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PubMed1989

[Activation of complement by hemodialysis membrane].

Incubation of normal human serum with hemodialysis membranes in vitro resulted in conversion of C3 which was detected by crossed immunoelectrophoresis. In addition, formation of C3d was also observed, as was detected by double-decker rocket immunoelectrophoresis. Furthermore, breakdown products of complement (iC3b, C4d & Bb) in plasma samples were measured by ELISA. The microassay plates were coated with monoclonal antibodies which bind specifically to human iC3b, C4d and Bb, respectively, while the plasma samples were drawn from five polycystic kidney patients during initial hemodialysis. As a result, the iC3b and Bb levels in plasma were seen to increase during hemodialysis but the C4d levels revealed no significant changes. It was also observed that the Bb levels in patients undergoing hemodialysis were significantly higher than those in various renal and collagen diseases. Terminal complement complex (TCC) was not present in detectable amounts in normal human serum when measured by ELISA. However, incubation of normal human serum with hemodialysis membranes in vitro resulted in detection of TCC. TCC was present in the same plasma samples drawned from the five polycystic kidney patients during initial hemodialysis. It is suggestive that activation of complement by hemodialysis membrane is predominantly mediated through the alternative pathway and products such as TCC and anaphylatoxin are formed by this activation.

Complement Activation↗
PubMed1976

Analysis of complement-dependent antibody-mediated lysis of target cells acutely infected with measles.

A sensitive assay for the detection of complement-dependent cytolytic measles-antibodies in monkey and human sera is described. The high sensitivity of the technique is dependent upon the use of Vero or MA-104 cells acutely infected with a high-titered, non-syncitiogenic strain of attenuated measles virus. Cytolytic antibody titers of serum can be determined either by endpoint dilution in the presence of a standard dilution of heterologous (guinea pig) complement or by percentage of lysis of a specific number of target cells at a standard dilution of immune serum (1:32). The latter technique proved expedient in the comparison of cytolytic activities of large numbers of serum samples. Clearly, the alternative complement pathway is effective in lysis of these cells, but neither the classical nor the alternative pathway alone appears to be as effective as both pathways combined. No prozone effect occurred with homologous complement, and inhibition of lysis was eliminated by washing sensitized cells before addition of heterologous complement. Lysis of measles-infected cells untreated with measles antibody occurred in the presence of both normal and C4-deficient guinea pig serum at high concentrations, but no such activity occurred with non-immune human or rhesus serum. Antibody-mediated complement-dependent lysis of measles-infected cells may be an important immune defense against acute measles infection.

Animals↗
PubMedDate not supplied

Complement activation via the alternative pathway in a patient with insulin-dependent diabetes mellitus.

A 41-year old male with insulin-dependent diabetes mellitus previously unsuccessfully treated with a controlled diet and glibenclamide, and subsequently with increasing insulin doses (5 and 20 IU/day) experienced polyuria, glycosuria and loss of weight. On admittance to hospital serum C3 concentrations were found to be depressed. The insulin dose was further increased to 30 IU/day and the patient was also treated with 20 mg nafamostat mesylate given intravenously twice daily for 6 days. On completion of nafamostat mesylate treatment serum C3 concentrations were increased but after 17 days they started to decrease again.

Adult↗
PubMed2001

Complement activation in factor D-deficient mice.

To assess the contribution of the alternative pathway in complement activation and host defense and its possible role in the regulation of systemic energy balance in vivo, factor D-deficient mice were generated by gene targeting. The mutant mice have no apparent abnormality in development and their body weights are similar to those of factor D-sufficient littermates. Complement activation could not be initiated in the serum of deficient mice by the alternative pathway activators rabbit erythrocytes and zymosan. Surprisingly, injection of cobra venom factor (CVF) caused a profound and reproducible reduction in serum C3 levels, whereas, as expected, there was no C3 reduction in factor B-deficient mice treated similarly. Studies of C3 and factor B activation in vitro by CVF demonstrated that in factor D-deficient serum the alpha chain of C3 was cleaved gradually over a period of 60 min without detectable cleavage of factor B. CVF-dependent C3 cleavage in the deficient serum required the presence of Mg(2+), whereas in normal mouse serum the presence of divalent cations was not required. These results suggest that in mouse proteolytic cleavage of factor B by factor D is not an absolute requirement for the zymogen to active enzyme conformational transition of CVF-bound factor B. Kinetics of opsonization of Streptococcus pneumoniae by C3 fragments was much slower in factor D-deficient serum, suggesting a significant contribution of the alternative pathway to antibacterial host defense early after infection.

Animals↗
PubMed1986

Breakdown of C3 covalently bound to F(ab')2 immune complexes after complement activation by the alternative pathway.

The activation and subsequent degradation of C3 covalently bound to immune complexes (IC) has been studied by using immune aggregates antiovalbumin-125I-F(ab')2-ovalbumin or 125I-C3 in the presence of serum. Kinetic experiments were performed in order to establish the physiological sequence of C3 degradation as a function of time. The results indicated: The interaction C3-IC, as analyzed in SDS-PAGE, results in bands of high molecular weight corresponding to C3 alpha-65-Fd and C3 alpha-41-Fd covalent complexes. In the first 7 min only C3 alpha-65-Fd complexes were detected. From 7 to 15 min a progressive increase in the C3 alpha-41-Fd complexes occurs. After this time the ratio C3 alpha-65-Fd/C3 alpha-41-Fd was kept constant for at least 45 min. Hence, C3b covalently bound to F(ab')2 IC is degraded in serum much faster than when it is bound to IgG IC. The spatial distribution of the Fab arms in the IC appears to be a critical feature in providing a protective environment for C3b. The orientation of the Fab arms was dependent on the presence of the Fc regions.

Antigen-Antibody Complex↗
PubMed1991

Isolation of a novel complement regulatory factor (GCRF) from glomerular epithelial cells.

Cultured rat glomerular epithelial cells (GEC) are able to prevent both antibody-directed and spontaneous (alternative pathway) complement activation. In this study, a novel complement regulatory factor (GCRF) was isolated from GEC. The ability to accelerate the decay of alternative pathway C3/C5 convertases formed on sheep erythrocytes (EC3bBbP) was used to guide purification. GEC were solubilized in Triton X-114 and GCRF was recovered in the aqueous phase. Complement inhibitory material also was present in the culture supernatant, which likely represented GCRF. By Mono Q anion exchange chromatography, GCRF eluted at greater than or equal to 0.6 M NaCl and by Superose 6 size-exclusion chromatography, it had a Kav less than or equal to 0.3. GCRF reduced the t1/2 of EC3bBbP from 128 minutes in buffer alone to 41 minutes in 3 micrograms/ml GCRF protein, and also prevented formation of EC3bBbP in a dose-dependent fashion. Digestion with chondroitinase ABC, neuraminidase, or trypsin, but not with heparitinase or chondroitinase AC significantly reduced the activity and size of GCRF, demonstrating that it is a sialic acid-containing dermatan sulfate proteoglycan. Thus, cultured rat GEC synthesize and secrete into the medium, GCRF, a dermatan sulfate proteoglycan with complement inhibitory activity.

Animals↗
PubMed2000

Factor H and the pathogenesis of renal diseases.

Complement factor H is a potent inhibitor of alternative pathway complement activation. The factor H gene, a member of the regulators of complement activation (RCA) gene cluster, encodes two plasma proteins, one 150 kilodaltons (kDa) and one 43 kDa. Homozygous deficiency of factor H results in low plasma levels of complement factor B and C3 and depletion of the terminal complement proteins C5-C9; heterozygotes may have reduced or normal levels of factor B, C3, and C5-C9. Although factor H deficiency is infrequently reported, it has been associated with a number of types of renal disease, the most common being atypical membranoproliferative glomerulonephritis and idiopathic (non-diarrhea-associated) hemolytic uremic syndrome (HUS). The molecular defects responsible for factor H deficiency have been described in only two cases; clearly more research is needed in this area. The possible role of factor H deficiency or dysfunction in the pathogenesis of HUS is discussed.

Complement Factor H↗
PubMed2005

Haemolytic complement activity and humoral immune responses to sheep red blood cells in indigenous chickens and in eight German Dahlem Red chicken lines with different combinations of major genes (dwarf, naked neck and frizzled) of tropical interest.

A total of 376 chickens from different ecotypes were immunized with the non-pathogenic multi-determinant antigen sheep red blood cells (SRBC). The ecotypes included indigenous chickens from various locations in Tanzania (n=102), India (n=86) and Bolivia (n=89). In addition, eight German Dahlem Red (GDR) chicken lines with different major genes (dwarf, naked neck and frizzled) of tropical interest were also immunized with SRBC. Immune competence of the breeds was assessed by measuring complement haemolytic activity, both from the classical calcium-dependent complement pathway (CPW) and alternative calcium-independent complement pathway (APW), alongside IgTotal, IgG and IgM antibody responses to SRBC at 7 days post immunization. Large variations in complement activity and antibody responses to SRBC were observed within and between the indigenous breeds. Many indigenous chickens, especially from Bolivia, showed decreased complement activity (APW) following immunization with SRBC. Breeds from India showed the highest CPW activity and humoral (especially IgM) responses to SRBC, suggesting high immune competence. In contrast, Bolivian chickens were characterized by low CPW activity, low APW activity and low antibody levels to SRBC suggesting an overall low immune competence. In the GDR chickens, characterized by high CPW activity and high IgG antibody responses to SRBC, the major genes for naked neck, frizzling and dwarfism had no significant effect on the antibody responses and complement activity to SRBC.

Animals↗
PubMed1988

Characterization of the susceptibility of Pseudomonas aeruginosa to complement-mediated killing: role of antibodies to the rough lipopolysaccharide on serum-sensitive strains.

The mechanism of complement-mediated killing of seven serum-sensitive Pseudomonas aeruginosa strains was examined. All seven strains were sensitive to the bactericidal activity of 20% pooled normal human serum (PNHS) containing magnesium EGTA, which blocks the classical complement pathway (CCP), or 20% PNHS preheated to 50 degrees C for 20 min, which inactivates the alternative complement pathway, suggesting that either pathway was effective against these strains. However, for four of these strains, optimal killing required the function of both pathways. Preabsorption of PNHS with serum-sensitive strains dramatically reduced the killing activity of serum for the homologous strains when a concentration of 10% serum was used, implying a role for antibody in the activation of complement via the CCP. Affinity purification of antibodies to the rough lipopolysaccharide (LPS) on strain 144M resulted in a pool of antibodies which could restore all of the bactericidal activity and most of the C3 activation-deposition activity of serum which had been lost by preabsorption with 144M. Confirmation that the LPS was the target for these bactericidal antibodies was provided by demonstrating that exogenously added 144M LPS inhibited the killing activity of PNHS. These anti-144M LPS-specific antibodies were also bactericidal for the six other serum-sensitive strains examined, suggesting that all seven strains shared an antigenic determinant recognized by these anti-144M LPS-specific antibodies. Results from cross-absorption studies imply that there are bactericidal antibodies in PNHS directed to additional bacterial targets. These studies suggest that part of the bactericidal activity of PNHS is due to binding of antibodies to the rough LPS on serum-sensitive strains, initiating activation of the CCP, and that all seven strains examined shared this bactericidal antibody-binding site.

Adult↗
PubMed1995

[The viewpoints of viral vertical transmission from fetal neonatal immunologic aspects].

A. The development of fetal Immune system 1. Complement: Alternative pathway is dominant in the development of fetal complement. 2. Neutrophil function: Phagocytosis in full term infants was increased to be adult-level, but bactericidal function was decreased. 3. NK activity: NK activity in full-term infants was significantly lower than in adults, however, IL-2-augmented NK activity did not indicate any significant difference with levels in adults. In pre-32 week infants both NK and IL-2-augmented NK activity were further decreased as opposed to in full-term infants. 4. LAK activity: LAK activity was fully developed already in 19 week infants, indicating that auto-monitoring of mutant cells is already under control from the early stages of fetal development. 5. Antibody production: Antibody production in infants was significantly decreased in comparison to adults. Reduced cytokine (IL-1, BCDF) production were considered to be the causal factors. 6. IL-2, IL-2R: In IL-2 production, no difference was recognized between normal neonates and adult subjects. In contrast, a significantly higher value of IL-2 production was observed for premature neonates born between 16 and 36 GW, compared with adults. IL-2 production and IL-2R system is fully developed at 22 weeks. 7. BCDF gamma, BCDF mu: Reduced compared to that of adults. 8. IL-6, IL-8, G-CSF: Much higher levels were found in cases of intrauterine infection, particularly in cases of premature delivery. The cytokine levels were 20-to-30-fold higher in chorioamnitis-positive premature delivery group. 9. M-CSF: M-CSF is increased, M-CSF may play a role in decidual function and placental function by the autocrine and paracrine system. 10. IL-1 alpha, IL-1 beta, IL-6: These production by macrophages was diminished in aborted fetuses, premature infants and IUGR infants. However, in the infants of mother with intrauterine infection, cytokine production was elevated to the level in full term infants and adults. 11. IFN gamma: Production of IFN gamma by memory T cells was diminished in premature infants. B. The vertical transmission of HTLV-I. The routes of vertical transmission of HTLV-I are intrauterine, intra-birth canal and via breast milk. Bottle-feeding is an effective way of avoiding mother-to-child infection. However breast milk is necessary for optimal infant nourishment, so we use -20 degrees C for 12 hours freeze-thawing of breast milk.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1983

Diethylcarbamazine dependent, complement mediated, adherence and cytotoxicity of cells on microfilariae of Litomosoides carinii.

Diethylcarbamazine (DEC) induced dose dependent adherence of normal spleen cells from Mastomys natalensis to microfilariae of L. carinii in the presence of serum from Mastomys infected with L. carinii or normal serum. The effect could be also induced, using fresh, normal human serum and human blood leucocytes. The responsible serum factor was heat labile (56 degrees C, 30 min) and was eliminated from the sera by pretreatment with Inulin. The activity could be reconstituted by normal serum. Cell adhesion was inhibited by 0.004 MEDTA while 0.004 M EGTA had only a weak inhibitory effect. The addition of Mg++ led to high adherence rates in the presence of EGTA. The data indicate that DEC activates complement on the surface of the larval sheath by the alternate pathway. Adherent Mastomys cells or human cells had a cytotoxic effect on the larvae. The death of the microfilariae did not depend on the loss of the larval sheath.

Animals↗
PubMed1978

Hereditary C2 deficiency and systemic lupus erythematosus associated with severe glomerulonephritis.

Although an unusually high incidence of immunological diseases has been described in patients with hereditary C2 deficiency, the severity of these illnesses has been relatively mild, suggesting that blocking complement activation beyond C4 may protect against significant complement-mediated inflammation. This report describes studies in a C2-deficient patient with severe systemic lupus erythematosus (SLE) and diffuse proliferative glomerulonephritis. An immunopathological study of the kidney revealed the deposition of properdin, properdin factor B, C3 and C5 in a pattern similar to immunoglobulin G deposits. Serum properdin and properdin factor B levels were low at various times during the patient's course. In vitro complement fixation studies showed C3 fixation by glomerular deposits could occur via the alternative pathway. Studies of the immune deposits in the patients' skin revealed similar results. These studies suggest that inflammation may be effectively mediated via the alternative complement pathway in the C2 deficiency-lupus syndrome.

Adolescent↗
PubMed1996

Mesophilic Aeromonas sp. serogroup O:11 resistance to complement-mediated killing.

The complement activation by and resistance to complement-mediated killing of Aeromonas sp. strains from serogroup O:11 were investigated by using different wild-type strains (with an S-layer characteristic of this serogroup) and their isogenic mutants characterized for their surface components (S-layer and lipopolysaccharide [LPS]). All of the Aeromonas sp. serogroup O:11 wild-type strains are unable to activate complement, which suggested that the S-layer completely covered the LPS molecules. We found that the classical complement pathway is involved in serum killing of susceptible Aeromonas sp. mutant strains of serogroup O11, while the alternative complement pathway seems not to be involved, and that the complement activation seems to be independent of antibody. The smooth mutant strains devoid of the S-layer (S-layer isogenic mutants) or isogenic LPS mutant strains with a complete or rather complete LPS core (also without the S-layer) are able to activate complement but are resistant to complement-mediated killing. The reasons for this resistance are that C3b is rapidly degraded, and therefore the lytic membrane attack complex (C5b-9) is not formed. Isogenic LPS rough mutants with an incomplete LPS core are serum sensitive because they bind more C3b than the resistant strains, the C3b is not completely degraded, and therefore the lytic complex (C5b-9) is formed.

Aeromonas↗
PubMed1994

Familial hemolytic-uremic syndrome and homozygous factor H deficiency.

Inherited hemolytic-uremic syndrome (HUS) is unusual. We report the occurrence of HUS in two siblings; one died at an early age while the other (the proband) has presented with three episodes of HUS since the age of 19 years. The finding of a persistently low serum C3 level in this patient led to a thorough evaluation of her complement cascade and a family investigation. The proband and her asymptomatic younger sister were found to have very low serum levels (5% of normal) of factor H, a regulatory protein of the alternative complement pathway. Both patients had low levels of serum C3, factor B, CH50 and VAH50, reflecting persistent alternative pathway activation. The father and mother both had half-normal serum factor H levels but an otherwise normal complement profile. Other members of the extended pedigree were also found to have half-normal serum factor H levels. In conclusion, in this family, factor H deficiency appears to be associated with HUS and is transmitted as an autosomal recessive trait. Persistent C3 hypocomplementemia in the setting of familial and/or recurrent HUS should be a clue to a possible inherited complement deficiency.

Adult↗
PubMed1991

Molecular basis of the enhanced susceptibility of the erythrocytes of paroxysmal nocturnal hemoglobinuria to hemolysis in acidified serum.

When incubated in acidified serum, the erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH) are hemolyzed through activation of the alternative pathway of complement (APC), but normal erythrocytes are resistant to this process. PNH cells are deficient in decay-accelerating factor (DAF), a complement regulatory protein that inhibits the activity of both the classical and the alternative pathways. However, deficiency of DAF alone does not account entirely for the aberrant effects of acidified serum on PNH cells. Recently, we have shown that PNH erythrocytes are also deficient in another complement control protein called membrane inhibitor of reactive lysis (MIRL) that restricts complement-mediated lysis by blocking formation of the membrane attack complex (MAC). To determine the effects of the DAF and MIRL on susceptibility to acidified serum lysis, PNH cells were repleted with the purified proteins. DAF partially inhibited acidified serum lysis by blocking the activity of the amplification C3 convertase. MIRL inhibited acidified serum lysis both by blocking the activity of the MAC and by inhibiting the activity the C3 convertase. When DAF function was blocked with antibody, normal erythrocytes became partially susceptible to acidified serum lysis. By blocking MIRL, cells were made completely susceptible to lysis, and control of C3 convertase activity was partially lost. When both DAF and MIRL were blocked, the capacity of normal erythrocytes to control the activity of the APC and the MAC was destroyed, and the cells hemolyzed even in unacidified serum. These studies demonstrate that DAF and MIRL act in concert to control susceptibility to acidified serum lysis; of the two proteins, MIRL is the more important. In addition to its regulatory effects on the MAC, MIRL also influences the activity of the C3 convertase of the APC. Further, in the absence of DAF and MIRL, the plasma regulators (factor H and factor I) lack the capacity to control membrane-associated activation of the APC.

Animals↗