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PubMed1994

Regulation of C3 and factor H synthesis of human glomerular mesangial cells by IL-1 and interferon-gamma.

Previous reports have shown production of complement components C4, C2 and factor B by renal tissue. We have shown recently that human proximal tubular epithelial cells (PTEC) synthesize C3 in vitro, and that IL-2 enhances this production. In the present study we demonstrate that human mesangial cells (MC) in culture produce factor H and that supernatants of activated peripheral blood mononuclear cells (T cell growth factor (TCGF)) induce C3 production and enhance factor H synthesis in both a time- and dose-dependent manner. To investigate whether certain defined cytokines from TCGF were responsible for the observed effect, we tested various cytokines for their effect on complement production by MC. It is shown that IL-1 induces C3 synthesis whereas factor H production is up-regulated by IFN-gamma, in both a dose- and time-dependent manner. Antibody blocking experiments revealed that C3 synthesis induced by both TCGF and IL-1 could be blocked with antibodies specific for IL-1, and also that TCGF and IFN-gamma enhanced factor H synthesis could both be blocked with antibodies specific for IFN-gamma. Cycloheximide was able to inhibit C3 and factor H production, suggesting de novo synthesis of the proteins. mRNA-polymerase chain reaction (PCR) analysis revealed mRNA encoding for C3 after stimulation with TCGF and IL-1. Factor H genes are constitutively expressed in cultured mesangial cells and its expression is up-regulated by TCGF and IFN-gamma. Northern blot analysis with specific probes for C3 and factor H revealed bands which support the results obtained by PCR analysis.

Base Sequence↗
PubMed1981

Recurrent chest infections, ciliary abnormalities and partial complement deficiency in a Jordanian family.

Four girls born to second cousin parents developed chronic chest infection and bronchiectasis in infancy. Three were studied in detail: they all had the same HLA haplotype, all showed random orientation of cilia or compound cilia in the respiratory tract, and all had low levels of the C1 and C2 components of the complement system. Although the cause of the respiratory disease in this family remains unclear, it is suggested that the low C1 levels may have contributed to the disease in two of the children while the low C2 levels were artefacts and the ciliary abnormalities were secondary to chronic chest infection.

Bronchiectasis↗
PubMed2004

Effects of platelet release products on neutrophilic phagocytosis and complement receptors.

INTRODUCTION: Platelets enhance leukocytic phagocytosis via the action of ATP and ADP in platelet release products (PRPr). The present study was designed to clarify the type of complements and complement receptors that are involved in phagocytosis activation by PRPr, ATP and ADP. MATERIALS AND METHODS: Human peripheral blood was used as the source of neutrophils and platelets. The supernatant of the platelet suspension after simulation was used as PRPr. The effects of PRPr, ATP, ADP, and other substances on neutrophilic phagocytosis, rosette formation and expression of several antigens were investigated. For the markers of neutrophilic phagocytosis and rosette formation, IgM-sensitized sheep red blood cells (SRBC) were treated with diluted human serum (EAC) or purified complements (C1, C4, C2 and C3) (EAC3b) followed by C3 inactivation (EAC3bi). The expressions of CD11b, CD11c, CD18, and CD35 were evaluated using a flow cytometer. RESULTS: Neutrophilic phagocytosis of EAC and EAC3bi was enhanced by PRPr, ATP, and ADP, whereas this phagocytosis activation was abolished by antibodies against CD11b and CD18. Neutrophil rosette formation with EAC3bi was increased by ATP and ADP. Flow cytometry revealed that the expressions of CD11b and CD35 on neutrophils were increased by PRPr, but not by ATP and ADP. The component in PRPr, responsible for the increase in expressions of these antigens, could not be identified. CONCLUSION: PRPr increases the neutrophilic phagocytosis of complement-coated particles through the action of ATP and ADP by increasing the binding avidity with iC3b, but not the number of Mac-1 (CD11b/CD18).

Adenosine Diphosphate↗
PubMed1980

Homozygous deficiency of the second component of complement presenting with recurrent bacterial meningitis.

A girl presented with purulent meningitis at ages 6, 8, and 11 years. She was in good health between these three episodes. When aged 16 one of her brothers also experienced an attack of pneumococcal meningitis. Complement studies showed lack of C2 in the patient and the brother, and intermediate values in the mother and a sister. No other member of the family was available for study.

Adolescent↗
PubMed1982

Opsonization and phagocytosis of mucoid and non-mucoid Pseudomonas aeruginosa strains.

The interaction between Pseudomonas aeruginosa strains (6 non-mucoid and 4 mucoid strains), serum factors and phagocytic cells was investigated. Strains were incubated in different concentrations of normal serum, chelated serum (with only the alternative complement pathway intact), IgG, Cls, C2 and C3 deficient serum and immune serum. After incubation complement consumption, C3 fixation and phagocytosis by polymorphonuclear leukocytes (PMN) were measured. In contrast to normal serum, immune serum raised against a mucoid and a non-mucoid strain exhibited heat-stable opsonic activity. All ten Pseudomonas aeruginosa strains were able to activate complement in 20% normal serum, leading to deposition of the activated form of the third complement component on the bacterial cell wall and to subsequent recognition and phagocytosis. One mucoid and four non-mucoid strains activated the alternative complement pathway and were effectively opsonized in chelated or in Cls, C2 or IgG deficient serum. Although mucoid strains were less able to activate complement via the alternative route, no differences were observed in opsonic requirements and phagocytosis between mucoid and non-mucoid strains.

Complement System Proteins↗
PubMedDate not supplied

[Levels of various components of the classical and alternative pathways of complement activation in diabetes mellitus patients].

The state of the complement system was studied in 91 patients with insulin dependent and in 47 patients with non-insulin dependent diabetes. A study was made of the quantity of hemolytically effective molecules of some components C2, C4, C3, C5 of classic and factors B and D of alternative pathway of activation. Complement components were studied for control in 51 healthy blood donors. Antigens B8 and B18 of the HLA-histocompatibility system were studied in parallel in 24 patients and 21 donors. A significantly raised level of components C3 and C4, factors B and D was revealed in the patients with insulin dependent diabetes as compared to the controls (p less than 0.05). In non-insulin dependent diabetes C4, factors B and D were significantly raised and the level of C5 was lowered (p less than 0.05). In the patients with insulin dependent diabetes having antigens B18 the level of C3 was raised and the level of C4 was lowered as compared to the controls. The level of factors B and D was also lower than that in the diabetic patients. An analysis of the content of the complement components in 31 diabetic patients with diabetic nephropathy indicated a decrease in the levels of components C3 and C5 and an increase in the content of C4 (p less than 0.001) as compared to the normal. Diabetes was accompanied by considerable variations as compared to normal values characterizing the state of the complement system and reflecting, to a certain extent, the main features of the pathogenesis of disease.

Complement C2↗
PubMed1995

Increased frequency of the C4A*6 rare allele in rheumatic heart disease.

The aim of the present investigation was to determine whether the alleles of the MHC class III complement proteins BF, C2 and C4 (C4A and C4B) could be markers for RHD in the Brazilian population. Forty-nine patients with chronic RHD were studied. The controls included 65 healthy unrelated individuals, matched with the patients according to sex, age and ethnical background. BF, C2, C4A and C4B allotypes were determined by standard technologies including Western blots for C2 and C4 variants with monoclonal and policlonal antibodies. The results showed a significantly elevated presence of the C4A*6 rare allele (p = 0.003 RR = 11.85) and a decrease of C4A*3 in the patients. In addition, C4 null and BF and C4 rare alleles were more frequent in patients than in the controls. Considering that in this investigation only RHD patients were included, further studies are necessary in order to clarify whether C4A6 is a marker for the cardiac form or for the disease itself.

Adolescent↗
PubMed1991

Antibody-dependent alternate pathway of complement activation in opsonophagocytosis of Porphyromonas gingivalis.

It has been suggested that the ability of Porphyromonas gingivalis to proteolyse complement, as well as its production of a capsule, contributes to resistance to phagocytosis by polymorphonuclear leukocytes. In this report, the opsonic role of serum complement and its activation pathways were investigated, using individual sera heat treated or depleted of factors B, C2, and C1q and the divalent cations Mg2+ and Ca2+. A fluorochrome microassay was used to quantitate phagocytosis of P. gingivalis A7436 by human polymorphonuclear leukocytes. Heat treatment of rabbit antiserum to P. gingivalis (RaPg) (56 degrees C, 30 min) resulted in a reduction in phagocytosis from 100% to 55% +/- 5%, while heat treatment of chronic adult periodontal disease serum abrogated phagocytosis. The heat-labile activity of RaPg was fully restored with MgEGTA-chelated rabbit serum but not EDTA- or EGTA-chelated rabbit serum. The addition of serum depleted of factor B but not C2 or C1q restored most of the heat-labile activity; however, the factor B-depleted serum was suspect, due to low-level opsonization of zymosan (inhibitable by EDTA but not MgEGTA). Adding C1q at 80 micrograms/ml to serum depleted of C1q restored much but not all of the activity lost through heat treatment or through depletion of C1q. A large part of opsonic activity with C2- and C1q-depleted sera was enhanced by the addition of 4 x 10(-3) M Mg2+. The data indicate that although opsonophagocytosis of P. gingivalis A7436 is dependent on the classical complement pathway, a significant contribution is made by an antibody-dependent alternate pathway.

Animals↗
PubMed1982

Increase of the in vitro complement-dependent cytotoxicity against autologous invasive human bladder tumor cells by neuraminidase treatment.

Complement-dependent cytotoxicity (CDC) was measured in a 51-Cr release assay against tumor cells from 13 non-invasive and 7 invasive transitional-cell tumors of the urinary bladder. CDC was compared between mechanically dispersed tumor cells and neuraminidase-treated tumor cells. Neuraminidase treatment of bladder tumor cells enhanced their susceptibility to complement-dependent cytolysis. There were no differences in CDC between autologous and allogenic sera. Mechanically dispersed tumor cells showed no significant differences in susceptibility when non-invasive and invasive tumor cells were compared, whereas significant differences in CDC were seen when neuraminidase-treated non-invasive and invasive tumor cells were used as targets. A C2 deficient serum showed significantly reduced cytotoxicity suggesting that the CDC reaction requires classical complement activation. A hypogammaglobulinemic serum showed stronger CDC compared to autologous and other allogenic sera and upon dilution of autologous sera and hypogammaglobulinemic serum CDC declined parallelly.

Adult↗
PubMed1989

Identification of a human non-interferon lymphokine activating monocyte complement biosynthesis.

A monocyte-stimulating activity produced by mitogen-induced mononuclear cells has been defined by its ability to enhance the synthesis in vitro of complement C1 subcomponents, C2 and C3. A lymphokine responsible for this activity was purified from culture supernatants of peripheral blood mononuclear cells activated by staphylococcal enterotoxin A. From 0.5 litre of supernatant the purification procedure [(NH4)2SO4 precipitation, phenyl-Sepharose chromatography and preparative electrofocusing] yielded about 100 pmol of purified lymphokine. Its pI is 7.9 and its Mr, estimated by SDS/polyacrylamide-gel electrophoresis, is 14,600, 27,000 and 56,000, the high-Mr species representing oligomeric forms of the Mr-14,600 molecule. Its amino acid analysis reveals a high percentage of hydrophobic amino acids (34%); the absence of histidine residues suggests that it is a novel monocyte-activating lymphokine. It enhances C1r and C1s biosynthesis at a pretranslational level. From its structure and activity this lymphokine appears different from gamma-interferon.

Amino Acids↗
PubMed1987

In vitro inhibition of the classical pathway of human complement by polymyxin B.

Polymyxin B 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 EAC1-9 formation from EAC1-3 and C5-9 though slightly less efficiently. It did not inhibit C3/C5 convertase of the alternative pathway or its formation. The inhibition of the classical pathway was reversible since hemolytic activity was almost completely restored after dialysis.

Animals↗
PubMed1984

Genetic polymorphism of the fourth component of complement and type 1 (insulin-dependent) diabetes.

The complement proteins, Bf, C2, C4A and C4B, are closely linked to HLA. In 74 propositi and their families, and 97 controls genotyped for HLA-A, -B, -C, DR, -Bf, a high incidence of the C4BQ0 variant was detected in the patient group (33% versus 12%, p less than 0.00001); C4BQ0 was more frequent in propositi than in non-affected siblings (40 out of 74 versus 36 out of 92, p less than 0.05). When comparing the distribution of the phenotype C4BQ0 in Type 1 diabetic patients and normal control subjects, the difference was significant in patients bearing DR3 or DR4 (56% and 25%, respectively, p less than 0.003). The main linkage disequilibria were observed among the 74 propositi: B18, BfF1, C4, A3, BQ0, DR3; B12, BfS, C4, A3, BQ0, DR4. The existence of a silent allele at the C4 B locus is known to be associated with a defective immune response.

Complement C4↗
PubMed1986

The molecular genetics of components of complement.

Rapid progress has been made in establishing linkages and in chromosome allocation of the genes of some 9 complement components. In the MHC, C2, Factor B, and two C4 or C4 related genes have been placed in some detail in both man and mouse. The gene coding for the cytochrome P-450 21-hydroxylase has been shown to be duplicated and immediately 3' to the two C4 genes, though it appears to be functionally and structurally unrelated to the complement components. Thus six genes have been mapped to this region where particular haplotypes are associated with increased susceptibility to a number of diseases, some of which are autoimmune in character. The complete gene structure of Factor B has been solved in man and rapid progress is being made with the C2 and C4 genes. The structural basis of the polymorphisms of these genes is being established. In C4, the polymorphism is exceptionally complex with varying numbers of loci and probably more than 50 allotypes occurring in man. A structural basis has also been found for the big differences in the biological activity of some of the C4 allotypes in man. Apart from the genes in the MHC, linkage has been found between the genes coding for C4bp, CR1, and Factor H. Remarkably there are sequence homologies between these proteins and C2 and Factor B, probably related to the ability to bind to one or other of the structurally similar proteins C3b and C4b. The complete cDNA sequences of C3 and C4 in mouse and man have given much information on the many posttranslational modifications of these proteins. A partial structure has been obtained for the C3 gene and the homology shown between C3, C4, C5, alpha 2-macroglobulin, and pregnancy zone protein. Although the amount of detailed information in the molecular genetics of complement components is accumulating rapidly, there appears to be a reasonable prospect that linkages and homologies will classify the data into a comprehensible form.

Alleles↗
PubMedDate not supplied

[Determination of proteinase activity of complement system by immunoenzyme methods].

Modern ELISA for determination of functional activity of component C2 and factors B and D, proteinases of a complement system, and component C3, substrate C3-convertases, key complex enzymes of the complement, have been developed. Essential feature of C3-convertases classical (C4bC2a) and alternative (C3bBb) pathways of the complement activation is that their substrate C3 after proteolytic cleavage is converted into C3b, carrying on the surface thioester covalent bond linking C3b with nucleophilic acceptors that results in immobilization of this proteolytic product near the activating enzyme. Cascade character of an activation of complement system allows to create artificial deficit of separate components in the experimental system and to determine (by ELISA) covalently immobilized component C3 during activation, and also to determine functional activity of any of pre-exhausted components. Use of such approach resulted in the development of the ELISA systems suitable for determination of functional activity of component C2 of classical pathway and factors B and D of the alternative pathway by testing quantity of the immobilized C3b at excess C3. The developed methods allow to investigate mechanisms of functioning of complement, inhibition of the cascade activation by endogenic and exogenous inhibitors, and also to find functional deficiency of components in serum and other biological fluids.

Animals↗
PubMed1984

Linkage disequilibrium of HLA-SB1 with the HLA-A1, B8, DR3, SCO1 and of HLA-SB4 with the HLA-A26, Bw38, Dw10, DR4, SC21 extended haplotypes.

Homozygous typing cells from 13 normal HLA-A1, B8, Dw3, DR3 and five normal HLA-A26, Bw38, Dw10, DR4 individuals were typed for the following markers: HLA-SB, MB, MT; complement proteins BF, C2, C4A, C4B; and GLO. Ninety-one percent of A1, B8, Dw3, DR3 homozygous individuals (HI) tested were homozygous for BF*S, C2*C, C4A*QO, and C4B*1 (SCO1 complotype), which indicates that the SCO1 complotype is in linkage disequilibrium with the A1, B8, DR3 haplotype in randomly selected normal populations. Sixty-seven percent of HLA-A1, B8, Dw3, DR3, SCO1 positive HI also expressed SB1; since the frequency of SB1 in random Caucasian populations is 11.2%, this finding indicates that SB1 is in linkage disequilibrium with the A1, B8, DR3, SCO1 extended haplotype. All HI with the A26, Bw38, Dw10, DR4 haplotype were homozygous for both SC21 and SB4, suggesting that SC21 and SB4 should be included in the A26, Bw38, Dw10, DR4 extended haplotype. On the other hand, neither of the GLO markers were found in association with either haplotype. The results of this study indicate that HLA-SB is included in some extended haplotypes and may be important in these markers for diseases such as insulin-dependent diabetes mellitus. This study also demonstrated an apparent influence of HLA-SB on primary mixed lymphocyte culture (MLC) responses. The mean relative response of primary MLCs between individuals matched for HLA-A, B, D, DR, MB and MT but not SB was 40% of that for the MLCs with mismatched HLA-D, significantly higher than the MLCs matched for all HLA and complotypes.

Complement System Proteins↗
PubMed1998

Aspects of leukocyte function and the complement system following aerobic exercise in young female gymnasts.

Recent studies have reported reduced immunity in trained athletes. Scant information exists on changes in the immune function among trained children. The purpose of this study was to assess the effect of aerobic exercise on the phagocytic process of neutrophils and the complement system in young athletes. Subjects included prepubertal elite female gymnasts (n = 7) and untrained girls (n = 6) aged 10-12 years. Venous blood was withdrawn before, immediately post and 24 h following a 20-min run at a heart rate of 170-180 beats.min-1. Neutrophil random migration, chemotactic activity, bactericidal function and PMA/FMLP-stimulated superoxide anion release as well as various complement components were assessed. Net chemotaxis was found reduced (P < 0.05) 24 h following exercise (58 +/- 11 vs. 36 +/- 11 cells/field in gymnasts and 47 +/- 7 vs. 42 +/- 8 cells/field in untrained girls pre- and 24 h post-exercise, respectively). The basal values, as well as post-exercise values of bactericidal activity were lower (P < 0.05) in gymnasts as compared with the control group (0.8 +/- 0.3, 0.8 +/- 0.2 and 0.8 +/- 0.1 log decrease of colonies in gymnasts at pre-, immediately post-, and 24 h post-exercise, respectively and 1.1 +/- 0.1, 1.1 +/- 0.1 and 1.0 +/- 0.2 log decrease of colonies in controls, respectively). No significant effect on the bactericidal activity was observed in either group following exercise. The addition of homologous sera did not correct the bactericidal activity. PMA-stimulated superoxide anion release decreased (P < 0.05) among gymnasts immediately following exercise (5.7 +/- 0.4 vs. 4.4 +/- 1.0 mmol O2/10(6) PMN.min) and remained low 24 h later. The same trend was observed in FMLP-stimulated neutrophils but the data were not significant. Significantly decreased levels (P < 0.05) of the early complement components (C1Q, C1R) were also found following exercise (1.34 +/- 0.64 vs. 1.27 +/- 0.28 and 1.09 +/- 0.07 vs. 1.02 +/- 0.06 pre- and post-exercise in gymnasts and untrained, respectively). Furthermore, consistently lower C2 and C3 were observed in gymnasts compared with controls. Neutrophil dysfunction as well as impairment of the complement system seem to occur following exercise.

Analysis of Variance↗
PubMed1981

Neutralization of vesicular stomatitis virus (VSV) by human complement requires a natural IgM antibody present in human serum.

Neutralization of VSV by human serum ws previously shown to involve C1, C2, C3, and C4 of the classical complement (C) pathway. All normal human sera tested were equivalently active in this regard. However, purified C1, C2, C3, and C4 were unable to mediate VSV neutralization. In the present studies an additional factor required for C-mediated neutralization was isolated from normal human serum and identified as a natural IgM antibody specific for a viral encoded antigen. Purified IgM bound to the virus and formed a complex that activated component C1. Normal serum concentrations of purified IgM, C1, C2, C3, C4 neutralized VSV to the same extent as normal serum. Purified IgM did not neutralize VSV alone or in conjunction with C1, C2, and C4. Inclusion of C3 resulted in full neutralization and C3b binding to the virus was demonstrated. Thus, normal human serum contains a natural antibody of the IgM class that is directed toward a viral antigen. The antibody facilitates neutralization by forming an immune complex that activates C1 and thus efficiently initiates the classical pathway at the viral surface. Neutralization occurs with C3b deposition on the viral envelope and probably results from a blanket of C protein that interferes with viral attachment to susceptible cells.

Absorption↗
PubMed1996

Molecular cloning and linkage analysis of the Japanese medaka fish complement Bf/C2 gene.

Evolutionary studies of complement factor B (Bf) and C2 in lower vertebrates have revealed the presence of the Bf/C2 common ancestor-like molecule in lamprey (cyclostome) and the Bf molecule encoded by the duplicated genes closely linked to the major histocompatibility complex (MHC) in Xenopus (amphibian). To further define when Bf/C2 gene duplication occurred and when linkage between the Bf/C2 gene and the MHC was established, we amplified the Bf/C2 sequences in teleost, the Japanese medaka (Oryzias latipes), by reverse transcription - polymerase chain reaction with primers corresponding to the common amino acid sequences shared by mammalian Bf and C2. Only a single molecular species has been amplified, and the corresponding cDNA clones were isolated from the liver cDNA library. The longest insert contained 2384 nucleotides with an open reading frame of 754 residues. The deduced amino acid sequence showed 33.6% and 34.1% overall identity with the human Bf and C2 sequences, respectively, hence this clone was named medaka Bf/C2. The single-copy medaka Bf/C2 gene had exactly the same exon-intron organization as the mammalian Bf and C2 genes, and spanned about 8 kilobases. The Bf/C2 locus was mapped to the close proximity (2.9 cM) of the superoxide dismutase locus on the linkage group XX by the use of a restriction site polymorphism between two inbred strains of the medaka.

Amino Acid Sequence↗