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PubMed1994

Complement C3 deficiency: human, animal, and experimental models.

The third complement component (C3) is a multifunctional glycoprotein that interacts with numerous serum proteins, cell surface receptors, and membrane-associated regulatory proteins. Deficiencies of C3 have been reported in several human kindred of different ethnic backgrounds and from different geographic regions. In addition, inherited C3 deficiency has been discovered in certain strains of guinea pigs, dogs, and rabbits, and has been experimentally induced in animals by injections of cobra venom factor. Studies of the C3-deficient humans and animals have demonstrated the important roles performed by C3 in the immune response, opsonization and phagocytosis of pathogens, and immune complex solubilization. Current knowledge of the molecular and cellular basis of complement C3 deficiency indicates that C3 deficiency is caused by numerous molecular genetic mutations that include splicing defects, a partial gene deletion, and a critical amino acid substitution. With the advent of gene ablation technology, C3-deficient murine models can now be established, making it possible to examine the role that C3 plays in the molecular pathogenesis of many different diseases.

Animals↗
PubMed1995

Immunoglobulin G and complement C3 levels in pregnancy induced hypertension.

The immunoglobulin G (IgG) and complement C3 (C3) were measured in the maternal as well cord blood sera of 30 cases of pregnancy induced hypertension (PIH) as well as 9 controls with normotensive pregnancy. A depression of IgG as well as C3 level was observed in the maternal as well as cord sera of the mothers with PIH. These findings suggest decreased immunological status of both mother and her offspring in PIH, irrespective of the gestation and intrauterine growth status.

Complement C3↗
PubMed1993

Studies on the structure of complement C3 and the stability of C3 derived phagocytic ligands C3b/iC3b in SJL/J and BALB/c mice.

Female SJL/J mice are more susceptible to development of experimental autoimmune myositis than most other mouse strains. Since complement has been implicated in the pathogenesis of inflammatory muscle disease in humans, quantitative and qualitative studies of complement C3 were undertaken in SJL/J and BALB/c mice to determine whether complement may influence disease susceptibility in SJL/J mice. In accordance with previous studies, mature male and female BALB/c mice were shown to have similar serum C3 concentrations. However, differences were found between mature male and female SJL/J mice. Male SJL/J mice have significantly higher serum C3 concentrations than SJL/J females and both sexes of BALB/c mice suggesting that serum C3 concentration may be variably influenced by sex in some mouse strains. Qualitatively, SJL/J mice were shown to have a different allotypic form of C3 (C3F) compared to the common electrophoretically slow form (C3S) found in BALB/c mice and most other mouse strains. Furthermore, studies on the decay rate of C3 revealed that C3b/iC3b fragments are converted to C3c/d at a faster rate in sera from female SJL/J mice compared to female BALB/c mice. Because removal and solubility of immune complexes is influenced by complement C3, it is possible that the more rapid decay of the phagocytic ligands C3b/iC3b may account for the increased susceptibility to development of autoimmune disease in female SJL/J mice.

Animals↗
PubMedDate not supplied

Effect of steroids on the synthesis of complement C3 in a human alveolar epithelial cell line.

The third component of complement, C3, is produced in the lung by several cell types, including alveolar epithelial cells. Steroid hormones are important in gene regulation in alveolar epithelial cells. The effects of steroids on C3 production were examined using A549 human pulmonary alveolar epithelial cells. Treatment of A549 cells with the glucocorticoids dexamethasone, hydrocortisone, corticosterone, and 11-deoxycortisol increased C3 production, as measured by ELISA. The glucocorticoid receptor antagonist RU486 inhibited C3 synthesis by dexamethasone- and hydrocortisone-stimulated cells. Because the glucocorticoid receptor is a member of a superfamily of receptors, the effects of steroid members of the superfamily on C3 production were examined. The mineralocorticoid, aldosterone, increased C3 production. RU486 completely inhibited aldosterone's stimulatory effects on C3 production, whereas the mineralocorticoid receptor antagonist spironolactone partially inhibited aldosterone's effects. In contrast, testosterone, progesterone 17 alpha-hydroxyprogesterone, and estradiol did not alter C3 production by A549 cells. Northern analysis showed that C3 mRNA abundance in A549 cells increased following stimulation with dexamethasone, hydrocortisone, corticosterone, and aldosterone. Testosterone, progesterone, 17 alpha-hydroxyprogesterone, and estradiol did not alter C3 mRNA levels. Therefore, among the steroids tested, only glucocorticoids and aldosterone altered C3 production by A549 cells suggesting that these steroids may play a role in the regulation of C3 in the lung.

Aldosterone↗
PubMed1990

Molecular basis of complement C3 deficiency in guinea pigs.

In experiments to ascertain the biochemical basis of a genetically determined deficiency of the third component of complement (C3) in guinea pigs, we found that C3-deficient liver and peritoneal macrophages contain C3 messenger RNA of normal size (approximately 5 kb) and amounts, that this mRNA programs synthesis of pro-C3 in oocytes primed with liver RNA and in primary macrophage cultures. In each instance, heterodimeric native C3 protein was secreted with normal kinetics but the C3 protein product of the deficient cells failed to undergo autolytic cleavage and was unusually susceptible to proteolysis. These data and a selective failure of C3 in plasma of deficient animals to incorporate [14C]methylamine suggested either a mutation in primary structure of the C3 protein or a selective defect in co- or postsynthetic processing affecting the thiolester bridge, a structure important for C3 function. A mutation in the primary structure of C3 was ruled out by comparison of direct sequence analysis of C3 cDNA generated from two C3 deficient and two C3 sufficient guinea pig liver libraries. Three base pair differences, none resulting in derived amino acid sequence differences were identified. Finally, restriction fragment length polymorphisms were identified in the C3 gene that are independent of the deficiency phenotype. This marker of the C3 gene permits testing of these hypotheses using molecular biological and classical genetic methods.

Amino Acid Sequence↗
PubMed1996

Regulation of complement C3 synthesis by interleukin-1 and transforming growth factor-beta in rat non-transformed intestinal epithelial cell line, IEC-6.

Intestinal epithelial cells are an important source of many biologically active molecules that modulate immune responses in the mucosa. The purpose of this study was to demonstrate the synthesis of complement C3 component in the rat non-transformed crypt-like intestinal epithelial cell line, IEC-6. Unstimulated IEC-6 cells secreted a low level of C3 protein and showed weak expression of C3 mRNA. The addition of interleukin (IL)-1 beta induced a dose- and time-dependent increase in C3 production. These effects of IL-1 beta were observed at a concentration as low as 0.01 ng/ml and reached a plateau at a concentration of 5 ng/ml. The effects were observed at the mRNA level as early as 6 h after the beginning of incubation. Transforming growth factor (TGF)-beta alone had no effect. However, TGF-beta at low concentrations (0.001-1 ng/ml) enhanced the effect of IL-1 beta in increasing C3 production; this enhancement was not observed at high concentrations (5-10 ng/ml). These effects of TGF-beta were also observed at the mRNA level. The present findings indicate that intestinal epithelial cells are indeed capable of synthesizing complement C3 in response to IL-1 beta and TGF-beta.

Animals↗
PubMed1993

Immunoglobulins IgG, IgA, IgM, complement C3, C4 and ferritin and transferrin levels in serum and follicular fluid in IVF patients.

Serum and follicular fluid immunoglobulin (IgG, IgA, IgM) and complement (C3, C4), as well as transferrin and ferritin concentrations were measured in 82 consecutive IVF patients (Pregnant: Group A, and non pregnant: Group B). Higher serum concentrations were observed in complement in all Immunoglobulins but IgM which was found to be significantly lower in follicular fluid in both groups. Also there were no statistically significant differences observed for transferrin and ferritin levels in either compartment or among the groups. No correlation was found for the above parameters and the in vitro fertilization outcome in terms of oocytes retrieved, fertilized and embryos implanted.

Adult↗
PubMed1995

Isolation of the C3 complement component and its C3d subunit from IY-1 fraction of Cohn's fractionation of human plasma.

C3 complement component and its C3d subunit were isolated from the IY-1 Cohn's fraction, which is the waste of industrially produced albumin and immunoglobulins. The first step was the fractionation of precipitate IY-1 by polyethylene glycol (PEG) 4000 to a final concentration of 16% PEG. The precipitate formed was separated by centrifugation. The supernatant contained the C3d subunit of C3, and the redissolved 16% PEG precipitate contained the C3 component. Then the supernatant and the dissolved precipitate were subjected to anion-exchange chromatography on DEAE-Toyopearl 650 M. In the last step fractions containing C3 and C3d concentrated by ultrafiltration were chromatographed on Sephacryl S-200.

Blood Proteins↗
PubMed1990

Synthesis of the third component of complement (C3) by lectin-activated and HTLV-infected human T-cells.

The third component of complement (C3) plays key roles in complement activation of both the classical and alternative pathways. The liver is the major site of C3 synthesis; monocytes, B-lymphocytes and leukemic cell lines of the myeloid lineage also synthesize C3. Here we report that the C3 gene is inactive in fresh T-cells, but active in T-cells treated with the lectin phytohemagglutinin (PHA). Northern blot hybridization studies show that PHA-activated T-cells and all the T-cell lines tested express the 5.3 kb RNA transcript reported for C3 in HepG2, a hepatoma cell line, and monocytes. We used radioimmune precipitation followed by polyacrylamide gel electrophoresis to show that PHA-stimulated T-cells and T-cell lines, which are not infected with the human T-lymphotropic virus (HTLV), synthesize and release C3 proteins with molecular masses of 185, 115 and 80 kD; HTLV-infected T-cell lines release C3 proteins of 170, 115 and 70 kD. In contrast, monocytes produced C3 proteins of 115 and 70 kD similar to the serum form of this protein. The role of T-lymphocyte C3 and the implications of HTLV-infection are discussed.

Blotting, Northern↗
PubMed1983

Inhibition of phagocytosis of complement C3- or immunoglobulin G-coated particles and of C3bi binding by monoclonal antibodies to a monocyte-granulocyte membrane glycoprotein (Mol).

Events that lead to phagocytosis of complement (C3)- or IgG-coated particles after their interaction with specific cell surface receptors are poorly understood. Two mouse monoclonal antibodies (an IgM and an IgG2a) to a human granulocyte-monocyte surface membrane differentiation antigen (Mol) inhibited ingestion by granulocytes both of oil Red O particles opsonized with normal human serum or with IgG and of sheep erythrocytes sensitized with IgG. In addition, they specifically inhibited rosetting between phagocytes and sheep erythrocytes coated with C3bi, a fragment of the complement component C3, generated by cleaving C3b with C3b inactivator and beta IH protein. These monoclonal anti-Mol antibodies did not inhibit IgG Fc, C3b or C3d receptor-mediated binding of erythrocytes coated with the respective proteins. The Fab fragment of the IgG2a monoclonal antibody inhibited noncytotoxic enzyme release from granulocytes when these cells were stimulated with zymosan coated with C3bi. Electrophoretic transfer of polymorphonuclear leukocyte detergent lysates to nitrocellulose, followed by immunofixation with monoclonal antibody, showed that these antibodies were directed to a 155,000-mol wt glycoprotein. This surface membrane structure appears to be involved in Fc and C3 receptor-dependent phagocytosis and closely associated with the C3bi receptor.

Antibodies, Monoclonal↗
PubMed1985

Inhibition of cleavage of the third component of human complement (C3) by its small cleavage fragment, C3a: inhibition occurs with the classical-pathway, but not the alternative-pathway, C3 convertase.

Activation of the third component of complement (C), C3, is central to the functioning of the C system in inflammation. Cleavage of C3 by the C3 convertases of both the classical and alternative pathways results in the formation of two split products, C3b and C3a. C3a inhibited cleavage of C3 by the classical-pathway C3 convertase. The inhibition varied in a concn-dependent relationship, with a concn of approximately 40 micrograms/ml yielding 50% inhibition. Removal of the carboxy terminal arginine from the C3a did not alter the inhibition. C3a did not inhibit cleavage of C3 by the alternative C pathway C3 convertase, or cleavage of C5 by C5 convertase. The C3-cleaving capacity of EAC142oxy that had been previously incubated with C3a could be recovered completely by washing the cells, indicating that the C3a binding to the EAC42oxy cell must have been reversed without having had an effect on the amount of C2 bound. Ribonuclease, a molecule of similar size and charge to C3a, did not affect C3 cleavage and C3a inhibition was not reduced by providing a surface for non-specific adsorption of the C3a, suggesting that the effect of C3a on C3 cleavage was not mediated by non-specific interaction with cell surfaces. C3a inhibited the C3-cleaving capacity of the fluid-phase enzyme, C42oxy, to the same degree as it inhibited the cell-bound enzyme, EAC42oxy, indicating that the C3a must interact with the C42 complex directly. Inhibition of C3 cleavage by C3a is the first demonstration of product inhibition of a complement enzyme. It may provide another control of C3 activation.

Arginine↗
PubMed1990

[A comparative study of serum complement (C3 and C4) in inflammatory joint diseases].

The third and the fourth fraction of the complement (C3 and C4), haptoglobin, fibrinogen, alpha 1-glycoprotein, alpha 2-macroglobulin and transferrin were examined in 692 patients with inflammatory joint disease--rheumatism, rheumatoid arthritis, ankylosing spondylarthritis, psoriatic arthritis, Reiter's syndrome, sacroiliitis [correction of sacroileitis], reactive arthritis, gout, osteoarthrosis and nosologically undefined arthritis in active or nonactive phase and in 60 healthy controls. The complement fractions studied show an increase of various degree and importance in almost all groups of patients in both phases studied. The relations between the complement fractions and the other acute phase indices show significant correlations between them and the other acute phase indices. C3 and to a certain degree C4 could be added to the acute phase reacting indices. Their place in the downgrade scale is as follows: fibrinogen, haptoglobin, alpha 1-glycoprotein, C3, C4, alpha 2-macroglobulin, transferrin.

Acute-Phase Proteins↗
PubMed1989

Development of an enzyme-linked immunosorbent assay to detect IgG, IgM, and complement (C3) on canine erythrocytes.

An ELISA was used to detect IgG, IgM, and complement (C3) on the surface of canine erythrocytes. Erythrocytes were placed in wells of a microtitration plate and incubated with affinity purified, alkaline phosphatase-conjugated anti-canine IgG, IgM, or C3. Results of the ELISA were compared with the direct antiglobulin test (DAT) by preparing standard reference curves from canine blood type A erythrocytes that had been incubated with serial dilutions (1:2 to 1:8, 192) of canine anti-A serum. The ELISA detected increased erythrocyte-bound immunoglobulin and complement at two- to fourfold dilutions greater than those required for positive results with the DAT. The ELISA required small sample and reagent volumes and detected lower concentrations of immune components than did the DAT.

Animals↗
PubMed1987

The third component of complement (C3) bound to tumor target cells enhances their sensitivity to killing by activated macrophages.

The third component of complement (C3) bound to P815 tumor cells enhanced their susceptibility to killing by Corynebacterium parvum-activated murine macrophages (M phi). Hemolytically active normal mouse serum and C5-deficient mouse serum were used to deposit complement (C) on P815 tumor cells, in the absence of exogenous antibody, by an alternative pathway mechanism. Cell-bound C3 was detected and was quantified by using a cellular enzyme-linked immunospecific assay. Activated M phi produced tumor cytolysis in a serum-free 16-hr 51Cr-release assay. The lysis of C-treated tumor cells was increased over targets treated with sera containing 10 mM EDTA, heat-inactivated mouse sera, or medium. In addition, C alone did not cause specific 51Cr release. M phi elicited by casein or PBS did not lyse any of the tumor targets tested. The increase in lysis was dependent on the dilution of serum used, and was strongly correlated with the amount of C3 detected on the tumor cells. The enhanced lysis was abrogated by incubating C3-bearing tumor cells with F(ab')2 fragments of a goat anti-mouse C3 antibody. C treatment did not alter the kinetics of tumor cell lysis, nor did it enhance the binding of the targets to effector cells. These results suggest that C may regulate M phi-mediated killing of tumor cells by increasing the lytic efficiency of M phi that are in contact with target-bound C3.

Animals↗
PubMed1992

[Complement (C3 and C4) in patients with rheumatoid arthritis during 6 months of treatment with gold salts].

The aim of research was to establish effect of gold-salts under protected name "Tauredon" Byk Gulden, on the dynamics of fraction of complements C3 and C4 at patients with rheumatoid arthritis. Following the dynamics of both parameters, was performed during 6 months continued application of "Tauredon", on 8 men and 35 women with certain diagnosis. Profile of the age of patients was 50 years old. With continuous observation of patients and their laboratory findings, in regular time intervals, we found out that "Tauredon" has significant influence on increase of level of C3 in serum of patients (P = 0.006) but not in increase of fraction of complement C4 (P = 0.117).

Adult↗
PubMed1980

Familial partial deficiency of the third component of complement (C3) and the hypocomplementemic cutaneous vasculitis syndrome.

Familial hypocomplementemia of the third component of complement (C3) was found in four members of a family. The prospositus had cutaneous vasculitis, hypocomplementemia, arthralgia, proteinuria and thrombocytopenia. The combination of clinical, laboratory and pathologic findings resembled the "hypocomplementemic cutaneous vasculitis syndrome" (HCVS) or the "SLE-like syndrome" but serum C3 concentration was 35 to 57 per cent of normal in the propositus and in three relatives. Results of Clq precipitins, cryoglobulins and serologic tests for systemic lupus erythematosus were negative. Proteinuria (815 mg/day) but no hematuria was present. Analysis of the C3 phenotypes in this family showed that three hypocomplementemic members were apparent homozygous C3 slow but one was heterozygous C3 fast-slow. Metabolic studies with 125-Iodinated C3 in the clinically normal mother showed a 50 per cent reduction in C3 synthesis which was consistent with hypocomplementemia documented by serum protein assay. The occurrence of an immune complex-like disease (with characteristics of the HCVS) in a patient with a familial deficiency of C3 suggests that the preexisting C3 deficiency may predispose such persons to certain diseases.

Adolescent↗
PubMed1989

Estimation of postmortem interval using kinetic analysis of the third component of complement (C3) cleavage.

To estimate postmortem interval (PMI), spontaneous cleavage of the third component of complement (C3) was studied in aged blood and cadaveric blood by crossed immunoelectrophoresis. Using the kinetics of C3 cleavage in vitro described as dC/dt = -kC, where C is the concentration of native C3 at time t and k is a first-order rate constant, Arrhenius' equation, and another equation which assumes a linear drop of body temperature after death, the percentages of C3 cleavage were calculated. There was a significant positive correlation between the calculated percentages and the measured percentages of up to 10% in cadaveric blood. We found that the comparison between the calculated percentage of C3 cleavage for each optional postmortem interval and the measured percentage of up to 10% in cadaveric blood leads to the estimation of PMI. This approach is one step towards the development of an accurate method for determining PMI based on C3 cleavage, that is, on a first-order reaction.

Blood Protein Electrophoresis↗