Function of the activated fourth component of complement (C4b) in activation of C2.
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Complement Activating Enzymes↗
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Human immunodeficiency virus type 1 induces expression of complement factors in human astrocytes.
Since the brain is separated from the blood immune system by a tight barrier, the brain-resident complement system may represent a central player in the immune defense of this compartment against human immunodeficiency virus (HIV). Chronic complement activation, however, may participate in HIV-associated neurodegeneration. Since the level of complement factors in the cerebrospinal fluid is known to be elevated in AIDS-associated neurological disorders, we evaluated the effect of HIV type 1 (HIV-1) on the complement synthesis of brain astrocytes. Incubation of different astrocytic cell lines and primary astrocytes with HIV-1 induced a marked upregulation of the expression of the complement factors C2 and C3. The synthesis of other secreted or membrane-bound complement proteins was not found to be altered. The enhancement of C3 production was measured both on the mRNA level and as secreted protein in the culture supernatants. HIV-1 laboratory strains as well as primary isolates were capable of inducing C3 production with varied effectiveness. The usage of viral coreceptors by HIV-1 was proved to be a prerequisite for the upregulation of C3 synthesis, which was modulated by the simultaneous addition of cytokines. The C3 protein which is secreted after incubation of the cells with HIV was shown to be biologically active as it can participate in the complement cascade.
Antibodies↗
[Consumption hypocomplementemia: comparative value of haemolytic and protein estimations of the components of the classical pathway (author's transl)].
Titrations of total complement (CH50) and of the different components of the classical pathway of the complement system in patients with supposed consumption hypocomplementemia, show that the complement depression involves in an order of decreasing severity hemolytic C4, hemolytic C2, total complement, hemolytic C1, protein C4 and protein C3. These results as well as correlative studies between these different parameters suggest that C4 is the most specific target of activited C1 esterase (C1s). They stress the interest of hemolytic titrations as well as the strong limitations of protein titrations.
Adolescent↗
Mode of interaction of different polyanions with the first (C1, C1), the second (C2) and the fourth (C4) component of complement--II. Effect of polyanions on the binding of C2 to EAC4b.
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Animals↗
Dual effects of TNF on synthesis of complement components by a gastric cancer-derived cell line, KATO-III.
BACKGROUND: Complement components are synthesized extrahepatically, although hepatocytes are the major source of plasma complement. It is now clear that local production of complement is important in homeostasis and immune defense in tissue. METHODS: The secretion of complement components was studied in vitro with a gastric cancer-derived cell line, KATO-III (signet-ring cell carcinoma). Complement components C2 and C3 were estimated by functional assay and/or ELISA in culture medium obtained after incubation of KATO-III cells for 3 days in protein-free culture medium, with or without addition of tumor necrosis factor (TNF), in a humidified atmosphere of 5% CO2/95% air at 37 degrees C. RESULTS: (1) While a higher amount of C3 was detected in medium when KATO-III cells were cultured in the presence of TNF than in medium lacking TNF, higher C2 activity was detected when cultured in medium lacking TNF than in TNF-supplemented medium. (2) TNF suppressed C2 secretion and enhanced C3 secretion in a dose-dependent fashion. (3) C3 secretion remained less than 20 ng/10(6) cells/24 h but increased from the first day of TNF (10U/ml) addition (concentrations approached 108.6- 115.6 ng/10(6) cells/24 h on the 3rd day) and decreased on the 1st day without TNF. In contrast, C2 activity, detected when cultured in the absence of TNF, was decreased on the 2nd day of TNF addition and increased again on the 1st day without TNF. The daily secretion of C2 in the absence of TNF was 3.75-6.30x10(7) effective molecules/10(6) cells. (4) Reversible inhibition of C2 and C3 secretion was observed when the cell line was cultured in the presence of cycloheximide, indicating that both components were synthesized de novo. CONCLUSION: It appears that TNF enhances C3 secretion and suppresses C2 secretion by KATO-III.
Complement Activation↗
Modulation of lymphocyte proliferative responses to mitogens and antigens by complement components C1, C4 and C2.
Recent data have shown a definite relationship between complement and lymphocytes. Genetic studies have demonstrated close linkage between the genes controlling synthesis of complement components C4 and C2 and the major histocompatibility complex. Working in a complement-free environment, we studied the effect of purified human complement components, individually and in various combinations, upon in vitro proliferative responses of human lymphocytes to mitogens and antigens. It was found that the early complement components C1, C4 and C2, together, modulate lymphocyte responses to these various stimuli. In general, doses up to 1,000 effective molecules of each component per lymphocyte enhanced the cells' responses to both mitogens and antigens. Higher doses, up to 3,000 effective molecules of each per lymphocyte, progressively inhibited the cells' responses to the mitogens whereas responses to the antigens showed continued enhancement. This effect was removed by prior heat-inactivation of the complement. It persisted when the cells were exposed to C1, C4 and C2 for 1 hr, then washed and cultured with mitogen. It required active C1 in the fluid-phase prior to addition of C4 and C2. It correlated with the amount of activated C2 to which the cells were exposed. Enriched populations of T and B cells were affected equally.
Antigens↗
Structure of the gene for cartilage matrix protein, a modular protein of the extracellular matrix. Exon/intron organization, unusual splice sites, and relation to alpha chains of beta 2 integrins, von Willebrand factor, complement factors B and C2, and epidermal growth factor.
The entire gene for chicken cartilage matrix protein (CMP) has been isolated and characterized by restriction mapping, electron microscopy, nuclease S1 mapping, and sequence analysis. The gene, which is present in a single copy in the chicken genome, is 18 kilobase pairs long and comprises eight exons and seven introns. It has two transcription initiation sites, 8 base pairs from each other. A sequence very homologous to the consensus nuclear factor III binding-site sequence, a CAT- and a TATA-like sequence are found in the promoter region and ATTAAA is used as a polyadenylation signal. The nucleotide sequence defines a primary translation product of 493 amino acids which consists of a 23-amino acid signal peptide and two large repeated domains connected by an epidermal growth factor module. Amino acid sequences homologous to those of the repeated domains are present in the type A repeats of von Willebrand factor, complement factors B and C2, and in the alpha chains of the integrins Mac-1, p150,95, and LFA-1. The exon-intron structure indicates that the CMP gene may have arisen by exon duplication and exon shuffling during evolution. The GT-AG splice rule cannot be applied for the excision of the last intron of the CMP pre-mRNA. The donor splice site of intron G is basically different from the consensus sequence indicating that a novel type of splicing mechanism might exist in cartilage.
Amino Acid Sequence↗
Staphylococcus aureus opsonization mediated via the classical and alternative complement pathways. A kinetic study using MgEGTA chelated serum and human sera deficient in IgG and complement factors C1s and C2.
Staphylococcus aureus opsonization was studied kinetically by: (1) determination of the uptake of [3H]-thymidine labelled bacteria by human PMN's; (2) fluorescent anti-C3 and anti-IgG staining of opsonized bacteria; and (3) measuring bacterial complement consumption. Maximum opsonization in normal serum occurred within 5 min of incubation. About 80% of staphylococci were then taken up by PMN's, and IgG and C3b could be detected on the bacterial surface. In the absence of a functional classical complement pathway, as in sera deficient in C1s and C2 and in MgEGTA chelated serum, maximal opsonization was only achieved after 30--60 min incubation. Opsonization in IgG deficient serum occurred at a rate similar to that found in C2 deficient or MgEGTA chelated serum. Opsonization was greatly enhanced when sera were reconstituted. It was concluded that in IgG deficient serum Staphylococcus aureus opsonization is mediated via the alternative complement pathway. Dilution of normal serum primarily affected the classical complement pathway, resulting in a decreased rate of opsonization. In normal serum IgG did not appear to be a rate-limiting factor. S. Aureus opsonization was best studied by the phagocytosis assay and the fluorescent-antibody technique. Measuring haemolytic complement consumption was found to be an insensitive indicator of bacterial complement activation and opsonization.
Complement Activation↗
[Direct reaction between complement system and cell nuclei (author's transl)].
A direct in vitro reaction between complement system and cell nuclei of human leucocytes and of cryostat sections of rat liver or kidney, has been demonstrated by an indirect immunofluorescence technique. The first step of this reaction involves a fixation of C1q to the nuclear DNA as shown by the peripheral distribution of the fluorescence and by the extinction of the fluorescence when the tissue-slices are pretreated by DNase but not by RNase or trypsin. This fixation gives rise to an activation of C1 which can be demonstrated by the capacity of the fixed C1 to induce a fixation of C4 of the same distribution. Although the sequential fixation experiments have not allowed to establish directly the fixation of the following components of the complement system (C2 and C3), the positive results obtained using whole fresh normal human serum as a source of complement and a fluorescent anti-human C3 serum clearly indicate that the activation of the classical pathway by whole cells DNA can go as far as the C3 step. All these results were obtained at physiological pH and molarity: this can suggest a physiopathological meaning for this reaction.
Animals↗
C2 and factor B: structure and genetics.
Complement components C2 and factor B are novel types of serine protease that are encoded by single loci in the major histocompatibility complex on human chromosome 6. The two proteins share 39% homology, or 50% taking into account conservative amino acid replacements. The catalytic chains, C2a (509 residues) and Bb (505 residues) show homology in their C-terminal domains to the catalytic polypeptides of other serine proteases. The non-catalytic chains, C2b (223 residues) and Ba (234 residues) both contain three tandem repeats of approx. 60 amino acids each, which are homologous to the repeats in C4b-binding protein and factor H, and also the repeats in the non-complement protein beta 2-glycoprotein I. Molecular mapping and DNA sequence analysis has shown that the factor B gene is 6 kb in length and contains 18 exons, while the C2 gene is 18 kb in length; 425 bp separates the 3' end of the C2 gene from the 5' end of the factor B gene. C2 and factor B are polymorphic and structural variants have been detected at the protein level by differences in charge. The degree of polymorphism at the factor B locus has been defined by DNA sequence analysis of the two common alleles F and S. In addition restriction fragment length polymorphisms have been detected in the C2 gene. These DNA polymorphisms subdivide the common allelic variant of C2 (C2C) and reveal that there is much greater variability at the C2 locus than that detected by protein typing.
Alleles↗
Two mechanisms for mannose-binding protein modulation of the activity of its associated serine proteases.
Serum mannose-binding protein (MBP) neutralizes invading microorganisms by binding to cell surface carbohydrates and activating MBP-associated serine proteases-1, -2, and -3 (MASPs). MASP-2 subsequently cleaves complement components C2 and C4 to activate the complement cascade. To analyze the mechanisms of activation and substrate recognition by MASP-2, zymogen and activated forms have been produced, and MBP.MASP-2 complexes have been created. These preparations have been used to show that MBP modulates MASP-2 activity in two ways. First, MBP stimulates MASP-2 autoactivation by increasing the rate of autocatalysis when MBP.MASP-2 complexes bind to a glycan-coated surface. Second, MBP occludes accessory C4-binding sites on MASP-2 until activation occurs. Once these sites become exposed, MASP-2 binds to C4 while separate structural changes create a functional catalytic site able to cleave C4. Only activated MASP-2 binds to C2, suggesting that this substrate interacts only near the catalytic site and not at accessory sites. MASP-1 cleaves C2 almost as efficiently as MASP-2 does, but it does not cleave C4. Thus MASP-1 probably enhances complement activation triggered by MBP.MASP-2 complexes, but it cannot initiate activation itself.
Amino Acid Sequence↗
The polymorphism of the complement genes in HLA.
Genes coding for the complement proteins C2, C4A, C4B and factor B lie between HLA-D and HLA-B in HLA, the major histocompatibility complex in man. All the complement components are polymorphic, particularly C4, which has many alleles at each locus. The genetic complexity of C4 extends to the number of loci each of which may be deleted or duplicated on the chromosome. The different forms of C4 showed markedly different reactivities with small molecules and on haemolytic activity in the complement system. Surprisingly, amino acid sequences of the several allelic forms of C4 appear to be very similar, with less than 1% of residue positions being changed between alleles of C4A and C4B. These results may be relevant to the increased susceptibility to autoimmune disease which is associated with particular haplotypes of the HLA complex.
Amino Acid Sequence↗
Protein Malnutrition and complement activity in guinea pigs, germ-free and conventional rats.
Malnutrition produces a pronounced effect on the complement system of man and animals. There is little information, however, to indicate whether individual complement components are affected at different stages of age. In the following studies, we have demonstrated that in guinea pigs and in both conventional and germ-free rats, protein malnutrition adversely affects the complement system. The levels of complement components C2 and C3 are suppressed by protein malnutrition at an early stage while C4 and C8 are less affected by malnutrition. Experiments in germ-free animals demonstrated that decreased complement component levels can be directly associated with decreased synthesis and/or secretion of components. In conventional animals, further reductions in complement levels could occur as a result of infection associated with malnutrition.
Animals↗
A complement factor B-like cDNA clone from the zebrafish (Brachydanio rerio).
An important molecule in the activation of the complement system in vertebrates is factor B, a serine protease with a molecular mass of 95,000. Factor B and the complement component C2 are thought to have arisen by gene duplication. In mammals and in Xenopus the factor B gene is linked to the major histocompatibility complex (MHC), whereas in domestic fowl it segregates independently of the MHC. Here we describe the isolation of a cDNA clone coding for factor B in the zebrafish, Brachydanio rerio. The deduced protein sequence exhibits a characteristic mosaic structure consisting of the short consensus repeat (SCR), the von Willebrand factor, and the serine protease domains. The estimated time of factor B and C2 divergence (approximately 350 million years ago), combined with the fact that C2 has thus far been found only in mammals, suggest that the factor B-C2 gene duplication occurred after the divergence of mammal-like reptiles from other reptiles and hence also birds. After the duplication, the C2 component evolved significantly faster than factor B.
Amino Acid Sequence↗
C1s-induced vascular permeability in C2-deficient guinea pigs.
Normal guinea pigs that have been intradermally injected with C1s exhibit increased vascular permeability at the injection site. Guinea pigs that are genetically deficient in complement component C2 do not exhibit increased vascular permeability when given a similar injection. The C2-deficient guinea pigs respond normally to injections of bradykinin and kallikrein, suggesting that these animals can respond to kinins and have a normal kininogen pathway. When the C2-deficient guinea pigs are given guinea pig C2 before C1s injection, increased vascular permeability is observed. These results demonstrate a definite requirement for complement component C2 in the generation of C1s-induced vascular permeability.
Angioedema↗
Inhibition of human complement by beta-glycyrrhetinic acid.
Licorice, the root extract of Glycyrrhiza glabra I., is used as a medicine for various diseases. Anti-inflammatory as well as anti-allergic activities have been attributed to one of its main constituents, glycyrrhizin. These activities are mainly ascribed to the action of the aglycone, beta-glycyrrhetinic acid. beta-Glycyrrhetinic acid has a steroid-like structure and is believed to have immunomodulatory properties. To determine whether interference with complement functions may contribute to the immunomodulatory activity of beta-glycyrrhetinic acid, its effects on the classical and alternative activation pathways of human complement were investigated. We found that beta-glycyrrhetinic acid is a potent inhibitor of the classical complement pathway (IC50 = 35 microM), whereas no inhibitory activity was observed towards the alternative pathway (IC50 > 2500 microM). The anticomplementary activity of beta-glycyrrhetinic acid was dependent on its conformation, since the alpha-form was not active. It was also established that naturally occurring steroids, e.g. hydrocortisone and cortisone, did not inhibit human complement activity under similar conditions. Detailed mechanistic studies revealed that beta-glycyrrhetinic acid acts at the level of complement component C2.
Administration, Topical↗
Lack of association between the HLA-A10 (A25), B18 and C2o haplotype and anaphylactoid purpura (AP).
In 41 patients with AP and 134 healthy relatives HLA haplotypes and total hemolytic complement and C2 concentrations were determined. Though complement levels were found in the lower normal range in none of the individuals studied, a genetically determined C2 deficient state could be established. No association between low C2 levels and the HLA haplotype A10(A25), B18 or an isolated A25 or B18 was observed. A comparison of phenotype frequencies of AP patients with controls showed no significant difference. Contingency table analysis of patients and control haplotypes showed a definite close association with HLA-A1, Bw22, A2, Bw16, and A29, B12.
Adolescent↗