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PubMed1980

Quantitation of proteins in sputum from patients with chronic obstructive lung disease. II. Determination of albumin, transferrin, alpha1-acid glycoprotein, IgG, IgM, lysozyme and C3-complement factor.

Albumin, transferrin, alpha1-acid glycoprotein, IgA, IgG, IgM, lysozyme and C3-complement factor have been immunologically determined in sputum and serum samples from 16 patients with chronic bronchitis. The sputa were effectively solubilized prior to the analysis. This is necessary for correct determination of the compositions of sputum. IgA (approx. 3 g/l) and lysozyme (approx. 1 g/l) were present in the highest concentrations. Lactoferrin was qualitatively shown to be present in all the sputa. The concentration of IgG, albumin and transferrin were much higher in the sera than in the sputa, their presence in sputum probably being a result of a passive "leakage" from serum. The ratios for IgA, IgM and lysozyme indicated that these macromolecules are locally synthesized in the respiratory tract. The concentrations of IgA and lysozyme were closely correlated, indicating that the biosynthesis of secretory IgA and bronchial lysozyme may be coupled or controlled by the same mechanism. Except for a weak correlation between the concentration of IgA in sputum and viscosity, no such correlations were obtained for the other proteins determined.

Complement C3↗
PubMed1976

Complement C3 in serum and plasma, as measured by radial immunodiffusion with four commercial kits.

Quantitation of the C3 component of complement by single radial immunodiffusion is subject to error because the C3 molecule has several antigenic determinants and anti-C3 sera differ in their specificity to these determinants. C3 was measured in plasma (ethylenediaminetetraacetate anticoagulant) and serum, in five normal individuals, by use of four such commercial kits. The effects of ethylenediaminetetraacetate and of incubation at -20, 4, and 37 degrees C for 1, 2, and 7 days were investigated. We found wide variations in C3 in the same sample, as measured with different kits. Incubation for longer than 48 h at 4 degrees C changed C3 concentrations as compared to those in fresh samples. Reference sera for C3 assay and standardized procedures for sample processing are both essential to valid results.

Adult↗
PubMed1975

Third component of complement (C3): structural properties in relation to functions.

The third component of complement (C3) fulfills a pivotal role in the functions of the complement system. We have investigated the topological relationships among its polypeptide chains, physiologic fragments, enzyme attack regions, and functional sites. C3 consists of two chains (alpha and beta) which are linked by disulfide bonds and noncovalent forces and which have molecular weights of, respectively, 120,000 and 75,000. C3 is activated by action of C3 convertase on the alpha-chain. With hydrolysis of one polypeptide bonds, C3a, the 9000 dalton activation peptide is dislocated from the NH2-terminal portion of the alpha-chain. A previously concealed binding region is thereby transiently revealed in the C3b-fragment (181,000 dalton) which displays affinity for apparently nonspecific acceptors present on biological membranes. Binding of nascent C3b membranes occurs through the C3d portion of the fragment because subsequent action of the C3b-inactivator or trypsin on bound C3b causes release of C3c, but not of C3d. Bound C3b and C3d possess stable sites that are capable of binding to specific receptors present on a limited variety of cells. We propose that all known physiologically occurring fragments of C3 arise by enzymatic cleavage of the alpha-chain: C3a, C3b, C3c, and C3d. Whereas C3a (alpha1) and C3e (alpha2) consist of a single chain and C3b consists of two chains (alpha' and beta), C3c is composed of the entire beta-chain and multiple fragments of the alpha-chain, each of which is linked by disulfide bonds to the beta-chain.

Binding Sites↗
PubMed1996

Production of the third and fourth component of complement (C3, C4) by smooth muscle cells.

Production of the third and fourth components of complement (C3, C4) by smooth muscle cells was investigated by using normal human aortic smooth muscle cells (AoSMC), human smooth muscle cell line (G402) and vascular smooth muscle cells obtained from human umbilical cord vein (UVSMC). AoSMC spontaneously produced both C3 and C4 at 15 ng/10(6) cells/72 hr and 22 ng/10(6) cells/72 hr, respectively, and both were enhanced by interferon-gamma (IFN-gamma). Although phorbol 12-myristate 13-acetate (PMA) and tumour necrosis factor-alpha (TNF-alpha) enhanced C3 production, C4 production was reduced by these agents. On the other hand, G402 produced C4 but not C3 in a dose-dependent manner when cultured with IFN-gamma. UVSMC produced only a small amount of C3 and C4 compared with AoSMC or G402. C3 and C4 produced by AoSMC were confirmed to be identical with their human serum counterparts as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and measurement of haemolytic activity. Northern blotting analysis showed that the expression of mRNA of C3 and C4 was enhanced by TNF-alpha and IFN-gamma, respectively, in AoSMC. Our findings suggest the importance of smooth muscle cells as a source of components of complement in vascular diseases including vasculitis.

Aorta↗
PubMed1994

Inherited human complement C3 deficiency. An amino acid substitution in the beta-chain (ASP549 to ASN) impairs C3 secretion.

We recently described a case of hereditary complement C3 deficiency (C3D) in a New Zealand male who has a small amount of serum C3 (7 micrograms/ml), a normal size 5.2-kilobase C3 mRNA that is present in normal quantities, and a normal size M(r) 180,000 proC3 molecule that is synthesized in normal amounts. Secretion of C3 from this patient's cells was greatly diminished, however, and an aberrant C3 trypsin cleavage profile indicated an abnormality in the proC3 structure. To determine the primary structure of the C3D proC3 molecule, the corresponding cDNA was cloned and sequenced in the present study, revealing a normal signal peptide, tetraarginine linker, and thiolester domain. One nucleotide substitution in exon 13 (G1705 AC to AAC) was found, however, that resulted in an amino acid change in a highly conserved region of the C3 beta-chain (Asp549 to Asn). This substitution has not been described in any individual with either C3 Fast or C3 Slow phenotypes. Immunoprecipitation of C3 from L-cells transfected with full-length normal and C3D cDNAs demonstrated that C3 was secreted by the cells transfected with the normal C3 cDNA; however, only a C3 precursor was detected in the intracellular compartment of the cells transfected with the C3D cDNA and none detected extracellularly. Immunofluorescence studies revealed a perinuclear localization of C3 in the C3D transfectants, arrested early in the secretory pathway. Allele-specific polymerase chain reaction analysis demonstrated that this New Zealand family is a compound heterozygous C3D kindred, with the Asn549 point mutation being inherited from the mother and a yet undescribed C3 defect being inherited from the father. Taken together, these data indicate that 1) C3 deficiency is caused in a New Zealand kindred by two distinct molecular genetic mutations, one being an amino acid substitution in a highly conserved region of the beta-chain that results in impaired C3 secretion, and 2) the molecular basis of this deficiency has not been described in any other C3-deficient individual, providing additional evidence that multiple defects cause inherited C3 deficiency in humans.

Alleles↗
PubMed1986

Intercellular complement C3 binding in normal skin of patients without pemphigus.

We report here direct immunofluorescence studies of normal skin biopsies that exhibited only complement C3 staining in intercellular areas of epithelium with a view toward evaluating the significance of such findings. During a 5-year period, 11,000 skin biopsy specimens were examined for in vivo binding of immunoglobulins, fibrin, and complement C3 by means of defined direct immunofluorescence methods. Four of ten patients demonstrating intercellular C3 deposits alone had drug-related reactions or erythema multiforme, and four were subsequently shown to have a connective tissue disease. Pemphigus was ruled out in all ten cases in these retrospective studies. These observations indicate that the finding of intercellular C3 deposits in the absence of IgG in normal skin is not a sign of pemphigus but, rather, a sign either of an unusual type of drug reaction or, possibly, of some connective tissue disease. However, the finding of intercellular C3 plus IgG (with or without other immunoglobulins) is a sign of pemphigus. The mechanism of C3 deposition without immunoglobulins is not clear.

Adult↗
PubMed1982

Increased level of the complement C3 protein in endogenous hypertriglyceridemia.

When compared to values obtained in normalweight, normolipidemic control subjects, the level of complement C3 protein and total complement activity (CH50) were found to be obviously decreased in patients with decompensated cirrhosis of the liver and slightly but significantly increased in subjects with type IIb and type IV hyperlipoproteinemia. C3 protein level was positively correlated with the concentration of serum cholesterol, the logarithm of serum triglyceride concentration, serum pseudocholinesterase and total complement activity. There were no significant differences concerning C3 protein level between hyperlipidemic subjects with clinical atherosclerosis and those without documented vascular disease. It is suggested that accelerated lipoprotein turnover occurring in many subjects with type IIb and type IV hyperlipoproteinemia might enhance the synthesis of several liver produced plasma enzymes and proteins including the C3 protein of the complement system.

Adult↗
PubMedDate not supplied

Laser nephelometric assay of complements C3 & C4 in unselected Nigerian population.

The renewed interest in the routine clinical use of complement assays raises the need to obtain reference values in a denominator population as Nigerians. The present study used laser nephelometry to quantitate complement C3 and C4 proteins and obtained the means as 87.9mg/dl and 46.9mg/dl respectively. When compared with those of Central Europeans there was no statistical difference between the C3 levels of the two populations but C4 was significantly elevated among the Nigerians than the Europeans. This may suggest increased activation of the classical pathway.

Adult↗
PubMed2004

Tamoxifen exerts agonistic effects on clusterin and complement C3 gene expression in RUCA-I primary xenografts and metastases but not normal uterus.

Tamoxifen is the most widely prescribed anti-neoplastic drug for the treatment of both localized and metastatic breast cancer. It is also the prototype for a class of drugs that are referred to as selective estrogen receptor modifiers (SERMs), most of which have both estrogenic and anti-estrogenic activity in estrogen target tissues including the breast and endometrium. The underlying mechanisms of action of SERMs in the breast and endometrium that lead to profound differences in the tissue-specific effects of tamoxifen have not yet been elucidated. We have compared the effects of tamoxifen and the pure anti-estrogen ICI 182,780 (Faslodex) in the RUCA-I hormone-responsive rat endometrial cell line in vitro and in vivo. In cell culture, RUCA-I cells responded to both estrogens and anti-estrogens, and the expression of clusterin and complement C3 mRNAs required the presence of estradiol and was repressed in the absence of estradiol or in the presence of the pure anti-estrogen ICI 182,780. Tamoxifen, on the other hand, induced both complement C3 and clusterin mRNA in the absence of estradiol and failed to repress their expression in the presence of estradiol. When grown as subcutaneous xenografts in syngeneic Da/Han rats for 5 weeks, the RUCA-I cells retained their sensitivity to estradiol, as demonstrated by significantly enhanced tumor growth in intact female rats compared with the growth in ovariectomized rats. But neither ICI 182,780 nor tamoxifen had a significant impact on tumor growth in cycling or ovariectomized animals. On the other hand, tamoxifen was potently estrogenic in metastatic lymph nodes, increasing the size of the lymph node tumors almost 6-fold over that seen in the intact cycling animals. In primary tumors, the expression of complement C3 mirrored that seen in vitro, although tamoxifen showed some agonist activity in ovariectomized animals. Tamoxifen also displayed marked agonist activity with respect to clusterin expression and enhanced clusterin mRNA levels and protein in both the primary tumors and lymph metastases in intact and ovariectomized animals. Given the recent demonstration that over-expression of clusterin increases the metastatic potential of breast cancer cells, these data may provide a mechanistic explanation for the increased incidence of endometrial cancer in postmenopausal patients treated with tamoxifen.

Animals↗
PubMed1992

Effects of cell differentiation on the synthesis of the third and fourth component of complement (C3, C4) by the human monocytic cell line U937.

Association of complement synthesis with cell differentiation in U937 cells was investigated using granulocyte-macrophage colony-stimulating factor (GM-CSF), vitamin D3 and interferon-gamma (IFN-gamma) as differentiation-inducing agents. GM-CSF or vitamin D3 enhanced the synthesis of the third component of complement (C3) by U937 cells, but had no stimulatory effect on the synthesis of the fourth component of complement (C4). IFN-gamma increased both C3 and C4 synthesis by U937 cells. Combination of two of these three agents resulted in synergistic enhancement and all three agents caused maximal enhancement of C3 synthesis. Vitamin D3 enhanced IFN-gamma-induced C4 synthesis by U937 cells. These results were confirmed by ELISA and SDS-PAGE after biosynthetic labelling. GM-CSF, vitamin D3 or IFN-gamma increased the expression of complement receptor type 3 (CR3), one of the markers of monocyte/macrophage differentiation. Two of these agents caused a further increase and all three agents maximal increase in CR3 expression. Since C3 was synthesized in parallel with the degree of CR3 expression, the synthesis of C3, but not C4, by U937 cells is thought to be closely related to cell differentiation. It was reconfirmed that the synthesis of C3 and C4 by U937 cells was independently regulated.

Cell Differentiation↗
PubMed1994

Crystallization of human methylamine-treated complement C3 and C3b.

Human methylamine-treated complement C3 (C3-MA) and C3b (C3b-MA) have been crystallized using ammonium sulfate as precipitant. The crystals of the two compounds are morphologically indistinguishable though they belong to different space groups. We show that only minor alterations in packing are responsible for the change in space group. Crystals of C3-MA are tetragonal [P4(1(3))22, a = b = 135, c = 610 A] with two molecules per asymmetric unit. Crystals of C3b-MA are also tetragonal [P4(1(3))2(1)2, a = b = 191, c = 610 A] with four molecules per asymmetric unit. The maximum diffraction observed is 7.7 A at cryogenic temperature using synchrotron radiation.

Journal Article↗
PubMed1975

Interactions of the third component of complement (C3) with cross-linked dextran. IV. Adherence of lymphocytes to C3 coated dextran gel particles.

In previous studies we could show that the third component of complement (C3) is bound from normal serum to cross-linked dextran (Sephadex) after activation via an alternate pathway. Data presented in this paper demonstrate that a subpopulation of human lymphocytes adheries to C3 coated Sephadex particles. The adhering subpopulation of lymphocytes is identical with or overlaps extensively with lymphocytes bearing easily detectable membrane Ig. This phenomenon can be used for the fractionation of lymphocyte subpopulations. After a single passage of tonsillar lymphocytes through C3 coated Sephadex bead columns, no membrane Ig positive lymphocytes were detectable in the effluent. 97-100% of effluent cells formed rosettes with untreated sheep red blood cells, thus resembling pure T cells. Apart from that, the use of C3 coated dextran gel particles allows also the recovery of adherent cells after dextranase digestion of the dextran gel particles. An investigation of retained cells showed enrichment of B cells, but also T cells were demonstrable. The retention of these T cells is probably due to nonspecific interactions.

Cell Separation↗
PubMed1977

Biosynthesis of the third component of complement (C3) in vitro by monocytes from both normal and homozygous C3-deficient humans.

Human monocytes synthesized the third component of complement (C3) up to 5 wk in vitro. Evidence for net C3 synthesis was based on (a) incorporation of 14C-labeled amino acids into C3 protein, (b) indentity of the allotype of C3 produced in vitro with that of the doner's serum C3, even in the presence of carrier C3 protein of a different allotype; (c) correspondence of electrophoretic mobility, size, and subunit structure of C3 protein produced in vitro with serum C3; (d) inhibition of C3 production with cycloheximide. Monocytes from two unrelated C3-deficient patients were studied under conditions that supported C3 synthesis by normal monocytes. Serum from each of the patients contained less than 1% of the normal C3 concentration, buth their monocytes produced C3 at approximately equal to 25% of the normal rate when studied after 2 wk in vitro. The C3 produced in vitro by monocytes from one of the patients had the molecular weight of normal serum C3 and dissociated appropriately under reducing conditions. Monocytes from C3-deficient patients could not be distinguished from normals on the basis of morphology, rosetting with C3-coated erythrocytes, or rates of C2, and total protein synthesis.

Blood Proteins↗
PubMed1998

Molecular analysis of the third component of canine complement (C3) and identification of the mutation responsible for hereditary canine C3 deficiency.

Genetically determined deficiency of the third component of complement (C3) in the dog is characterized by a predisposition to recurrent bacterial infections and to type 1 membranoproliferative glomerulonephritis. The current studies were undertaken to characterize the cDNA for wild-type canine C3 and identify the molecular basis for hereditary canine C3 deficiency. Amplification, cloning, and sequence analysis indicated that canine C3 is highly conserved in comparison with human, mouse, and guinea pig C3. Southern blot analysis failed to show any gross deletions or rearrangements of DNA from C3-deficient animals. Northern blot analysis indicated that the livers of these animals contain markedly reduced quantities of a normal length C3 mRNA. The full-length 5.1-kb canine C3 cDNA was amplified in overlapping PCR fragments. Sequence analysis of these fragments has shown a deletion of a cytosine at position 2136 (codon 712), leading to a frameshift that generates a stop codon 11 amino acids downstream. The deletion has been confirmed in genomic DNA, and its inheritance has been demonstrated by allele-specific oligonucleotide hybridization.

Amino Acid Sequence↗
PubMed1977

Immunoelectronmicroscopical demonstration of in vivo bound complement C3 in psoriatic lesions.

The presence of in vivo bound complement (C3) within the stratum corneum of 4 psoriatic cases is demonstrated ultrastructurally by the use of the peroxidase-antiperoxidase multistep technique. The positive reaction product was located in the intercellular space and on the surface of the parakeratotic cells within the horny layer. The membranes of the horny cells were not altered and peroxidase granules could also not be detected within their cytoplasm. The explanation of this finding as well as its pathogenetic significance is discussed.

Animals↗
PubMed1992

Serum immunoglobulin and complement C3 levels in workers exposed to lead.

Serum immunoglobulin and complement C3 levels were measured in workers exposed to lead at a secondary lead refinery and a solder factory. In the first survey, significant correlations were found between blood lead and IgA with a correlation coefficient of 0.296, and between blood lead and IgE with a correlation coefficient of 0.314. No other significant correlations were found among the indicators of lead exposure and humoral immunity. In the second survey, no significant correlations were found between blood lead and IgG and IgA. A significantly higher number of subjects with IgE of more than 400 IU/ml was found in the group with blood lead of more than 60 micrograms/100 g.

Adolescent↗
PubMed2004

Adhesion dependent release of hepatocyte growth factor and interleukin-1 receptor antagonist from human blood granulocytes and monocytes: evidence for the involvement of plasma IgG, complement C3 and beta2 integrin.

OBJECTIVE: Evolving evidence of anti-inflammatory effects is observed in patients with rheumatoid arthritis or ulcerative colitis following periodic adsorptive granulocyte and monocyte (GM) apheresis with a column containing cellulose acetate (CA) beads as apheresis carriers. This study was undertaken to obtain insights into mechanisms of anti-inflammatory actions of adsorptive GM apheresis with CA beads. METHODS: In a series of in-vitro experiments, we investigated the effects of plasma proteins and the leucocytes beta2 integrin (CD18) on granulocyte adsorption to CA beads. RESULTS: Granulocyte adsorption to CA beads required plasma IgG, the complement C3 and was inhibited by an antibody to leucocytes CD18. Further, hepatocyte growth factor (HGF) and interleukin-1 receptor antagonist (IL-1ra) which have strong anti-inflammatory actions were released by granulocytes that adhered to CA beads. CONCLUSIONS: Plasma IgG, C3 derived complement activation fragments and leucocytes CD18 are involved in granulocyte adhesion to CA beads and hence the release of HGF and IL-1ra.

Adsorption↗