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PubMed1989

A properdin dependent nephritic factor slowly activating C3, C5, and C9 in membranoproliferative glomerulonephritis, types I and III.

The IgG fraction of serum from patients with membranoproliferative glomerulonephritis (MPGN) types I and III was found to contain a nephritic factor (NFI/III) which differed from that usually present in MPGN type II and partial lipodystrophy (NFII) in that it converts C5 and C9 as well as C3, is dependent on properdin for its activity, and requires an incubation period of several hours rather than 30 min for its demonstration. C3 conversion occurred in the absence of an intact classical pathway. This nephritic factor was found in patients with reduced serum levels of terminal components and its activity, like that of the nephritic factor in MPGN type II, correlated with the serum C3 level indicating that these nephritic factors play a large role in producing hypocomplementemia. Although potentially nephritogenic because of its ability to activate the terminal pathway, the presence of this nephritic factor did not clearly correlate with clinical course.

Complement Activation↗
PubMed1990

Production of IgG and IgM autoantibody to the alternative pathway C3 convertase in normal individuals and patients with membranoproliferative glomerulonephritis.

To understand the origin of autoantibody production, we studied the ontogeny of antibody to the alternative pathway C3 convertase (C3 nephritic factor or C3NeF). Peripheral blood mononuclear cells from newborns, normal adults, and patients with membranoproliferative glomerulonephritis produced IgM and IgG C3NeF after culture for 14 days with pokeweed mitogen. Both IgM and IgG moieties appear to have the same paratope and are able to inhibit each other's binding and function. The affinity constant for each of the C3NeF molecules was moderately high (10(8) liters/mol) and there appeared to be little difference between the Ka values for the IgG and the IgM autoantibodies or between Ka values for autoantibodies isolated from newborns, adults, and patients. These data, then, indicate that the ability to produce C3NeF autoantibody is present from the time of birth in normal individuals. The high affinity of these autoantibodies under normal conditions suggests that C3NeF may play a more important physiological role than previously anticipated.

Antibody Formation↗
PubMed1983

Complement-like activity in sea urchin coelomic fluid.

A complement-like activity in echinoid coelomic cell-free fluid is described. The activity is detected by the lytic action on rabbit erythrocytes (RRBC), and by the opsonic effect on echinoid coelomic phagocytes and mouse peritoneal macrophages. This activity is very heat-labile, being completely destroyed at 37 degrees C 1/2 hr, and is inhibited by Ca2+ concentrations below 10 mM and by low pH. Lysis was complete within 3-4 min, and the titer (10(7) RRBC/ml) was 20-60 between animals. Various substances known to inhibit human complement also inhibited the lytic and opsonic activities in echinoid fluid. RRBC opsonized with echinoid fluid were attached to mouse macrophages without being internalized, an effect which resemble complement opsonization. It is concluded that an activity is present in echinoid coelomic fluid, which strongly resembles mammalian complement activated via the alternative pathway. A lectin-like activity with specificity for D-fucose was detected by the agglutination of RRBC (titer 300-600). Hemagglutination was inhibited by sugars which did not inhibit the lytic and opsonic process. On the other hand, hemagglutination was resistant to various physio-chemical treatments which led to inactivation of the complement-like system; thus these two activities seem to be unrelated. The lectin-like activity did not mediate any opsonic effect.

Animals↗
PubMed1986

Inhibition of complement by a series of substituted 2-aryl-1,3-indandiones: interaction with the fifth component of complement.

A series of substituted 2-aryl-1,3-indandiones were investigated for their ability to inhibit the complement system. Some of them were found to be considerably strong inhibitors. The inhibitory activity was mainly dependent on substitutions at positions 3 and 5 of the phenyl ring. 3,5-dichloro-(8), 3,5-bis(trifluoromethyl)- (7), 3,5-diisopropyl- (3) and 3,5-di-t-butyl- (5) phenylindandiones were the strongest inhibitors of the series. The generation of EAC1-5 cells from EAC1-3 cells and C5 was most strongly inhibited by these compounds although some inhibition of the interaction of EAC1-5 with C6-C9 and EAC1-6 with C7-C9 was also observed. Slight inhibition at other steps of complement activation was also seen but this was not considered to be appreciable. Dialysis of normal serum or purified C5 pre-incubated with compounds 3, 5, 7 and 8 did not cause recovery of the hemolytic activity of normal serum or purified C5. Thus, the main site of inhibition in the complement cascade appeared to be at C5. The total alternative pathway was also inhibited to some extent by these compounds, probably due to their interaction with C5.

Animals↗
PubMed1987

A natural auto-inhibitory factor of the terminal complement pathway in serum of Ctenodactylus gondi.

The serum of Ctenodactylus gondi, a Tunisian rodent, contains a unique inhibitor of the terminal complement pathway. The auto-inhibitor has been partially characterized as a heat-stable euglobulin that is slightly retarded on a DEAE-ion exchange column at pH 7 and elutes as a symmetrical peak on Sephacryl S-300 in the mol. wt region of approximately 200,000. The inhibitor acts by preventing attachment of cytolytic C5b-9 complexes to natural target cells. It does not appear to affect formation and function of C3-convertase, does not exert inhibitory effects at stages later than C5b-7 formation, and also does not prevent formation of SC5b-9 in serum. That the factor prevents attachment of C5b-7/C5b-9 to cells has been demonstrated in hemolysis model systems using sheep EA + human serum, and in the C3-independent reactive lysis system with the use of ELISA methods and quantitative assays with radioiodinated C8. Addition of partially purified inhibitory factor to human sera or to sera of other animal species abolishes the hemolytic activities of these sera. The inhibitory factor of Gondi serum is the first inhibitor of the terminal pathway which has been shown to be capable of preventing cytolysis of cells undergoing complement attack under physiological conditions. The presence of this factor is probably partially responsible for the remarkable susceptibility of C. gondi towards bacterial and parasitic infections.

Animals↗
PubMedDate not supplied

Sulfonated dextran inhibits complement activation and complement-dependent cytotoxicity in an in vitro model of hyperacute xenograft rejection.

In the present study, we demonstrate that a substituted soluble dextran derivative bearing 73% carboxylic groups and 15% benzylamide sulfonate groups, termed CMDBS25, inhibits complement activation and complement-mediated damage in an in vitro model of xenogeneic rejection. Incubation of porcine aortic endothelial cells with normal human serum resulted in time-dependent complement consumption as assessed by C3a generation in the fluid phase and deposition of activated complement fragments C3, C5 and of C5b-9 on target cells. The presence of C5b-9 membrane attack complex was associated with 51Cr release from prelabelled endothelial cells. The addition of 5-25 mg of CMDBS25/ml under the experimental conditions used, inhibited complement activation and C3a generation in a dose-dependent fashion. CMDBS25 (25 mg/ml) totally suppressed iC3b, C5 and C5b-9 cytolytic complex deposition on cells and inhibits by 42% lysis of target endothelial cells. Native dextran had no effect. Our observations document the anti-complementary properties of sulfonated dextran derivatives and their potential as therapeutic agents for the prevention of complement-dependent hyperacute xenograft rejection.

Animals↗
PubMedDate not supplied

The complement system in xenotransplantation.

The immediate barrier to xenotransplantation across phylogenetically distant species, a manifestation of natural immunity, is hyperacute rejection of the xenograft. Complement (C) plays a central pathophysiological role in hyperacute rejection. Hyperacute rejection is initiated when C is activated by natural antibodies against the vascular endothelium of the transplanted organ or by the endothelium itself. C activation fragments alone or in conjunction with natural antibodies set in motion a series of events in the vasculature of the xenogeneic organ which result in loss of endothelial functional integrity and fibrin deposition. This article reviews recent findings concerning the role of C in hyperacute rejection and evidence suggesting that inhibition of C activation may be a critical approach to avert hyperacute rejection.

Animals↗
PubMed1983

A sensitive microassay for the determination of hemolytic complement activity in bovine milk.

A 51Cr release microhemolytic complement assay is described to detect hemolytic complement activity in bovine milk. 51Cr-labeled guinea-pig erythrocytes (GPRBC), which have been sensitized with a subagglutinating amount of rabbit anti-GPRBC, are placed in microtiter plates. Pooled bovine sera as source of complement to achieve about 50% of 51Cr release were added to each well prior to the addition of the samples on the test. Determination of CH100 titer was obtained by difference of counting between heated and unheated diluted whey samples from a standard linear regression. Comparative hemolytic values throughout lactation were established for the first time and confirmed the improved sensitivity of the assay.

Animals↗
PubMed1985

Anti-complementary amines are immunological adjuvants in mice.

Complement (C) inactivation by ammonia, ethylenediamine and methylamine in mouse serum was studied in relation to a possible adjuvant effect of the substances in a cell-mediated immune response. The amines caused a dose-dependent depletion of both alternative pathway (AP) and overall C activity in vitro and showed also pronounced adjuvant effects in the delayed type hypersensitivity response of mice to SRBC. A significant correlation between momentary inhibition of AP activity and adjuvanticity was observed (r = 0.9995; P approximately 0.02), suggesting a causative relationship between these two phenomena. Both effects seem to be a direct function of the number of amino-groups per molecule. Since, on the other hand, lysosomotropic activity of amines is known to decrease with the number of amino-residues, our findings exclude an important role of direct phagocyte inhibition in the immuno-adjuvanticity of these compounds. A longer persistence and improved presentation of antigen as indirect result of local C-depletion could account for the immunological adjuvant effects of amines.

Adjuvants, Immunologic↗
PubMed1986

Inhibition by lysine and arginine of the conversion of C3 and B in the serum and a purified system.

When human serum was incubated at 45 degrees C for 30 min, C3 and B were converted to C3b and Bb. Molecular weights of purified C3 and B were shown not to change after incubation at 50 degrees C. Spectropolarimetry indicated that the secondary structures of C3 and B changed after incubation at higher temperature. The titration of SH groups in the C3 molecule showed the liberation of an SH group. These results show that the alternative complement pathway is activated at raised temperatures without known activators such as zymosan or lipopolysaccharide (LPS). This may be due to the accelerated interaction of conformationally changed components of the alternative pathway such as C3 and B. Using this system, effects of various substances on the interaction of C3 and B in serum and the purified system were investigated. The addition of arginine and lysine resulted in the inhibition of the conversion of C3 and B in the serum at elevated temperature. Other amino acids such as anionic amino-acids and NaCl did not influence the conversion. In the purified system, only arginine and lysine prevented the conversion of C3 and B, when C3, B and D were incubated in the presence of Mg++ and amino-acids. Since lysine and arginine did not inhibit the enzymatic activity of D, these data suggest that arginine and lysine prevent the interaction of C3 and B in the serum at elevated temperatures.

Animals↗
PubMed1991

The inhibitory effect of rosmarinic acid on complement involves the C5 convertase.

Rosmarinic acid (RA), a naturally occurring extract from Melissa officinalis, inhibits several complement-dependent inflammatory processes and may have potential as a therapeutic agent for the control of complement activation in disease. Rosmarinic acid has been reported to have effects on both the classical pathway C3-convertase and on the cobra venom factor-induced, alternative pathway convertase. In order to define the mechanism of inhibition, the effect of RA on classical and alternative pathway lysis, C1q binding, the classical pathway convertase, the alternative pathway convertase, membrane attack pathway lysis and the generation of fragments of C3 and C5 during activation, was tested in vitro. The results showed that RA inhibited lysis by the classical pathway more than by the alternative pathway. This effect was dose-dependent with maximum inhibition of classical pathway lysis observed at 2.6 mmoles of RA. There was little effect on C1q binding or on the classical and alternative pathway convertases. However, there was highly significant inhibition of lysis of pre-formed EA43b cells by dilutions of human or rabbit serum in the presence of RA (1 mM); this was accompanied by inhibition of C5a generation. We conclude that the inhibitory effect of RA involves the C5 convertase. Such inhibition could be advantageous to the host in disorders where the terminal attack sequence plays a role in pathogenesis.

Animals↗
PubMed1985

Characterization of a monoclonal anti-Bw4 antibody (Tü109): evidence for similar epitopes on the Bw4 and Bw6 antigens.

The production and serologic, as well as immunochemical properties of a cytotoxic murine IgG monoclonal antibody (Tü109) that precipitates HLA-class I molecules, are described. In the microcytotoxicity assay Tü109 supernatant was demonstrated on a panel of 424 HLA-ABC, -DR, -DQ, -MT typed normal Caucasian blood donors to define an epitope on HLA-B locus molecules in great association with the supertypic specificity Bw4. Reactivity of supernatant showed MHC linked inheritance of the Tü109 determinant and discriminated the HLA-Bw4/Bw6 associated HLA-B locus split antigens. Weak or lack of binding on lymphocytes from some HLA-Bw4 heterozygous individuals, particularly typing for HLA-Bw44, appeared to be due to qualitative and/or quantitative variations of HLA-B locus molecules on the cell surface. With Tü109 ascites fluid, however, extra-reactivity on all HLA-Bw6+ cells was demonstrated. Preferential binding of supernatant to HLA-Bw4, but reactivity of ascites fluid with HLA-Bw6+ molecules in addition, was furthermore confirmed by IEF analysis of antigens immunoprecipitated with Tü109 from cell lysates. Thus the antibody may help to analyze the evolutionary relationship of the diallelic specificities Bw4 and Bw6.

Antibodies, Monoclonal↗
PubMed1986

The role of carrageenan in complement activation.

A study has been made of the nature of the interaction between complement and carrageenan, which has been widely reported to inhibit haemolytic complement activity both in vivo and in vitro. Using modified haemolytic complement-fixation tests, the degree of complement consumption by various forms of carrageenan was measured in whole human and rat sera. The median effective concentrations of the carrageenans studied were found to lie in the range 3-300 micrograms/ml for the classical pathway and 500-7800 micrograms/ml for the alternative pathway and were unrelated to sulphate content, as determined by energy dispersive X-ray analysis. It was also found that carrageenan-coated sheep erythrocytes were lysed by complement. This activity was suppressed by ethylene glycol-bis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, which inhibits the classical, but not the alternative pathway, providing conclusive evidence that carrageenan preferentially activates the classical pathway. This finding may help in elucidating the inflammatory reaction induced by carrageenan.

Animals↗