficiently. It did not inhibit formation of C3/C5 convertase of the alternative pathway. The inhibition of the classical pathway was reversible since hemolytic activity was completely restored after dialysis.

Animals↗
PubMed1986

Complement in the pathophysiology and diagnosis of human diseases.

Complement is a humoral effector system composed of 21 plasma proteins that was identified initially because of its cytolytic effects. In addition to cytolysis, complement has a number of different functions related to inflammatory and other host defense processes. The description of the reaction mechanism includes: (1) activation of the classical pathway through recognition of IgG and IgM antibodies by C1q, (2) activation of the alternative pathway which is usually achieved without participation of immunoglobulins, (3) generation of proteolytic enzymes composed of heteropolymers that cleave certain precursor proteins, (4) formation of the membrane attack complex (MAC), and (5) participation of control mechanisms. Methodologies for studying protein concentration and functional activities of complement components include not only the classical hemolytic techniques but also the extremely sensitive new radioimmunoassays and enzyme immunoassays for measuring the products of complement activation that are generated in vivo. Examples of genetically controlled complement deficiencies have been published for most complement components. The symptomatology of some of these patients serves to emphasize the protective role of complement. Acquired deficiencies are significant not only as laboratory aids in diagnosis and to evaluate the course of certain diseases, but also to indicate possible pathogenic disease mechanisms. Recently, it has been recognized that the complement proteins with genes located in the HLA region are polymorphic. Certain variants of proteins C2, C4, and factor B occur with higher frequencies in certain diseases than in the general population, which appears to be of great practical importance in laboratory medicine.

Bacterial Infections↗
PubMed1993

Complement polymorphism in herpes gestationis: association with C4 null allele.

BACKGROUND: Herpes gestationis (HG) is a rare, pregnancy-related skin disease characterized by the production of an autoantibody to a component of the hemidesmosome. It is associated with the class II antigens HLA-DR3 and HLA-DR4, but its potential association with the "class III antigens" C2, C4, and factor B has not previously been studied. OBJECTIVE: Our purpose was to study complement polymorphism in HG. METHODS: Using electrophoresis and immunofixation techniques, we determined the allele frequencies of C4A, C4B, C3, and factor B in 42 patients with a history of HG. RESULTS: Ninety percent of patients carried a C4 null allele (C4*QO). No statistically significant association with C3 or factor B alleles was seen. CONCLUSION: HG is associated with the presence of a C4*QO. Whether the C4*QO is the primary genetic association, or whether the C4*QO is related to its linkage disequilibrium with DR3 and DR4 has yet to be determined.

Adult↗
PubMed1998

Human heart generates complement proteins that are upregulated and activated after myocardial infarction.

In human heart, we detected mRNAs and proteins for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 with the use of reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical techniques. We found an upregulation of both mRNAs and proteins in areas of recent and old myocardial infarctions. In both situations, the classical complement pathway was activated, with C4d, C3d, and the membrane attack complex (C5b-9) being deposited on damaged cardiac myocytes. These activated complement components were also identified on Western blots of infarcted tissue. Complement mRNAs in infarcted heart tissue were higher than those in liver, and liver complement mRNAs were not upregulated in cases with infarcted hearts. Our results establish that (1) complement proteins are endogenously produced by human heart; (2) the classical complement pathway is fully activated after myocardial infarction; (3) complement activation is directly involved in myocardial damage after ischemic insults; and (4) damage from complement activation may be chronically sustained. These data suggest that inhibition of the complement system should be effective in treating myocardial infarction.

Adult↗
PubMed2000

Molecular cloning and linkage analysis of complement C3 and C4 genes of the Japanese medaka fish.

The thioester-containing complement components, C3 and C4, are believed to have arisen by gene duplication from a common ancestor, and the mammalian C4 gene resides in the vicinity of the C2 and B genes within the major histocompatibility complex (MHC) class III region. To analyze the evolution of both the complement system and the MHC, we determined the complete primary structures of two C3 genes, termed Orla C3-1 and Orla C3-2, and one C4 gene, termed Orla C4, of a teleost, Japanese medaka fish (Oryzias latipes), by analyzing cDNA clones isolated from a liver library constructed using the inbred AA2 strain. The deduced basic structures of Orla C3-1, C3-2, and C4, such as the subunit chain structure, the thioester site, and the proteolytic activation site, are similar to their mammalian counterparts. However, the catalytic His residue which greatly increases the rate of thioester reaction, is replaced by Ala in Orla C3-2, implying functional differentiation between two C3 molecules. Mapping analysis revealed a close linkage between the C3-1 and C3-2 genes, indicating that they arose by a local duplication rather than by a genome-wide tetraploidization. The C4 gene belongs to a different linkage group, and no linkage was observed among the C3, C4, Bf/C2, MHC class I, and MHC class II loci. These results suggest that the MHC class III complement region was established in the tetrapod lineage, or lost in the teleost lineage.

Amino Acid Sequence↗
PubMed2005

Crystal structure of the RIM2 C2A-domain at 1.4 A resolution.

RIMs are large proteins that contain two C2-domains and are localized at presynaptic active zones, where neurotransmitters are released. RIMs play key roles in synaptic vesicle priming and regulation of presynaptic plasticity. A mutation in the RIM1 C2A-domain has been implicated in autosomal dominant cone-rod dystrophy (CORD7). The RIM C2A-domain does not contain the full complement of aspartate residues that commonly mediate Ca2+ binding at the top loops of C2-domains, and has been reported to interact with SNAP-25 and synaptotagmin 1, two proteins from the Ca2+-dependent membrane fusion machinery. Here we have used NMR spectroscopy and X-ray crystallography to analyze the structure and biochemical properties of the RIM2 C2A-domain, which is closely related to the RIM1 C2A-domain. We find that the RIM2 C2A-domain does not bind Ca2+. Moreover, little binding of the RIM2 C2A-domain to SNAP-25 and to the C2-domains of synaptotagmin 1 was detected by NMR experiments, suggesting that as yet unidentified interactions of the RIM C2A-domain mediate its function. The crystal structure of the RIM2 C2A-domain using data to 1.4 A resolution reveals a beta-sandwich that resembles those observed for other C2-domains, but exhibits a unique dipolar distribution of electrostatic charges whereby one edge of the beta-sandwich is highly positive and the other edge is highly negative. The location of the mutation site implicated in CORD7 at the bottom of the domain and the pattern of sequence conservation suggest that, in contrast to most C2-domains, the RIM C2A-domains may function through Ca2+-independent interactions involving their bottom face.

Amino Acid Sequence↗
PubMed1993

Isolation of avirulent clones of Candida albicans with reduced ability to recognize the CR2 ligand C3d.

Four clones of the yeast Candida albicans, isolated on the basis of their tolerance to clotrimazole, were compared with their parental strains in terms of growth, morphology, virulence, and cell surface complement receptor activity. In a newly described synthetic medium, these clones, designated C1, C2, N, and P, produced germ tubes or pseudohyphae, but no true hyphae, in a pattern which was specific for each strain. The growth of each clone at 37 degrees C, under conditions which favor the filamentous growth form of the organism, was equal to that of the parental strain (H12). The pathogenicity of each clone was tested in an intravenous mouse model. None of the mice infected with the tolerant clones but all of the mice infected with H12 developed severe renal candidiasis after infection with 1.4 x 10(6) to 2.0 x 10(6) CFU/ml. The number of CFU of each clone from the mouse kidney was reduced about 3 or 4 orders of magnitude in comparison with the wild type. As a correlate, we measured the complement receptor activity (CR2 and CR3) of each clone. The C3 ligands, iC3b and C3d, were conjugated to sheep erythrocytes (E) sensitized with antibody (A) to the erythrocytes (EA). We found that all tolerant clones showed reduced recognition of C3d-bearing sheep erythrocytes (EAC3d) in rosetting assays. Clone P showed more than an 80% reduction in rosetting of EAC3d in comparison with H12 cells. In contrast, recognition of iC3b (EAiC3b) by each of the clones was similar to that by H12 cells. When dithiothreitol extracts of clone P and H12 were compared by immunoblot, both quantitative and qualitative differences in reactivities were observed with antibodies specific for the Candida C3d receptor and with antiserum from a patient with chronic mucocutaneous candidiasis.

Animals↗