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The complement system in central nervous system diseases.

The activation of complement system is an important factor participating in inflammatory, neurodegenerative, and cerebrovascular diseases. Astrocytes and neurons are able to synthesize complement components. Myelin and oligodendrocyte (OLG) activate the classical pathway of complement in vitro in the absence of antibodies. Sublytic C5b-9 in the absence of cell death induces proto-oncogenes, activates cell cycle, and enhances cell survival in OLG. In addition, C5b-9 reverses the differentiation phenotype in OLG and enhances cell survival. beta amyloid protein is an activator of the complement system and neurons are susceptible to bystander complement mediated damage. These findings indicate that complement activation and membrane assembly of C5b-9 play an important role in pathogenesis of central nervous system (CNS) disorders.

Animals↗

Opsonic requirements for hepatic clearance of pneumococci.

An in situ isolated, perfused rat liver system was used to evaluate various opsonins for hepatic trapping and killing of encapsulated, virulent, type 3 pneumococci. Pneumococci were rapidly trapped in the liver in the presence of all potential opsonins including Hanks balanced salt solution with added colloid. However, with some of the potential opsonins the organisms remained viable and could be recovered from the liver. With others there was killing of pneumococci. The combination of rat antibody and complement was effective as an opsonin and produced about the same degree of killing as the same human components. When tested separately killing was not promoted by rat complement, human complement, or human antibody. However, when ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid-Mg2+ was added to block the classical pathway and preserve the alternative pathway there was significant pneumococcal killing which may have been complement mediated or due to an adverse effect of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid-Mg2+ on the organisms. Fibronectin and C-reactive protein reduced the number of surviving microorganisms, although the change was not significant. Immunoglobulin G (IgG)-IgM, IgG, or IgM with complement, and antibody + the classical complement pathway, significantly reduced survival of the organisms. The best killing occurred with antibody plus complement plus fibronectin, which reduced mean survival to 24% during the 1-h perfusion.

Animals↗

The complement profile in babesiosis.

Rats have been infected with Babesia rodhaini, a protozoan agent that induces immune complex disease. Assays for complement have revealed depletion of C2, C3, C4, C5, and whole complement in the course of infection. No evidence of depletion in the alternative (properdin) pathway was found. These findings are consistent with the conclusion that the classical complement pathway is activated during the course of the protozoan infection.

Animals↗

Complement activation by cellulosic dialysis membranes.

AIMS: To assess the effect of cellulosic dialysis membranes on the production of complement degradation products to determine to the role of the classical pathway. METHOD: Complement activation was studied in 33 patients during a single haemodialysis session using cellulosic membranes. Pre- and post-dialysis plasma EDTA valves of C3, C4, C3dg, C4d and C reactive protein (CRP) were measured. Statistical analysis was done using the Wilcoxon signed rank test. RESULTS: Post-dialysis C4 (p = 0.0003), C3dg (p < 0.0001), and C4d (p = 0.003) concentrations were increased compared with pre-dialysis values. There was no significant change in C3 (p = 0.095) and CRP (p = 0.13) values. Post-dialysis C3dg and C4d concentrations correlated significantly (p = 0.007). IgG, an undialysed molecule, was quantified and post-dialysis valves were significantly higher than those before dialysis (p = 0.0002), indicating a degree of haemoconcentration. To remove this effect, the C3:IgG, C4:IgG, C3dg:IgG, C4d:IgG and CRP:IgG ratios were calculated. Compared with pre-dialysis values, post-dialysis C3dg:IgG and C4d:IgG ratios were increased and C3:IgG decreased significantly. No change was observed in C4:IgG and CRP:IgG ratios. CONCLUSION: This study confirms that significant complement activation takes place following dialysis with cellulosic membranes. This is denoted by an increase in C3dg. This was paralleled by a rise in C4d, implying a contributory role for the classical pathway. Concomitant post-dialysis increases in IgG and C4 indicate a degree of haemoconcentration; but removal of this effect shows that C3dg and C4d are increased following dialysis--suggesting classical, in addition to alternative, pathway activation.

Adult↗

Immunomodulators and the complement system.

The possible role of immunomodulators in the host-defense mechanism against neoplasm is discussed from the standpoint of the complement system. Serum complement is activated by the majority of immunomodulators in vitro via either the classical or the alternative pathway, and this activation is sometimes observed following systemic administration of immunomodulators. Besides activating the complement, systemic administration of immunomodulators elevates serum complement levels, and in some cases binds complements to tumor cells. Activated serum complement by an immunomodulator induced an accumulation of PMNs in ascites with tumor cell destruction when intraperitoneally injected, indicating that complement-derived chemotactic factors C3a and C5a generated by an immunomodulator had an antitumor effect. This evidence strongly supports the concept that complement system plays an important role in the host-defense mechanism against neoplasm.

Adjuvants, Immunologic↗

Complement mediated lysis in chickens.

Rat erythrocytes, when either injected i.v. into chickens, or incubated in vitro with chicken serum, will be lysed within minutes. This lysis is complement dependent but does not involve specific antibodies since Ig-free bursectomized chickens behave in exactly the same way as normal chickens with high levels of haemagglutinating antibodies. The lysis is mediated by activation of complement component C3 via the alternative complement pathway and various observations lead us to doubt the functional existence in this lytic reaction of the classical complement pathway.

Animals↗

Properties of glycans that activate the human alternative complement pathway and interact with the human monocyte beta-glucan receptor.

The glycans used in an earlier study to define the ligand specificity of the human monocyte phagocytic receptor for unopsonized particulate activators were assessed for their capacities to activate the proteins of the human alternative complement pathway. Normal human serum was preincubated with glycans under conditions of chelation to prevent activation of the classical complement pathway, and the activation-depletion of the alternative complement pathway was determined by the subsequent capacity of the serum to lyse rabbit erythrocytes (Er). When serum was preincubated at a 1/2 dilution in 8 mM EGTA/2 mM Mg with increasing numbers of yeast glucan or zymosan particles, and was evaluated at final serum dilutions of 1/8, its capacity to lyse Er was found to be reduced by 50% with 1.9 X 10(6)/ml yeast glucan particles and 1.4 X 10(6)/ml zymosan particles. At 2 mg/ml of serum diluted 1/2 in 8 mM EGTA/2 mM Mg, nonturbid preparations of mannan, laminarin, or pyrogen-free inulin and turbid suspensions of cellulose, Sephadex, agarose, or purified inulin failed to activate the alternative complement pathway. In contrast, activation-depletion of the alternative pathway was induced by turbid preparations of crude inulin, nigeran, pachyman, barley beta-glucan, and pustulan, which at 700 micrograms/ml, 500 micrograms/ml, 350 micrograms/ml, 60 micrograms/ml, and 27 micrograms/ml, respectively, effected 50% reductions in the subsequent lysis of Er. After centrifugation of 2 mg/ml suspensions of barley beta-glucan at 1100 X G for 5 min and at 15,000 X G for 15 min, the supernatants contained 90 to 92% and 65% of the barley beta-glucan, respectively, as determined by the anthrone method. On a weight basis, the 1100 X G supernatant exhibited the same capacity to activate the alternative pathway as the corresponding original suspension, whereas the 15,000 X G supernatants had less than 3% of the original anti-complementary activity. Preincubation of adherent human monocytes with increasing concentrations of barley beta-glucan suspensions, 100,000 X G supernatants containing 64% of the original beta-glucan, and laminarin all decreased subsequent ingestion of 1.25 X 10(6) zymosan particles in a dose-related fashion. The numbers of monocytes from three different donors phagocytosing zymosan were reduced by 50% after pretreatment with 30 to 65 micrograms/ml, 25 to 48 micrograms/ml, and 12 to 15 micrograms/ml of barley beta-glucan suspensions, 100,000 X G supernatants of barley beta-glucan, and laminarin, respectively, even though the latter two preparations were fully soluble and had no capacity to activate the alternative pathway.(ABSTRACT TRUNCATED AT 400 WORDS)

Complement Activation↗

Antibody and complement-binding activity of viable and nonviable human spermatozoa.

Antibody and complement fixation by viable and nonviable spermatozoa were studied by means of immunofluorescence and a hemolytic assay (CH-50). Spermatozoa were incubated in sera from fertile male and female donors and in peritoneal fluid from fertile women undergoing laparoscopy. Nonviable spermatozoa were able to bind antibody or complement from sera and peritoneal fluid. There was no evidence of antibody or complement fixation by viable spermatozoa. The antibodies present in the serum that bind to spermatozoa belong to the IgG and IgM class; in peritoneal fluid, only IgG could be found. Complement fixation occurred via the classical (antibody-mediated) and alternative pathway. Viable spermatozoa possess antigenic properties different from nonviable spermatozoa. The lack of immunological reaction of women to viable spermatozoa and a possible mechanism for immunological infertility is considered.

Antibodies↗

Signal transduction mechanisms of C1q-mediated superoxide production. Evidence for the involvement of temporally distinct staurosporine-insensitive and sensitive pathways.

C1q, a plasma glycoprotein and the recognition component of the classical complement pathway, interacts with specific cells of the immune system resulting in the enhancement of cell function. For example, interaction of C1q with its cell-surface receptor on neutrophils induces the activation of the respiratory burst, a finding previously documented using a chemiluminescent assay to detect oxygen radical formation. In an alternative approach we have now used a modified cytochrome c reduction assay to characterize C1q-mediated production of superoxide anion (O2-) in more detail. C1q coated to microtiter wells induced O2- release, which occurred microtiter wells induced O2- release, which occurred after a lag period of 10 to 20 min, and was then sustained over approximately 1 h. O2- production could be triggered by the purified pepsin-resistant, collagen-like fragment of C1q, but not by mannose-binding protein and pulmonary surfactant protein A, proteins that also contain collagen-like domains. Concentrations of C1q which promoted a vigorous O2- generation did not induce release of neutrophil primary granules and caused little or no secondary granule release. Investigation of the biochemical events mediating C1q stimulated O2- production by neutrophils revealed that the response invoked two biochemical pathways with distinct sensitivities to previously described inhibitors. A role for Ca2+ in initiation of the response was suggested by the inhibitory effect of EGTA, the calmodulin antagonist W7, and the intracellular Ca2+ chelator BAPTA. The protein kinase inhibitor staurosporine did not inhibit the induction of the response, but did block that component of the response occurring after approximately 30 min. Neither phase of C1q-mediated O2- production was inhibited by pertussis toxin, a strong inhibitor of the G-protein-coupled FMLP-mediated response. In summary, C1q-triggered O2- production is relatively unique both in terms of the kinetics of the response and the biochemical pathways evoked. These data support the hypothesis that more than one biochemical pathway induced by ligand-receptor interaction can activate the neutrophil NADPH oxidase.

Alkaloids↗

Activation of the complement system in human immunodeficiency virus infection: relevance of the classical pathway to pathogenesis and disease severity.

In vitro studies implicate classical and alternative complement pathway activation in the pathogenesis of human immunodeficiency virus (HIV) infection. To ascertain their importance in vivo, activation fragments of the classical (C4d), alternative (Ba), and common (C3d) pathways were measured and fragment to parent molecule ratios derived in 74 HIV-infected individuals and related to circulating immune complex (CIC) levels, Centers for Disease Control (CDC) stage, and beta 2-microglobulin, neopterin, and CD4-positive (CD4+) lymphocyte levels. All fragments and ratios were significantly higher in patients (P less than .01) than controls. C4 conversion indices (C4d and C4d to C4) increased linearly with increasing CDC stage (P less than .001), while CD4+ lymphocytes decreased linearly (P less than .001). C4d, C3d, C4d to C4, and C3d to C3 correlated with increasing CIC and beta 2-microglobulin, and C4d and C4d to C4 correlated with decreasing CD4+ lymphocytes (P less than .05). The relationship of classical complement pathway activation to disease progression and CD4+ lymphocytes suggests its involvement in the pathogenesis of HIV infection.

Adult↗

Anticomplementary activity of tuberculin: relationship to platelet aggregation and lytic response.

Experiments were performed to examine the interaction of tuberculin with platelets and complement. Hemolytic complement titrations show that tuberculin consumes complement in human, rabbit, and guinea pig serum. Evidence in support of classical pathway activation was provided by observation of C1 consumption and failure to detect significant conversion of alternative pathway factor B to B by immunoelectrophoresis. Platelets in plasma from guinea pigs deficient in the fourth component of complement were not affected by tuberculin. However, studies on platelet aggregation in plasma chelated with ethyleneglycolbis(beta-aminoethyl ether)-N,N-tetraacetic acid indicated that tuberculin may initiate sluggish activation of the alternative pathway. That the reaction between tuberculin and platelets is a lytic one was evidenced by observing the release of the cytoplasmic enzyme lactic dehydrogenase and efflux of rubidium-86. Studies with C6-deficient rabbits indicated that platelet release of exogenously supplied tritiated serotonin is caused by platelet lysis.

Animals↗

The role of antibody and complement in the reticuloendothelial clearance of pneumococci from the bloodstream.

An experimental model of pneumococcal bacteremia in guinea pigs has been developed. By use of this model, complement has been shown to play a critical role in clearance of Streptococcus pneumoniae from the bloodstream and in survival of guinea pigs after iv challenge with type 7 S. pneumoniae. In nonimmune animals, complement activation occurs primarily via the alternative pathway. However, anticapsular antibodies increase the rate of clearance of pneumococci primarily via activation of the classical complement pathway. Detailed studies of the reticuloendothelial localization of cleared radiolabeled pneumococci showed that clearance took place primarily in liver and spleen and that anticapsular antibody increased hepatic and decreased splenic sequestration. This effect could be blocked by depleting complement with cobra venom factor. Comparison of nonimmune animals injected with unencapsulated pneumococci or encapsulated types 7 or 12 pneumococci showed that the virulence of these organisms for guinea pigs correlated with the extent of splenic sequestration. Sensitization of encapsulated pneumococci with anticapsular antibodies led to an antibody dose-dependent increase in the rate of bloodstream clearance. Sensitization of encapsulated pneumococci with anticell wall antibodies had no effect on clearance rates despite the ability of these antibodies to bind to the bacteria and to activate and fix complement to the organisms. In vitro studies showed that C3b deposited by these opsonically ineffective antibodies interacted poorly with C3b receptors. Electron microscopic studies showed that C3b deposited by anticapsular antibodies bound to the pneumococcal capsule while C3b deposited by anti-cell wall antibodies did not. Thus, the localization of C3b deposition on the pneumococcus markedly affects its opsonic potential.

Animals↗

Effect of aspirin on the complement system in vitro.

Aspirin (acetylsalicylic acid), ASA and sodium salicylate (NaSA) activate the complement system in vitro. The activation involves the components of the classical pathway. It is, however, antibody independent. Evidence for activation are (1) consumption of C and C component activities; (2) activation of C1 evidenced by release of C1s from the macromolecular complex, and (3) C3 and C5 conversion.

Aspirin↗

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↗

Oxygen and serum complement in phagocytosis and killing of Propionibacterium acnes.

Phagocytosis and killing of Propionibacterium acnes by human peripheral blood leukocytes were promoted by normal human serum and by serum depleted of immunoglobulin G and M. Serum that had been heat-inactivated, depleted of complement component C3, or depleted of C4 and factor B, did not promote phagocytosis or killing. Depletion of complement-component C4 or factor B from normal human serum did not impair its capacity to promote phagocytosis and killing of P. acnes. These results indicate that phagocytosis of P. acnes is mediated by complement component C3, activated either by the classical or by the alternative pathway. P. acnes was phagocytosed as efficiently under anaerobic as under aerobic conditions. The bacteria were, however, killed at a considerably slower rate by anaerobically incubated leukocytes than by leukocytes incubated in air. Thus, oxygen dependent mechanisms were essential for killing of P. acnes.

Adult↗

Complement system is not activated in primary biliary cirrhosis.

There is controversial evidence suggesting that the classical pathway of complement system is chronically activated in primary biliary cirrhosis (PBC) and that complement activation may be important in development of bile duct injury. We have reevaluated this issue by measuring by-products of complement activation such as C4a, C3a, Bb, and terminal complement complexes (SC5b-9) in plasma of 44 PBC patients with sensitive methods not previously used to detect complement activation in this disease. Age-matched healthy women and patients with chronic hepatitis of different etiology were studied as controls. We found that PBC patients have normal C4a concentrations. This finding argues strongly against chronic classical pathway activation. Although a minor increase of C3a levels was observed in a minority of PBC patients, the C3a/C3 ratio, an index used to evaluate the extent of native protein conversion, was remarkably similar in all groups. Potentially lytic terminal complement complexes were not increased. PBC patients had normal Bb plasma levels, indicating that the alternative pathway is also not activated. C3 concentration was higher in PBC patients than in healthy subjects and in chronic hepatitis patients, particularly in the early stages of the disease. C3 and C4 concentrations became lower in PBC and chronic hepatitis with the progression of the disease. The increase of C3 concentration in PBC does not reflect liver inflammation, since serum levels of C-reactive protein are normal. We found high serum C3 levels in patients with rare chronic cholestatic syndromes without superimposed infections and observed that serum C3 levels paralleled those of bilirubin in a patient with benign recurrent intrahepatic cholestasis. In conclusion, our data indicate that complement is not activated in PBC and that the increase of serum C3 levels is related to cholestasis.

Adult↗

A new complement-mediated cytolytic mechanism--the C1-bypass activation pathway.

A new cytolytic pathway is described whereby cells sensitized with cytotoxic antibody can be specifically lysed in the complete absence of intact, classical complement pathway function. Evaluation of this model with sera deficient in the 4th (C4), 2nd (C2), and 6th (C6) components of complement has revealed that this new lytic mechanism, termed the C1-bypass activation pathway, is initiated by the antibody-mediated activation of C1. Utilizing components of the previously described alternate complement pathway, this pathway bypasses C4 and C2 to activate the third to ninth components of complement (C3-9) with induction of membrane damage.

Animals↗

Hereditary angioneurotic edema: clinical and laboratory findings in 58 subjects.

An in-depth analysis of clinical and laboratory findings in 58 patients affected by hereditary angioneurotic edema (HANE) is reported with special focus on problems related to the diagnosis of the disorder. The functional C1 inhibitor (C1INH) assay is the method of choice in the diagnosis of HANE, as it is capable of revealing the disorder with 100% accuracy. The immunochemical assay of C1INH detected HANE in 84.5% of the cases, i.e., immunochemical deficiency of C1INH (type I HANE). C4 was markedly reduced in both type I and type II HANE; thus, C4 levels can be particularly useful when C1INH functional tests are not available. CH50 testing is of little diagnostic value since total hemolytic complement activity is reduced in a variety of other congenital or acquired pathologies involving the complement system. The CH50 assay after incubation in low ionic strength buffer may be utilized in mass screening programs for qualitative evaluation. However, the test has the drawback of not being applicable in cases of frank hypocomplmentemia. While a depletion of the complement classical pathway was detected in most cases, no alteration in the complement alternative pathway was recorded, nor there was any reduction in immunoglobulin levels. Family history was positive in 100% of the cases. Attacks were almost always brought on by stress and/or trauma, though the causes were sometimes unknown. Edema could be cutaneous (non-pitting and non-pruritic) in 94.2%, laryngeal (often life-threatening) in 48% and abdominal (almost always painful) in 88.4% of patients. Associated pathologies were found in 2 patients, i.e., lupus rash and C3NeF-positive chronic membranoproliferative glomerulonephritis, respectively.

Adolescent↗