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PubMed1991

Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19.

The complement system augments the humoral immune response, possibly by a mechanism that involves the B lymphocyte membrane receptor, CR2, which binds the C3dg fragment of C3 and triggers several B cell responses in vitro. The present study demonstrates that CR2 associates with a complex of membrane proteins that may mediate signal transduction by ligated CR2. Monoclonal antibodies to CR2 immunoprecipitated from digitonin lysates of Raji B lymphoblastoid cells a membrane complex containing CR2, approximately equimolar amounts of CD19, which is a member of the immunoglobulin superfamily, and three unidentified components: p130, p50, and p20. The complex, which was immunoprecipitated also with anti-CD19, could be dissociated by Nonidet P-40, accounting for its absence in previous studies of CR2. Expression of recombinant CR2 and CD19 in K562 erythroleukemia cells led to formation of a complex that contained not only these two proteins but also p130, p50, and p20, and another component, p14. These unidentified components of the CR2/CD19 complex coimmunoprecipitated with CD19 and not with CR2 from singly transfected cells, indicating primary association with the former. CD19 replicated the capacity of CR2 to interact synergistically with mIgM for increasing free intracellular Ca2+, suggesting that the complex mediates this function of CR2. Therefore, CR2 associates directly with CD19 to become a ligand-binding subunit of a pre-existing signal transduction complex of the B cell that may be representative of a family of membrane protein complexes. This interaction between the complement and immune systems differs from that between immunoglobulin and Clq by involving membrane rather than plasma proteins, and by having complement involved in the afferent phase of the immune response.

Antigens, CD↗
PubMed1989

The IgG subclass pattern of complement activation depends on epitope density and antibody and complement concentration.

Using a matched series of human-mouse chimaeric IgG anti-5-iodo-4-hydroxy-3-nitrophenacetyl (anti-NIP) antibodies and NIP-bovine serum albumin (NIP-BSA) we examined how different variables influence the activation pattern of complement. When BSA was used with different hapten densities and the input of NIP-BSA was altered, we observed a change in the subclass reaction pattern. IgG3 fixed more Clq than IgG1 and IgG2 in all situations. IgG1 was slightly better than IgG3 and IgG2 at high antigen concentrations at activating C4 and C3 and inducing formation of the terminal complement complex (TCC). When the epitope density and/or the NIP-BSA concentration was reduced, IgG3 became best, followed by IgG1 and IgG2. IgG1 now revealed a marked prozone. Furthermore, IgG4 was found to activate C3 and mediate TCC formation at high epitope and complement concentrations.

Antibodies↗
PubMed1989

Assessment of the activation pathways of the complement in psoriatic patients by use of complement fragment C4d and Bb measurements.

We have measured the complement fragment C4d and Bb levels in the plasma of 51 psoriatic patients and 54 normal controls. The C4d and Bb levels were not significantly elevated in the plasma of the psoriatic patients when compared with those of controls, except in patients with more than 60% skin involvement who exhibited an increase in Bb levels. C4d levels, however, did decrease slightly after successful treatment of psoriasis. Although these results suggest that the C4d and Bb levels partly reflect the complement activation in vivo, they do not seem to be suitable parameters to clarify the mechanism of complement activation in psoriasis.

Adolescent↗
PubMed1981

The effect of vitamin C deficiency on complement systems and complement components.

The changes in the complement systems and complement hemolytic activities through classical and alternative pathways, and the individual components, C1, C4, C2 and C3 were demonstrated in the course of vitamin C deficiency in guinea pigs. During the course of vitamin C deficiency during the first week after the start of the experiment, all components except C1 slightly decreased, gradually increasing in the following weeks. This indicates that this period is important in the formation of an immune defence system in the host. At the time the symptoms of vitamin C deficiency appeared, C1, C2 and CH50 started to decrease. C3 increased when vitamin C deficiency became severe and showed a completely different pattern from those of the other components. The lowered C1 will be due to a collagen-like region in the characteristic of Clq subcomponent, since insufficient vitamin C state produces impaired collagen formation. The activity of the alternative pathway did not produce any change in this course, even in the severe stage. This indicates that the increase in C3 will contribute to maintaining the level of the alternative pathway and maintaining the body defence system in the vitamin D-deficient state, and that the complement system will be supported through the alternative pathway.

Animals↗
PubMed1977

Measurement of hemolytic complement and the third component of complement in nonhuman primates.

Complement, determined by hemolytic assay, and the third component of complement (C3), determined by radial immunodiffusion assay, were measured in nine nonhuman primate species. The species studied were the titi (Callicebus mollach). The sooty mangabey (Cercocebus atys), the thick-tailed galago or bushbaby (Galago crassicaudatus panganiensis), the crab-eating monkey (Macaca fascicularis), the rhesus monkey (Macaca mulatta), the bonnet monkey (Macaca radiata), the stumptailed macaque (Macaca speciosa), the yellow baboon (Papio cynocephalus), and the black-and-red tamarin (Saguinus nigricollis). Both sheep and bovine erythrocytes were used in the hemolytic complement assays. With the sheep erythrocyte system, sera from four species (yellow baboon, sooty mangabey, bonnet monkey, black-and-red tamarin) had similar titers with both antibody sensitized and non-sensitized erythrocytes. In contrast, the titers obtained using sensitized bovine erythrocytes was always higher than the values obtained using non-sensitized bovine erythrocytes. In all species, the titers for non-sensitized sheep erythrocytes was higher than the titer for non-sensitized bovine erythrocytes. When the species were compared for cross reactivity using the radial immunodiffusion assay for human C3, the rhesus monkey showed the strongest cross reaction; the thick-tailed galago, a prosimian, showed no detectable cross reactivity; and the other species examined showed intermediate degrees of reactivity.

Animals↗
PubMed1984

[Activation of the alternative complement pathway by Newcastle disease virus. I) Effect of the virus on the complement system in vivo and in vitro].

The authors have studied the effect of the paramyxovirus of Newcastle disease on the complement system in the mouse. The results obtained show that NDV activate both in vivo and in vitro the alternative complement pathway, suggesting that the intervention of complement system during viral infections represents a general biological phenomenon.

Animals↗
PubMed1980

Experimental bovine trypanosomiasis (Trypanosoma vivax and T. congolense). II. Serum levels of total protein, albumin, hemolytic complement, and complement component C3.

Serum levels of total protein, albumin, activity of hemolytic complement, and complement component C3 were decreased in cattle infected with either T. congolense or T. vivax. The hemolytic complement activity was reduced most, i.e. to 20% (T. congolense) or 5% (T. vivax) of control levels. The development of hypocomplementemia was closely associated with the first peak of parasitemia.

Animals↗
PubMed1977

The cold activation of the classical complement pathway: The cause of the differences between plasma and serum complement in liver cirrhosis.

The mechanism responsible for making the differences between plasma and serum complement (CH50) was studied on eight patients with hepatitis-B(s) antigen negative alcoholic liver cirrhosis. CH50 and C4 activities of the sera of all patients were equal to those of the corresponding EDTA-plasma, when sera wre separated after clotting the blood at 37 degrees C. CH50 and C4 activities of the sera, prepared at 21 degrees C or 4 degrees C, from four of eight patients were very low. When serum from one of these four patients was added to normal human serum, C4 activity of the serum mixture markedly decreased at 4 degrees C but not at 37 degrees C. The inactivation of C4 was prevented by adding EDTA or heparin to the serum mixture. These results indicated that very low complement in the sera, prepared at 21 degrees C or 4 degrees C, of the four cases were due to the cold activation of the classical complement pathway.

Cold Temperature↗
PubMed1981

Activation of the alternative pathway of complement: efficient fluid-phase amplification by blockade of the regulatory complement protein beta1H through sulfated polyanions.

Current concepts of activation of the alternative pathway of complement (APC) focus on the central role of an amplification mechanism triggered by C3b which is covalently bound to the surfact of activating substances. Using sulfated polyanions as model substances, an efficient fluid-phase activation of complement is demonstrated in contrast to solid-phase activation. It is shown that particulate high-molecular weight sulfated polyanions are capable of reversible binding the guinea pig and human regulatory protein beta1H. This fixation leads to an extensive activation of C3 and factor B because the regulatory function of beta1H is blocked in the fluid-phase C3b-dependent amplification system of the APC. Addition of beta1H-depleted C4-deficient guinea pig serum reconstitutes the physiological control mechanisms of the APC. Guinea pig beta1H, purified to homogeneity, is described as a 160000 dalton protein of a single-chain structure. In addition, highly specific and sensitive test systems for beta1H are described.

Absorption↗
PubMed1991

A flow cytometric assay for measuring complement receptor 1 (CR1) and the complement fragments C3d and C4d on erythrocytes.

A flow cytometric assay (FCA) was developed to measure complement receptor 1 (CR1) and the complement fragments C3d and C4d on erythrocytes. It was possible to measure these parameters accurately with intra- and interassay coefficients of variation of 2.0% and 6.5% respectively. The method was able to discriminate between low and high levels of erythrocyte CR1, C3d and C4d. Comparison with a previously described RIA method gave excellent correlation coefficients with r2 values of 0.94, 0.93 and 0.91 for CR1, C3d and C4d respectively. The flow cytometric assay was used to measure CR1, C3d and C4d on the erythrocytes of 98 healthy individuals and the 95% upper limits for C3d and C4d were established. There was a wide distribution of CR1 levels amongst these individuals but their C3d and C4d levels were low and often not above background. The possible application of this method in clinical medicine is discussed.

Antigens, CD↗
PubMed1988

The cytolytic C5b-9 complement complex: feedback inhibition of complement activation.

We describe a regulatory function of the terminal cytolytic C5b-9 complex [C5b-9(m)] of human complement. Purified C5b-9(m) complexes isolated from target membranes, whether in solution or bound to liposomes, inhibited lysis of sensitized sheep erythrocytes by whole human serum in a dose-dependent manner. C9 was not required for the inhibitory function since C5b-7 and C5b-8 complexes isolated from membranes were also effective. No effect was found with the cytolytically inactive, fluid-phase SC5b-9 complex. However, tryptic modification of SC5b-9 conferred an inhibitory capacity to the complex, due probably to partial removal of the S protein. Experiments using purified components demonstrated that C5b-9(m) exerts a regulatory effect on the formation of the classical- and alternative-pathway C3 convertases and on the utilization of C5 by cell-bound C5 convertases. C5b-9(m) complexes were unable to inhibit the lysis of cells bearing C5b-7(m) by C8 and C9. Addition of C5b-9(m) to whole human serum abolished its bactericidal effect on the serum-sensitive Escherichia coli K-12 strain W 3110 and suppressed its hemolytic function on antibody-sensitized, autologous erythrocytes. Feedback inhibition by C5b-9(m) represents a biologically relevant mechanism through which complement may autoregulate its effector functions.

Complement Activation↗
PubMed1981

Complement receptor is an inhibitor of the complement cascade.

A glycoprotein from the membrane of human erythrocytes has been identified as a receptor for C3b (CR1). It promotes the dissociation of the alternative pathway C3 convertase C3b,Bb and the cleavage of C3b by C3b/C4b inactivator. We find that CR1 also inactivates the C3 and C5 convertases of the classical pathway. CR1 inhibits the consumption of C3 by C3 convertase EAC142 and enhances the decay of C4b,2a sites. On a weight basis, CR1 is approximately 5-10 times more active than C4 binding protein, a serum inhibitor of C4b,2a. The binding of 125I-CR1 to EAC14 cells is inhibited by C2. Therefore, it is likely that CR1 and C2 compete for a site on C4b. CR1 inhibited C5 convertase even more effectively, but had no effect on the assembly of the late complement components. At high concentrations, CR1 alone has no irreversible effects on cell-bound C4b. In the fluid phase, CR1 can function as a cofactor for the cleavage of the alpha' chain of C4b by C3b/C4b inactivator. A well-known function of CR1 is to promote adherence of microbes or immune complexes bearing C3b and C4b to cells. This interaction could result in a microenvironment damaging to the plasma membrane of the responding cell because the extrinsic C3b and C4b fragments can serve as additional sites of assembly of enzymes of the cascade. We therefore wish to propose that CR1 on the surface of cells supplies an increased local concentration of a strong inhibitor of the amplifying enzymes of the complement system and provides cells with a mechanism for circumventing damage when they bind C3b- and C4b-bearing substrates.

Complement C3-C5 Convertases↗
PubMed1988

A physical map of the human regulator of complement activation gene cluster linking the complement genes CR1, CR2, DAF, and C4BP.

We report the organization of the human genes encoding the complement components C4-binding protein (C4BP), C3b/C4b receptor (CR1), decay accelerating factor (DAF), and C3dg receptor (CR2) within the regulator of complement activation (RCA) gene cluster. Using pulsed field gel electrophoresis analysis these genes have been physically linked and aligned as CR1-CR2-DAF-C4BP in an 800-kb DNA segment. The very tight linkage between the CR1 and the C4BP loci, contrasted with the relative long DNA distance between these genes, suggests the existence of mechanisms interfering with recombination within the RCA gene cluster.

CD55 Antigens↗
PubMed1975

Complement-mediated bactericidal system: evidence for a new pathway of complement action.

The early components of human complement (C1, C4, and C2) plus certain serum euglobulins will kill pathogenic strains of Shigella sonnei. Serum from patients with hereditary C3 deficiencies and specific antiserums to C3, C5, and C6 were utilized to demonstrate the absence of requirements for late-acting complement components in this unusual bactericidal system.

Antibodies, Bacterial↗
PubMed1985

C56 formation in the reaction mixture of isolated complement components through the classical complement pathway.

The mechanism of hemolysis of unsensitized erythrocytes by a mixture of 9 isolated, human-derived complement components, C1s, C4, C2, C3, C5, C6, C7, C8 and C9 (C1s-C9) was studied. Of the tested erythrocytes, guinea pig erythrocytes (Egp) were the most susceptible to lysis by C1s-C9, followed by human and sheep erythrocytes. Contamination of the isolated complement components by C56 was ruled out. It was determined that a factor was generated in the reaction mixture of C1s, C4, C2, C3, C5 and C6 (C1s-C6), which had lytic activity against Egp when C7, C8 and C9 were added. We found that the lytic factor was similar to C56 in the following properties: (1) the activity of the lytic factor decreased when incubated with isolated C7 prior to its reaction with Egp; (2) the lytic factor did not bind to Egp by itself but it did bind in the presence of C7; (3) EDTA did not have any inhibitory effect on the lytic factor; (4) the activity of the lytic factor decreased by treatment with anti-C5 and anti-C6 but not by treatment with anti-C3 and anti-C4, and (5) gel filtration of the reaction mixture (C1s-C6) indicated that the elution volumes of the lytic factor and of isolated C56 were similar. Thus, it is likely that C56 is generated in the reaction mixture of C1s-C6 and the lytic factor binds to unsensitized erythrocytes together with C7, to form an intermediate EC567 which is susceptible to lysis by the action of C8 and C9.

Animals↗
PubMed1981

The binding of human complement proteins C5, factor B, beta 1H and properdin to complement fragment C3b on zymosan.

The covalent binding of complement fragment C3b to zymosan by the action of the alternative-pathway C3 convertase and the reversible binding of several complement proteins (component C5, factor B, beta 1H and properdin) to C3b on zymosan have been investigated. When C3b is deposited on zymosan after activation by a surface-bound C3 convertase, the C3b molecules are deposited in foci around the C3 convertase site, with an average of 30 C3b molecules per site. The association constants of C5, factor B, beta 1H, and properdin for C3b bound to zymosan have been determined. The association constants ranged from 6.5 x 10(-5) M-1 for factor B to 2.9 x 10(7) M-1 for properdin. An approximate stoichiometry of 1 : 1 for C5, factor B, and properdin binding to C3b has been observed. Curvilinear Scatchard plots were observed for beta 1H binding to C3b, with the maximal extrapolated ratio of beta 1H to C3b of 0.32. Physiological amounts of properdin increase by 7-fold the affinity constant for factor B binding to C3b with no alteration in the stoichiometry. Similarly, physiological amounts of factor B increase the affinity constant of properdin to C3b about 4-fold with only a small measured difference in stoichiometry. Competition binding studies and protein modification suggest that C5, factor B, beta 1H, and properdin each bind to a distinct region on C3b.

Binding, Competitive↗
PubMed1982

Complement activation and complement control proteins in acute pancreatitis.

Serum levels of the complement proteins C3, C4, C1 inhibitor (C1 INH), factor I (C3b inactivator) and factor H (BIH) and plasma levels of cleavage products of C3 (C3c) and factor B were measured in 26 patients with acute pancreatitis. Breakdown of C3 occurred in 19 patients, as shown by a reduction in C3 level and the presence of C3c. C4 levels, however, did not fall and factor B breakdown products were not detected, thus suggesting that enzymatic cleavage of C3 occurred without significant involvement of either the early classical pathway or the alternative pathway. C1 INH and factor H both showed increases, presumably reflecting an acute phase response. Factor I showed an initial fall followed by a rise. There was no correlation between the presence or extent of C3 breakdown and the clinical condition of the patients. It is concluded that C3 cleavage in pancreatitis probably results from tryptic activity and that the measurement of complement components has no part to play in the management of the disease.

Acute Disease↗