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PubMed1981

Choice and specificity of complement in complement fixation assay.

This study examines the relative activity of various complement sources in a variety of antigen-antibody (Ag-Ab) complement fixation assay systems. Studied were Ag-Ab systems of cytomegalovirus, adenovirus, Pneumococcus, Coccidiodes, and guinea pig kidney. Ab titers in each system were determined by microcomplement fixation assay using two batches of titrated rabbit, monkey, cat, dog, human cord, human adult, and guinea pig sera as complement sources. Assay sensitivity and Ab titers proved to be strongly related to the complement sources. There was considerable variation in the ability of Ag-Ab complexes to bind the complement of each of the species tested. Guinea pig, rabbit, and monkey sera gave comparable titers in four of the five Ag-Ab systems tested. Cat serum complement was able to detect anti-adenovirus and anti-Pneumococcus reactivity only. Human adult, human cord, and dog sera exhibited anti-complementary activity. The study emphasizes the importance of complement source in determining both the specificity and sensitivity of complement fixation assays in a given Ag-Ab system.

Animals↗
PubMed1986

Inherited deficiencies of complement and complement-related proteins.

The complement cascade and cell-surface proteins related to the complement system are critically important to host defense, immune complex catabolism, and possibly immunoregulation. Genetically determined deficiency states have been described for many complement proteins as well as for fluid phase and cell-borne inhibitors of the complement cascade and cellular complement receptors. Autoimmune diseases and enhanced susceptibility to infection are the dominant clinical manifestation of these deficiencies. Classical pathway deficiencies and low numeric expression of erythrocyte C3b receptors (CR1) are typically associated with autoimmune disorders, while alternative pathway, terminal component, and leukocyte iC3b receptor (CR3) defects predispose to pyogenic bacterial disease. This distinction is not absolute, however, and both classes of disease may appear in most of the reported deficiency states. Specific pharmacologic therapy exists for C1-inhibitor deficiency (hereditary angioedema). Management of other complement deficiencies currently involves sustained diagnostic suspicion and meticulous management of complicating diseases.

Anaphylatoxins↗
PubMed1985

Cigarette smoke can activate the alternative pathway of complement in vitro by modifying the third component of complement.

Cigarette smoking is associated with significant increases in the number of pulmonary mononuclear phagocytes and neutrophils. A potent chemoattractant for these cells is C5a, a peptide generated during complement (C) activation. We, therefore, investigated the possibility that cigarette smoke could activate the complement system in vitro. Our results show that factor(s) (mol wt less than 1,000) present in an aqueous solution of whole, unfiltered cigarette smoke can deplete the hemolytic capacity of whole human serum in a dose-dependent manner. The particle-free, filtered gas phase of cigarette smoke is inactive. The smoke factor(s) do not activate serum C1, but do deplete serum C4 activity. Treatment of purified human C3 with whole smoke solution modifies the molecule such that its subsequent addition to serum (containing Mg/EGTA to block the classical pathway) results in consumption of hemolytic complement by activation of the alternative pathway. Smoke-modified C3 shows increased anodal migration in agarose electrophoresis, but this is not due to proteolytic cleavage of the molecule as evidenced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In contrast to methylamine-treated C3, C3 treated with smoke is only partially susceptible to the action of the complement regulatory proteins Factors H and I. In addition, smoke-modified C3 has diminished binding to Factor H as compared with methylamine-treated C3. Finally, smoke-modified C3 incorporates [14C]methylamine which suggests that the thiolester bond may be intact. These data indicate that aqueous whole cigarette smoke solution can modify C3 and activate the alternative pathway of complement, perhaps by a previously unrecognized mechanism. Should this occur in vivo, complement activation might partly account for the extensive pulmonary leukocyte recruitment observed in smokers.

Complement Activation↗
PubMed1985

Familial occurrence of complement dysfunction in Crohn's disease: correlation with intestinal symptoms and hypercatabolism of complement.

Complement was studied in Crohn's disease probands with early onset and in their first degree relatives. Controls included 24 healthy volunteers and 24 patients with ulcerative colitis or peptic ulcers. Subnormal generation of chemotactic activity by the alternative pathway was shown in eight of 21 probands and in six of 33 relatives, a frequency in both groups significantly different from controls (p less than 0.005), with a strong connection between findings in patients and relatives. As previously shown in patients with Crohn's disease, the subnormal generation was related to decreased utilisation of complement C3 in relatives. Raised levels of circulating complement C3c split products suggested complement involvement in Crohn's disease probands. In contrast, plasma C3c was normal in all relatives, and none of the six cases with complement dysfunction had gastrointestinal symptoms or a history of inflammatory bowel disease. Our data suggest, that complement abnormality seen in Crohn's disease patients does not simply reflect mucosal inflammation or hypercatabolism of complement.

Adolescent↗
PubMed1988

Restriction of cell lysis by homologous complement: II. Protection of erythrocytes against lysis by newly activated complement.

Our previous work revealed that homologous complement (C) was ineffective in lysing antibody-sensitized erythrocytes (EA) even at high concentrations. It was also shown that activation of complement on homologous EA resulted in the binding of C9 and the formation of EA bearing complement proteins C1 through C9 (EAC1-9), yet few hemolytic sites were formed. Instead, as shown here, the formation of homologous EAC1-9 caused the cells to become resistant to lysis even by heterologous complement during a second incubation. In contrast, when homologous EAC1-8 were produced by incubating EA with C9-depleted serum, such intermediates were not protected against lysis by heterologous complement during a second incubation. Furthermore, homologous C9 on EAC1-9 was able to reduce the hemolytic efficiency of heterologous complement without blocking C activation and the formation of new C5b-9 complexes. Protection was not modified when homologous EAC1-9 were produced in one step, by incubation of EA with serum, or sequentially by adding C9 to EAC1-8. The minimum number of 9-sites required to confer a protective effect on EAC1-9 was less than 200 per cell. Thus, in addition to its known effect in heterologous cell killing, homologous C9 is capable of protecting homologous cells against inadvertent complement lysis.

Ammonia↗
PubMed1980

Complement activating property of the protein-rich endotoxin (OEP) of Pseudomonas aeruginosa. I. Activation of both the classical and the alternative pathways of guinea pig complement.

Complement activating property of the protein-rich endotoxin (OEP) of Pseudomonas aeruginosa was investigated. The ability of OEP to consume the hemolytic complement (CH50) of guinea pig serum (GPS) was relatively lower than zymosan, a potent activator of the alternative pathway (AP). The profiles of the complement consumption with OEP in GPS suggested that classical pathway (CP) activation seems to occur in addition to the AP-activation, because the consumption of the C3-C9, i.e., C3 total was relatively higher than those of C1, C4 and C2. Further results stated below is confirmed this. OEP consumed complement in certain extent in C4-deficient GPS and also in factor B- or D-depleted GPS. In these sera either pathway of the AP or the CP was operated. However, OEP consumed complement quite in full extent in the EGTA-chelated serum, in which AP-activation took place in normal level. OEP was therefore found in this experiment to activate only the AP. The conversion of C3 in immunoelectrophoresis which is a evidence of the CP-and/or AP-activation was observed with OEP. It was suggested that the antibody against OEP did not participate in the consumption of complement, because the GPS priorly absorbed with OEP-coated sheep RBC, was retained fully to react with OEP. It was discussed that the active site of OEP as to the complement activation located on the LPS portion of OEP.

Animals↗
PubMed1990

Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis.

The complement system is an important mediator of the acute inflammatory response, and an effective inhibitor would suppress tissue damage in many autoimmune and inflammatory diseases. Such an inhibitor might be found among the endogenous regulatory proteins of complement that block the enzymes that activate C3 and C5. Of these proteins, complement receptor type 1 (CR1; CD35) has the most inhibitory potential, but its restriction to a few cell types limits its function in vivo. This limitation was overcome by the recombinant, soluble human CR1, sCR1, which lacks the transmembrane and cytoplasmic domains. The sCR1 bivalently bound dimeric forms of its ligands, C3b and methylamine-treated C4 (C4-ma), and promoted their inactivation by factor I. In nanomolar concentrations, sCR1 blocked complement activation in human serum by the two pathways. The sCR1 had complement inhibitory and anti-inflammatory activities in a rat model of reperfusion injury of ischemic myocardium, reducing myocardial infarction size by 44 percent. These findings identify sCR1 as a potential agent for the suppression of complement-dependent tissue injury in autoimmune and inflammatory diseases.

Animals↗
PubMed1987

Complement in local biliary tract defense: dissociation between bile complement and acute phase reactants in cholecystitis.

Biliary complement concentrations and activity are lower in patients with infected bile than in those with sterile bile in cholecystitis. Plasma complement is increased during the acute phase response to inflammation. To determine whether low biliary complement in infected bile is a specific response to biliary tract infection or part of a general systemic reaction, we analyzed bile complement proteins (C3 and C4) and activity (C4H50) and acute phase reactants fibronectin, C-reactive protein, and alpha 1-antitrypsin concentrations in acute and chronic cholecystitis. Results were correlated with bile cultures and gallbladder histology using the Wilcoxon rank sum test. While biliary C3, C4, and C4H50 were significantly lower in infected bile than in sterile bile, none of the acute phase reactants were different. The biliary acute phase reactants were all significantly higher in acute cholecystitis than in chronic disease, but there was no difference in the biliary C3, C4, or C4H50 levels. There was no clear relationship between plasma levels of complement and the acute phase reactants. The dissociation between biliary complement and acute phase reactants indicates that bile complement is not a reflection of a systemic reaction to inflammation. We propose that biliary complement is a specific host defense mechanism against bacterial infection in the biliary tract.

Acute Disease↗
PubMed1990

Complement, complement activation and anaphylatoxins in human ovarian follicular fluid.

Functionally active complement was sought and detected in human follicular fluids obtained during the pre-ovulatory period. All the functional complement activities tested, including total haemolytic complement, classical pathway activity and alternative pathway activity were present in nine fluids from four different donors with values within the normal serum range. The immunochemical analysis demonstrated the presence of complement factors from C1 to C9, of B and of C1 INH, H, I. Complement anaphylatoxins were found employing RIA techniques in amounts significantly higher than in human plasma, thus demonstrating that follicular fluid complement, at least during the pre-ovulatory period, is partially activated. A possible role for urokinase-like substances in such an activation was indicated by further in vitro experiments. The presence of active complement in follicular fluid can be relevant for the function of the enzymatic multi-factorial mechanism of ovulation.

Anaphylatoxins↗
PubMed1991

Complement fragment C4d and Bb levels in inflammatory skin diseases (e.g. SLE, atopic dermatitis, erythroderma and pustulosis palmaris et plantaris) for assessment of complement activation.

The complement is one of the major effector system in the process of inflammation. Complement activation has been shown to occur in inflammatory dermatoses such as systemic lupus erythematosus, atopic dermatitis, erythroderma of unknown origin, and pustulosis palmaris et plantaris by the elevated blood levels of complement fragments. To clarify the complement activation, especially the alternative pathway involvement, we have measured the concentrations of classical pathway-specific C4d and alternative pathway-derived Bb in the plasma of patients with these inflammatory disorders at a mild to exacerbated stage. Only the SLE plasma showed significantly elevated Bb levels. These results suggest that assessments of plasma C4d and Bb levels may be of value in monitoring the involvement of the complement system in patients with inflammatory dermatoses with significant complement activation.

Adult↗
PubMed1979

Staphylococcus aureus opsonization mediated via the classical and alternative complement pathways. A kinetic study using MgEGTA chelated serum and human sera deficient in IgG and complement factors C1s and C2.

Staphylococcus aureus opsonization was studied kinetically by: (1) determination of the uptake of [3H]-thymidine labelled bacteria by human PMN's; (2) fluorescent anti-C3 and anti-IgG staining of opsonized bacteria; and (3) measuring bacterial complement consumption. Maximum opsonization in normal serum occurred within 5 min of incubation. About 80% of staphylococci were then taken up by PMN's, and IgG and C3b could be detected on the bacterial surface. In the absence of a functional classical complement pathway, as in sera deficient in C1s and C2 and in MgEGTA chelated serum, maximal opsonization was only achieved after 30--60 min incubation. Opsonization in IgG deficient serum occurred at a rate similar to that found in C2 deficient or MgEGTA chelated serum. Opsonization was greatly enhanced when sera were reconstituted. It was concluded that in IgG deficient serum Staphylococcus aureus opsonization is mediated via the alternative complement pathway. Dilution of normal serum primarily affected the classical complement pathway, resulting in a decreased rate of opsonization. In normal serum IgG did not appear to be a rate-limiting factor. S. Aureus opsonization was best studied by the phagocytosis assay and the fluorescent-antibody technique. Measuring haemolytic complement consumption was found to be an insensitive indicator of bacterial complement activation and opsonization.

Complement Activation↗
PubMed1982

Complement activation in muscle fiber necrosis: demonstration of the membrane attack complex of complement in necrotic fibers.

The membranolytic C5b-9 complement membrane attach complex (MAC) is assembled after activation of either the classic or the alternative complement pathway. The quaternary configuration of the MAC macromolecule presents neoantigenic determinants not present on precursor molecules. Consequently, antibodies specific for these neoantigen(s) do not detect nonspecifically bound native complement precursors of MAC. By means of antibodies rendered specific for MAC neoantigen(s), MAC was localized by the immunoperoxidase reaction in cryostat sections of human muscle. In 66 biopsy specimens containing necrotic muscle fibers (Duchenne dystrophy, 13; other dystrophies, 15; inflammatory myopathies, 31; miscellaneous myopathies, 7) all of the necrotic fibers reacted for MAC neoantigen(s). C3 and C9 were also consistently localized in necrotic fibers, but localization of C1q, C4, and IgG was variable and often did not exceed background staining. None of the nonnecrotic fibers reacted for immunoglobulin or complement. Detection of MAC neoantigen(s) in necrotic fibers in a wide variety of muscle disease unambiguously shows that (1) the lytic complement pathway is consistently activated and participates in muscles fiber necrosis in vivo, and (2) complement reaction products are generated than can stimulate cellular infiltration and phagocytosis of the necrotic fiber. The findings also suggest that cell necrosis in general may involve participation of complement.

Antigens↗
PubMed1995

Complement regulation in the rat glomerulus: Crry and CD59 regulate complement in glomerular mesangial and endothelial cells.

The complement regulators, decay accelerating factor, membrane cofactor protein, and CD59 are present in human glomeruli. Crry is the rodent analogue to the former two proteins. In this study, we examined complement regulation in cultured rat glomerular endothelial cells (GEnC) and mesangial cells (MES). Immunoprecipitation of 125I-labeled membrane proteins and Western blotting studies were performed with anti-Crry and anti-CD59. In both GEnC and MES, Crry was present as 53, 65, and 78 kD proteins. The 20 kD CD59 was apparent in GEnC. CD59 was also present in MES, but in relatively smaller quantities. By Northern analyses, 1.8 kb CD59 mRNA was present in GEnC as well as in RNA from isolated rat glomeruli. mRNA for Crry was present in both GEnC and MES as 2.2 kb species. The functional significance of these proteins was evaluated next. Anti-Thy 1.1 IgG was used to activate the complement classical pathway in MES. To inhibit the function of the complement regulators, anti-CD59 and/or anti-Crry F(ab')2 antibodies were added with anti-Thy 1.1. Inhibition of Crry function led to enhanced cytotoxicity, while there was no effect when CD59 function was inhibited. The complement alternative pathway was studied by adding complement in Mg-EGTA buffer. Inhibition of Crry led to productive alternative pathway activation, which was accentuated by anti-CD59 when Crry was incompletely inhibited. Alternative pathway regulation was also evaluated in GEnC. Inhibition of CD59 function alone had no effect in GEnC, while inhibition of Crry led to significant cytotoxicity from alternative pathway activation. Under conditions in which Crry was inactive, inhibition of CD59 further enhanced cytotoxicity. Therefore, Crry is present in both GEnC and MES and restricts the complement alternative pathway in both cell types. Crry also regulates the classical pathway in MES. CD59 is present and functionally active in GEnC, while it appears to have a minor role in MES.

Animals↗
PubMed1995

Enhanced complement susceptibility of avidin-biotin-treated human erythrocytes is a consequence of neutralization of the complement regulators CD59 and decay accelerating factor.

Biotinylation of erythrocytes (E) followed by avidin cross-linking at specific sites has been suggested as a novel means of drug delivery. Upon avidin cross-linking, biotinylated E become complement-activating and highly susceptible to complement lysis, thus bringing about release of entrapped drug. We set out to examine the mechanisms of this biotin-avidin-induced lytic susceptibility, focusing on the effects of biotinylation and avidin cross-linking on the major E complement regulatory molecules, decay accelerating factor (DAF) and CD59. We demonstrate here that biotinylation of E, which does not render them complement activating, partially inhibits DAF but has little effect on CD59. Subsequent cross-linking with avidin causes complete inhibition of DAF and near complete loss of CD59 activity. Following cross-linking, DAF and CD59 become associated in high molecular mass avidin-containing complexes on the membrane. Incorporation of physiological amounts of CD59 into the membranes of biotinylated and avidin cross-linked E is sufficient to render these cells resistant to complement lysis whereas incorporation of DAF has relatively little effect. An understanding of the molecular mechanisms underlying complement susceptibility of biotin-avidin treated E should allow a rational design of strategies for drug delivery using E or other large, potentially complement-activating carriers.

Antibodies↗
PubMed1986

Immobilized doxorubicin increases the complement susceptibility of human melanoma cells by protecting complement component C3b against inactivation.

Human melanoma cells resistant to killing by monoclonal antibody R24 plus human complement became susceptible after treatment with doxorubicin (adriamycin). Treatment with doxorubicin prevented the rapid degradation of surface-bound complement component C3b that has been identified as a protective mechanism of complement-resistant melanoma cells. Doxorubicin caused the increased complement susceptibility as free drug and after immobilization onto glass beads to prevent cellular uptake. Immobilized doxorubicin was more effective than free drug, causing enhanced complement susceptibility at concentrations where the free drug was no longer active. In contrast to free doxorubicin, which exhibited a direct cytotoxic effect leading to cell death within 4 days, immobilized doxorubicin did not affect cell viability. These findings suggest that combination therapy of the complement-activating monoclonal antibody R24 with the complement-enhancing drug doxorubicin may be a promising approach for the treatment of melanoma.

Antibodies, Monoclonal↗
PubMed1972

Role of antibody and complement in the immune clearance and destruction of erythrocytes. II. Molecular nature of IgG and IgM complement-fixing sites and effects of their interaction with serum.

A model for the immune clearance and destruction of homologous erythrocytes has been further explored. In this model, every IgM anti-erythrocyte antibody molecule in an antibody preparation was shown to fix Cl. About 2000 IgG antibody molecules were required to form a Cl-fixing site on the guinea pig erythrocyte surface. 60 IgM complement-fixing sites per erythrocyte were required for the immune clearance of IgM-sensitized erythrocytes. This number of sites could be detected by a direct agglutination test. 1.4 complement-fixing sites were required for immune clearance of IgG-sensitized cells, a number of molecules which could not be detected by direct agglutination. This number could, however, be detected with the use of a Coombs antiglobulin reagent. Depletion of the late components of complement (C3-9) with cobra venom was associated with the loss of ability to clear IgM-sensitized cells and a marked deficit in the ability to clear IgG-coated cells. Thus, late (C3-9) components of complement as well as an early component (C4) were required for normal clearance of sensitized erythrocytes. There was no evidence that activation of the alternate pathway of complement action could lead to accelerated erythrocyte clearance. In vitro incubation of IgG and IgM-sensitized erythrocytes in fresh serum led to deposition of C3 and C4 on the erythrocyte surface. IgM-sensitized cells treated in this way had a normal survival. IgM-sensitized cells also were shown to remain Coombs positive after their release from the liver. The evidence suggests that the interaction of an IgM site with fresh serum in vitro and in vivo leads to formation of a site which allows for sequestration of cells in the liver. With continued exposure to serum components, this site is destroyed or inactivated. This serum-dependent inactivation is complement-dependent as shown by the use of EDTA-treated and C4-deficient serum. IgG complement-fixing sites are only partially inactivated by incubation in fresh serum, further emphasizing the differences in the biologic activity of IgM and IgG antibodies.

Animals↗
PubMed1989

Differential susceptibility of haemolysin-sensitized erythrocytes to complement-mediated cytotoxicity: a biological manifestation of the relationship between antibody availability and complement fixation.

The influence of the concentration of membrane-bound antibody on the susceptibility of individual human erythrocyte populations to complement-mediated haemolysis has been examined using cold competition analysis. It was observed that under conditions where complement is limiting, the relative susceptibility of erythrocytes to complement lysis is dependent on the availability of sensitizing antibody, even when all target red cells possess sufficient membrane antibody to permit maximal lysis in the presence of excess complement. Furthermore, preliminary evidence is presented which suggests that, where the availability of complement is limiting, sensitized blood group A erythrocytes are more susceptible to complement lysis than are sensitized group B cells. Taken together the data indicate that the quantity, and possibly the distribution, of the membrane antibody dictates the relative susceptibility of erythrocytes to complement haemolysis.

ABO Blood-Group System↗
PubMed1992

Assessment of disease activity and impending flare in patients with systemic lupus erythematosus. Comparison of the use of complement split products and conventional measurements of complement.

OBJECTIVE: To determine whether increased levels of the complement split products generated in the activation of the alternative or classical pathway accompany more severe disease activity in patients with systemic lupus erythematosus (SLE) and whether these measurements are useful in predicting flares of disease. METHODS: Levels of Ba, Bb, SC5b-9, and C4d were measured in 380 plasma samples obtained from 86 SLE patients who were prospectively followed up for 15 months. RESULTS: In the 20 patients who had inactive disease at the initiation of the study, the mean values of all of the complement split products at entry were within the normal range. In the 47 patients with stable or moderate disease activity, levels of Ba were significantly increased, while the mean values for Bb, SC5b-9, and C4d did not differ significantly from those in patients with inactive disease. The mean entry value of each analyte was highest in the group of 19 patients who had the most severe disease activity at initial evaluation. Traditional measurements of complement, i.e., C3, C4, and CH50, followed similar trends, but did not discriminate between the 3 groups of patients as well as did measurements of the split products. Analysis of the disease course in the patients with inactive or stable/moderate disease revealed that an elevated level of C4d had the most sensitivity with regard to subsequent flare, while an elevated Bb level had the highest specificity and the greatest predictive value. CONCLUSION: These data suggest that elevated levels of complement split products, particularly products of alternative and terminal pathway activation, more accurately reflect disease activity than do conventional measurements of complement in SLE and may be useful in the prediction of impending disease flares.

Complement C3 Convertase, Alternative Pathway↗