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PubMed1990

Two types of C3 nephritic factor: properdin-dependent C3NeF and properdin-independent C3NeF.

The IgG fraction of serum from patients with membranoproliferative glomerulonephritis (MPGN) types I and II or partial lipodystrophy (PLD) was found to contain C3 nephritic factor (C3NeF) which reacts with the alternative pathway C3 convertase C3bBb and stabilizes it. Two types of C3NeF were detected, of which one was heat sensitive (56 degrees C for 30 min) and properdin dependent (C3NeF:P) but the other was heat stable and properdin independent (C3NeF:nP). C3NeF:P was found in sera from patients with MPGN types I and II and it displayed the properties of properdin and IgG. C3NeF:P was observed in patients with reduced serum concentrations of C3 and terminal complement components (TCC), and the generation of SC5b-9 complex was increased in mixtures with normal human serum. C3NeF:nP was found in sera from patients with MPGN type II and PLD, whose sera revealed a selective decrease in C3 concentrations.

Autoantibodies↗
PubMed1983

Potentiation of factor H by heparin: a rate-limiting mechanism for inhibition of the alternative complement pathway.

The mechanism by which heparin inhibits the alternative complement pathway (ACP) by a fluid-phase activator, CoVF, has been studied. Results presented here indicate that heparin's major (rate-limiting) effect on the fluid-phase activation of the ACP was to potentiate Factor H activity. Such an effect results in a very efficient inhibition of C3b and C3bBb function and restriction of subsequent complement activation and hemolytic activity. Evidence was obtained to indicate that soluble heparin H shifted anodally. Assuming that the rate-limiting inhibitory effect of heparin is to potentiate Factor H, then C3-converting complexes such as CoVF-Bb, which do not require C3b for activity, should not be effected by heparin. Indeed, the inhibitory effect of heparin on C3 conversion in EGTA-Mg2+ serum-CoVF mixtures was lost with a prolonged incubation time (i.e. 60-90 min at 37 C). This finding indicated that with time ACP-mediated cleavage of C3 was able to bypass the heparin-mediated inhibitory step. From these studies it is suggested that heparin restricts the C3-converting activity due to soluble C3bBb complexes but not the C3 conversion due to CoVF-Bb complexes. Heparin-mediated restriction of the ACP activation by CoVF was used to calculate the relative percentages of C3 conversion due to C3bBb or CoVF-Bb complexes. In carefully controlled experiments, heparin could not prevent the spontaneous conversion of C3 which occurs upon removing functional Factor H from the sera. Addition of isolated Factor H restored heparin's inhibitory effect on the ACP. Kinetic studies of heparin's inhibition of ACP-mediated lysis of rabbit erythrocytes indicated that heparin's inhibitor functions did not occur until after the addition of an ACP activator. Each of these findings is consistent with the postulate that the major (rate-limiting) effect of heparin on the ACP is to potentiate the function of Factor H on activated C3b.

Complement Activation↗
PubMed1986

Use of a high-efficiency expression vector to isolate cDNA clones for factor H and map their positions within the molecule.

A human liver cDNA library, cloned in a novel high-efficiency bacterial expression vector (PEX), was screened with an affinity-purified antibody to human factor H. Four distinct cDNA clones, H-2, H-40, H-46 and H-49, were identified. Of these, H-2 also reacted with two monoclonal antibodies to H, MAH-4 and OX-24, which were previously shown to recognize the 38,000 N-terminal tryptic fragment of H, carrying the binding site for C3b. By using polyclonal antibodies specific for the domains in H coded for by these cDNA-clones, it could be established that H-2 codes only for the 38,000 N-terminal tryptic fragment of H, whereas H-40, H-46 and H-49 are derived from the 142,000 C-terminal fragment of H. By subcloning H-2 the epitope for OX-24 could be localized as being coded near the central Sma-site of H-2.

Antibodies↗
PubMed1987

Regulation of the alternative pathway of human complement by C1q.

The interaction of C1q with C3b and its effect on C3b activities in the alternative pathway of complement (APC) have been studied. Purified C1q markedly inhibited C3b deposition on and lysis of rabbit erythrocytes by the isolated cytolytic APC. It also blocked formation of the C3 convertase, C3b, Bb as well as binding of Factors B and H to sheep erythrocytes (E) bearing C3b. The direct and specific binding of C1q to C3b was clearly demonstrated using the hemagglutination technique at low ionic strength (0.1 M NaCl). C1q concns of 2 micrograms/ml and higher agglutinated, in a dose-dependent fashion, EC3b but not E, EC3bi or EC3d. Addition of C1r and C1s to C1q and formation of C1 did not affect its capacity to agglutinate EC3b. The C1q-mediated agglutination of EC3b was inhibited by EDTA, MgEGTA, C3b and Factor B but not by native C3 or collagen. Heating C1q (56 degrees C) markedly potentiated its agglutinating activity whereas collagenase-treated C1q lost most of its activity. Taken together, these results suggest that C1q binds through its "heads" and in the presence of calcium ions to a site on C3b that is adjacent to the Factor B and Factor H binding sites. This interaction may down-regulate the activity of the alternative pathway of complement on surfaces which activate both the classical and alternative pathways of complement.

Animals↗
PubMed1990

Proteolytic activity of the different fragments of factor B on the third component of complement (C3). Involvement of the N-terminal domain of Bb in magnesium binding.

Kinetic experiments measuring the proteolytic activity of Bb and 33Kd fragment (the C-terminal domain of factor B) on C3 were performed in several conditions, in order to assess the role of factor B domains in the catalytic activity and magnesium binding. The experiments were carried out in fluid phase with 125I-C3 or C3(H2O) as substrates and in the presence of nonradioactive C3b as cofactor. The results indicate: (a) The C-terminal domain, 33Kd, possesses proteolytic activity on C3, which is Mg2(+)-independent, whereas proteolysis by Bb is enhanced in 5 mM Mg2+. (b) C3b behaves as cofactor of 33Kd proteolytic activity on C3 and factor H is able to inhibit this activity. (d) Kinetics of C3 proteolysis by 33Kd shows a lag phase which is also displayed by Bb in the absence but not in the presence of Mg2+. Taken together these data are consistent with the involvement of the N-terminal domain of Bb in Mg2+ binding, which results in an enhancement of the proteolytic activity on C3 of the adjacent C-terminal domain. A C3 convertase model accounting for these results is presented.

Complement C3↗
PubMed1985

Mechanisms of complement activation by crystalline cholesterol.

The mechanism by which cholesterol crystals activate complement in human serum has been studied. Crystals treated with serum and washed with buffer contain a fixed C3/C5 convertase. Its generation is dependent on the presence of divalent cations (and of factor B). The cholesterol-fixed convertase is subject to decay and can be regenerated by factors B and D. C2 in combination with C1 is not essential but enhances the convertase formation. These findings indicate that it is predominantly the alternative C3/C5 convertase C3bBb(P) that assembles on cholesterol during exposure to human serum. By the use of different antisera and immunofluorescence a C3 fragment, probably C3b, was demonstrated on serum-treated crystals. Its fixation is resistant to washing with urea, and with buffers of differing pH: by hydroxylaminolysis the C3 fragment dissociates from the crystals. This indicates a covalent ester bond linking the labile binding site of activated C3 to the hydroxyl group of cholesterol. Cholesterol acetate does not fix C3 nor acquire a C3-cleaving activity upon contact with serum. In addition, cholesterol crystals bind factor I (C3b inactivator) and in this way may facilitate fixation and amplification of the alternative C3/C5 convertase.

Cholesterol↗
PubMed1983

Importance of factors H and I for the adherence of C3b-coated erythrocytes to cells.

The role of cell membrane-associated human factor H for the binding of cell-bound C3b to complement receptor-carrying (CR+) cells was investigated. Pretreatment of CR+ cells with antibodies to factor H inhibited the adherence of C3b-coated red cells to human tonsil lymphocytes (TL) and peripheral blood monocytes (M phi). The C3b receptor reactivity of human polymorphonuclear leucocytes (PMN) was not influenced and the one of Raji lymphoblastoid cells only slightly influenced; iC3b and C3d receptor reactivity was in no case affected. When diisopropylfluorophosphate (DFP) in a concentration of 0.1 mM was present during pretreatment of the CR+ cells with anti H, the antibodies gained the capacity to inhibit the adherence of C3b-coated erythrocytes to Raji cells; this effect was dose-dependent with respect to DFP. In contrast, there was no influence of DFP on the inhibition pattern of anti H in the case of TL and M phi. The adherence of C3b-coated erythrocytes to PMN remained unaffected by anti-H antibodies in the presence of DFP. Polyclonal as well as monoclonal antibodies directed against human factor I inhibited the binding of C3b cells to Raji cells but not to TL. Additionally, when anti I and anti H antibodies were both present, C3b receptor reactivity of Raji cells was inhibited to a larger extent than with either antibody alone; again, TL remained unaffected. Results obtained by washing the Raji cells before and after treatment with anti H and anti I suggest that the respective antibodies act on factor H primarily on the level of the cell membrane and on factor I in the fluid phase.

Animals↗
PubMed1986

Lipopolysaccharides as complement inhibitors by complex formation with the purified third complement component (C3).

Lipopolysaccharides (LPS) from different bacteria in smooth or rough form (Y. enterocolitica, Y. pseudotuberculosis, E. coli, S. typhimurium, S. marcescens) strongly inhibited hemolytic C3 in incubation mixtures with purified C3. LPS from a core deficient mutant was still reactive, whereas lipid A no longer affected C3 activity. The physical state of LPS was critical for its effect on C3. Strand-like LPS structures formed by Ca++-induced aggregation of solubilized LPS, as shown by electron microscopy, demonstrated the highest reactivity with C3. Inhibition of hemolytic C3 was found to be due to complex formation between LPS and C3 by a hydrophobic reaction. The binding capacity of 1 microgram LPS-R and LPS-S was as high as 125 ng C3 and 56 ng C3, respectively. The C3b fragment required different reaction conditions for maximal binding. The strong binding capacity of LPS for the complement component C3 raises the possibility that LPS act as inhibitors of complement by interruption of the reaction cascade at local infectious sites with gram-negative bacteria.

Centrifugation, Density Gradient↗