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PubMed1982

Effect of C-reactive protein on the complement-mediated stimulated of human neutrophils by Streptococcus pneumoniae serotypes 3 and 6.

C-reactive protein (CRP) has long been known to appear in the sera of individuals with inflammatory processes, but its role in host defense against bacterial infection is unclear. We have recently demonstrated that CRP in the presence of the classical complement pathway markedly enhances the opsonization of Streptococcus pneumoniae serotype 27 by polymorphonuclear leukocytes (Edwards et al., J. Immunol. 128:2493-2496). In this report we have extended these studies to characterize the role of CRP in the opsonization of other S. pneumoniae serotypes. Two clinically important serotypes, 3 and 6, were tested along with the nonpathogenic rough strain R36a. All strains were found to bind radiolabeled CRP in the presence of calcium and to activate the classical complement pathway in normal human serum. However, the opsonophagocytic response of polymorphonuclear leukocytes to the strains, measured by chemiluminescence, was quite different. In contrast to the marked enhancement by CRP of the chemiluminescent response to serotype 27 in normal human serum, CRP had no effect on the opsonization of serotype 6 or R36a and inhibited opsonization of serotype 3 in normal serum. In serum from a hypogammaglobulinemic patient, CRP enhanced the lowered chemiluminescent response to serotype 3 and 6 organisms but did not restore the response to normal. The greater opsonic effect of CRP on serotype 27 may be related to the ability of CRP to bind to the capsule as well as to the cell wall of this serotype or to differences in the amount of CRP bound to the different strains.

C-Reactive Protein↗
PubMed1985

The development of complement activating ability as an age related factor in murine brains.

We recently reported on the ability of the myelin fraction of the murine brain to activate the complement system through the classical pathway, which might be important in the induction of secondary inflammation in various pathological conditions where brain tissue has been exposed to the complement. The present study was undertaken to investigate the relationship between the appearance of complement activity in the mouse brain and the synthesis of myelin in ICR mice up to ninety days of age. Here, we show that anti-complementary activity in the murine brain is closely related to murine brain weight and that its activity seems to be dependent on the amount of myelin in the murine brain. Myelin was isolated from brains of equal weight taken from both two-day old and ninety-day-old mice, and we found that ninety-day-old myelin consumed a much greater amount of complement (C) than two-day-old myelin. However, for equal concentrations of myelin, almost an equal amount of C was consumed by the myelin of the two-day-old mice and by that of the ninety-day-old mice. It was suggested that the difference of anti-complementary activity was caused by the myelin contents of the murine brains, but the possibility of maturation of myelin was not excluded. The mechanism involved in the anticomplementary activity of the myelin was found to be related to the consumption of complement, mainly via the classical pathway but also less activity via the alternative pathway.

Aging↗
PubMed1984

Tissue culture demyelination by normal human serum.

Serum from all of 20 normal individuals induced some degree of demyelination when applied to well-myelinated mouse cerebellum cultures. An intact complement sequence through C5 is required. Demyelinating activity was heat labile at 56 degrees C for 30 minutes but was not destroyed at 50 degrees C for 30 minutes (which inhibits properdin factor B and alternate complement pathway activation, but not the classic complement pathway). Sera from patients with agammaglobulinemia, C4 deficiency, or C6 deficiency all induced demyelination. Our results suggest that tissue culture demyelination results from nonimmunoglobulin activation of the alternate complement pathway and is not limited to sera from patients with neurological disease.

Animals↗
PubMedDate not supplied

A complement-sensitive mutant of Pseudomonas aeruginosa.

The role of complement in the bactericidal activity of human serum against a mutant strain of Pseudomonas aeruginosa used as a model was demonstrated. The involvement of complement in the bacterial destruction of P. aeruginosa, and the contribution of the alternative and classical pathways of the complement system were directly evidenced by using sera from complement-deficient patients.

Animals↗
PubMed1978

Host defense against opportunist microorganisms following trauma. II. Changes in complement and immunoglobulins in patients with abdominal trauma and in septic patients without trauma.

Total hemolytic complement (CH50), conversion of C3 by inulin and cobra venom factor (CoVF), and immunochemical levels of Clq, C4, C2, C3, C5, factor B, properdin, C3b inactivator (KAF), and immunoglobulins (Igs) G, A, and M were measured in the sera of ten patients with abdominal trauma and ten medical patients with septicemia without trauma. Reduction in C3 conversion by CoVF and decrease in the levels of properdin and KAF were demonstrated in the trauma sera. CH50 and the level of C5 were also decreased. Conversion of C3 by inulin and levels of factor B, Clq, C4, C2, and C3 were found to be normal in the patients' sera. Complement levels and activities were found to be normal in the sera of the septic non-trauma patients. A decrease in serum IgM was observed in both patient groups; levels of IgG and IgA were normal. These results indicated that abnormalities of immunoglobulin and of the alternative and classical complement pathways were associated with nonburn trauma. Moreover, the data suggested that consumption of the classical complement pathway associated with septicemia in the thermally injured patient resulted from synergism between the trauma and infection rather than from septicemia per se.

Abdominal Injuries↗
PubMed1994

The inhibitory effect of factor J on the alternative complement pathway.

Factor J (FJ) is a cationic glycoprotein with inhibitory activity in C1, the first component of the classical complement pathway. This study demonstrates that FJ is able to regulate the activity of the alternative complement pathway. FJ inhibits the generation of fluid-phase and cell-bound alternative pathway C3 convertase, C3b,Bb (C3-cleaving enzyme). Thus, FJ interferes with the generation of alternative pathway C3 convertase when sheep erythrocytes bearing antibody and activated C3 and C4 (EAC4b,3b) are incubated with the individual complement components, factors B, D, and P. FJ accelerates the decay of C3 convertase with a time course similar to that of factor H, and when both regulators are present together, the decay of enzyme activity is faster than when they are added separately. Furthermore, FJ is able to inhibit the cleavage of C3 by factor B in a fluid-phase assay. FJ prevents the initiation of alternative pathway activation in "more stabilized systems" with well known activators of alternative pathway C3 convertase such as C3 nephritic factor (an autoantibody against alternative pathway C3 convertase), cobra venom factor, and rabbit erythrocytes. In these systems, FJ has no effect on C3 convertase stabilized by rabbit erythrocytes or cobra venom factor. In contrast, FJ promotes the dissociation of C3 convertase stabilized by C3 nephritic factor, but with much lower efficiency than in preventing initiation. Direct interaction of FJ with individual components of C3 convertase was shown by a solid-phase binding assay using plates coated with C3, C3b, B, Bb, or FJ. FJ inhibitory activity in the alternative pathway can be modulated by polyanions like heparin. FJ-mediated inhibition in the alternative complement pathway can be modified by surface interactions, as occurs during alternative pathway C3 convertase activation. Thus, when FJ is adsorbed by and eluted from hydroxylapatite and reverse-phase columns, its inhibitory effect on more stabilized systems is lost. This loss of inhibitory activity is fully reversed when FJ is rechromatographed on heparin-Sepharose or Sepharose columns. Taking into account these data, FJ may be included in the group of highly charged molecules that inhibit the activation of classical and alternative complement pathways (i.e. eosinophil major basic protein, protamine, and heparin).

Animals↗
PubMed1982

Complement-mediated inhibition of immune precipitation. I. Role of the classical and alternative pathways.

This study has examined the mechanisms involved in complement-mediated inhibition of immune precipitation using radiolabelled BSA and rabbit anti-BSA. Purified proenzyme C1 was capable of maintaining the complexes in soluble form during the first few minutes of reaction whereas immune precipitation was immediate in the presence of purified C1q or C1 + EDTA (ethylenediamine tetra-acetate). In C1q deficient serum, initial immune aggregation was followed by partial solubilization of the formed precipitate similar to that obtained with normal human serum in the presence of Mg EGTA. In C2 deficient serum precipitation occurred at a slow rate. Repletion of the deficient component (C1q or C2 respectively) restored fully inhibition of precipitation. These experiments establish a critical role for the classical pathway, in this phenomenon. By contrast the role of the alternative pathway in maintaining complexes in solution was less important; only partial and delayed precipitation occurred in sera depleted of factor D (RD) or factor B (RB). B and D restored normal complement activity to depleted sera. No precipitation was detected in a reagent depleted of properdin (RP). The mechanisms of inhibition of precipitation are therefore distinct from those responsible for solubilization of an immune precipitate, which is largely dependent on the alternative pathway.

Animals↗
PubMed1996

CRP-mediated activation of complement in vivo: assessment by measuring circulating complement-C-reactive protein complexes.

The in vivo function of C-reactive protein (CRP) is unknown. Among the in vitro functions assigned to CRP is the ability to activate complement via the classical pathway. To date, there is no evidence supporting that CRP exerts this function in vivo. We here show a novel approach to assess CRP-mediated complement activation in vivo, which is based on the property that activated complement factors C3 and C4 fix to CRP during complement activation induced by this acute phase protein. We developed specific ELISAs for complexes between CRP and C4b, C4d, C3b, or C3d. We established that in vitro complement-CRP complexes were formed only during CRP-dependent activation, and not during activation by other activators, even in the presence of high CRP levels. Circulating levels of complement-CRP complexes were undetectable in normal donors, but significantly increased in nine patients following implantation of a renal allograft. Importantly, levels of complement-CRP complexes did not change in these patients upon a bolus infusion of mAb OKT3, which induces activation of the classical complement pathway, demonstrating in vivo that complement-CRP complexes are not formed during CRP-independent activation of complement, even when CRP is elevated. We conclude that measurement of complement-CRP complexes provides a suitable tool to study CRP-mediated activation of complement in vivo. Furthermore, increased levels of these complexes occur in clinical samples, indicating that CRP may induce activation of complement in vivo.

Adult↗
PubMed1977

Host cell modification of lymphocytic choriomeningitis virus and Newcastle disease virus altering viral inactivation by human complement.

Complement in human serum inactivated several enveloped viruses, but for some viruses the degree of inactivation depended on their passage history. In short, human serum detected cell-induced modifications of virions. Normal human serum, lacking detectable neutralizing antibodies to the virions, inactivated lymphocytic choriomeningitis virus (LCMV) and Newcastle disease virus (NDV) when the viruses were passed through some cell lines but not others. Host cell modification was further documented with LCMV since antibody to the cell (in conjunction with a complement source) inactivated virus produced by that cell. The mechanism by which human serum inactivated LCMV passed through L cells was determined. By using serum immunochemically depleted in the classical complement pathway component C4 and/or the alternative complement pathway component factor B, as well as other methods, it was shown that LCMV was inactivated via the classical complement pathway. Absorption and immune precipitation experiments indicated that the inactivation of LCMV by complement was mediated by natural antibody directed against the host (L-929) cell. NDV grown in chick embryo cells could be unactivated by either complement pathway in the absence of the other. A requirement for antibody could not be demonstrated in the NDV system. On the basis of these data it is proposed that alterations in virulence dependent upon passage of the virus in cells or animals may be partially explained by changes in virus sensitivity to human serum inactivation.

Animals↗
PubMed1987

Mouse peritoneal macrophages cultured serum-free deposit complement on IgM-coated sheep erythrocytes in vitro.

We conclude that the macrophages during cultivation produce the complement components of the classical pathway of complement, deposit complement components on EIgM and then phagocytose these cells via complement receptors. The conclusion is based on the following: EIgM, an activator of the classical pathway, are ingested when cultured serum-free with mouse peritoneal macrophages. We found a significantly higher binding of labelled protein to EIgM than to E kept in macrophage cultures in the presence of tritiated leucine, showing that de novo synthesis of macrophage-derived protein with affinity to EIgM takes place. A fraction of the bound protein is C3b and iC3b, since anti-mouse C3 antibodies bound to the co-cultured EIgM. Cycloheximide or anti-Mac-1 in the cultures inhibited macrophage attachment and uptake of EIgM. The phagocyte uptake of EIgM coated with complement by serum pretreatment was not inhibited by cycloheximide. This shows that the phagocytosis of the EIgM is dependent on erythrocyte-bound complement proteins made by the macrophage.

Animals↗
PubMedDate not supplied

Dialysis leukopenia and hypoxemia in a patient without measurable complement activity.

We have studied complement activity, total leukocyte counts, PO2 and acid-base balance during a single hemodialysis with cuprophan membranes in a patient with hereditary angioedema and C3NeF-positive chronic membranoproliferative glomerulonephritis. Before, during and after the dialytic procedure plasma complement activity (total hemolytic complement, classical and alternative pathway activities) was not detectable and no C3-conversion occurred, while profound leukopenia (from 8,500 to 1,800 leukocytes/microliter) and hypoxemia (from 101.8 to 86 mmHg PO2) were found within 20 min from the initiation of hemodialysis. Similar results were obtained by studying the same parameters during two additional hemodialytic procedures. In vitro experiments showed that the patient's C3 could not be converted, either by cuprophan or zymosan, a specific and potent complement activator, even under optimal experimental conditions. Our data demonstrate that complement activation is not the only possible mechanism responsible for early leukopenia (as well as hypoxemia) during dialysis with cuprophan membranes.

Acid-Base Equilibrium↗
PubMed1982

Mechanism of enhanced complement-dependent cytotoxicity of papain-treated lymphocytes: evidence for increased stability of classical pathway C3 convertase.

The mechanisms of enhanced antibody-mediated, complement-dependent cytotoxicity caused by proteolytic treatment of cells was studied in a model system based on HLA microlymphocytotoxicity methods. In this model, papain treatment of lymphocytes resulted in a) no change in antibody binding, b) a slight decrease in initial binding of C4, c) a marked increase in stability of cell-bound C4b, resulting in d) an increase of cell-bound C3, and e) no increase in lytic efficiency of the C5b-9 membrane attack complex. We conclude that the most important step in papain enhancement of lysis of lymphocytes is an increased stability of cell-bound C4b, possibly through decreased surface binding of C4-bp. This mechanism may be relevant to the pathologically increased lysis of cells occurring in patients with hereditary erythroblastic multinuclearity with a positive acidified-serum test (HEM-PAS).

Anemia, Dyserythropoietic, Congenital↗
PubMed1979

Complement in tears from normal humans.

Tears from ten normal persons were used in hemolytic assays to test for activity of total hemolytic complement (tested in all ten subjects), activities of each of the nine complement components (tested in two subjects), and activity of the alternate pathway (tested in two subjects). A modified radial-immunodiffusion method was used to confirm the presence of C3 and C4 complement proteins in the tear samples from all ten subjects. Factor B protein was detected in tears from two of four normal subjects tested. In dilutions up to 1:4, hemolytic activity was observed in tears from five of the ten subjects. Samples from the remaining five subjects had CH50 activity at dilutions up to 1:2. In control tests, human serum had CH50 activity at 1:32. No lysis occurred in Veronal-buffered saline or in serum and tears heated to 56 degrees C for 30 minutes. Complement proteins C3 through C9 displayed hemolytic activity in tears from each of two subjects tested for complement components. The classic and alternate complement pathways in tears can be included among the defense mechanisms of the ocular surfaces.

Complement C3↗
PubMed1985

Susceptibility of Campylobacter isolates to the bactericidal activity of human serum.

Although Campylobacter jejuni and related thermophilic organisms are more common human pathogens than are Campylobacter fetus, most bloodstream or systemic isolates are C. fetus. To understand the pathophysiology related to this observation, the authors studied susceptibility to the bactericidal activity of normal human serum of Campylobacter coli, C. jejuni, and C. fetus isolates from feces and blood. In standardized assays, 10 of 15 C. jejuni and related isolates showed 90% kill (mean, 90.6% +/- 5.9); under more stringent conditions, the relatively resistant strains were completely killed. In contrast, all C. fetus strains were highly serum resistant under both standard and stringent conditions. Killing of C. jejuni was ablated by heating serum to 56 C but restored by addition of complement. Both classical and alternative complement pathways may contribute to killing, and adsorption studies demonstrated antibody dependence. Serum resistance may permit systemic infection by C. fetus, whereas complement- and antibody-mediated serum sensitivity of C. jejuni may account for the relative infrequency of systemic invasion.

Antibodies, Bacterial↗
PubMed1993

Opsonic requirements of Helicobacter pylori.

The opsonic requirements of Helicobacter pylori were investigated in a series of experiments with human polymorphonuclear leucocytes (PMNL). Pre-incubation of H. pylori with pooled normal human serum (NHS) in concentrations of 5-20% significantly increased the uptake of radiolabelled bacteria by PMNL. Treatment of the bacteria with NHS 30% caused the release of radiolabel and this effect was abolished by heating serum to 56 degrees C, suggesting that H. pylori is serum-sensitive and that complement is involved. Opsonisation of H. pylori with NHS concentrations of 10-30% significantly increased PMNL chemiluminescence. Removal of specific antibody had no effect. Removal of either the classical or alternative complement pathways produced no significant change in PMNL chemiluminescence, indicating that either pathway is sufficient for opsonisation on its own. The results confirm that complement is the most efficient opsonin for H. pylori.

Analysis of Variance↗
PubMed1986

Pneumococcal intracellular killing is abolished by polysaccharide despite serum complement activity.

Normal human serum absorbed at 0 degrees C with pneumococcal serotype 1, 12, or 25 lost the ability to support polymorphonuclear leukocyte intracellular killing of some pneumococcal serotypes even if immunoglobulin was provided. The absorbed serum contained no organisms but had residual polysaccharide when measured by counterimmunoelectrophoresis against type-specific antisera. The influence of pneumococcal polysaccharide (PPS) on serum support of intracellular polymorphonuclear leukocyte killing was evaluated. Normal human serum was mixed with PPS serotype 1, 12, or 25 at 0 degrees C for up to 120 min and then used as the opsonic source in standard phagocytic killing assays with serotype 1, 12, or 25. Immediately after mixing, each serum combined with PPS serotype 1, 12, or 25 supported killing of all serotypes tested. With increasing time at 0 degrees C with serotype 1 PPS, serum exhibited a marked progressive decline in killing of serotype 25, a similar but less marked impairment in killing of serotype 12, and essentially no impairment for serotype 1. Serum treated with type 25 PPS did not support killing of type 25, but allowed normal killing of types 1 and 12. Incubation with type 12 PPS impaired opsonization of types 12 and 25, but not 1. Addition of PPS-specific antisera did not restore killing. Residual serum hemolytic activity of classic and alternative complement pathways was not reduced below opsonizing levels after 120 min at 0 degrees C. Furthermore, PPS treatment of normal human serum did not alter the attachment or ingestion of 14C-labeled pneumococci by polymorphonuclear leukocytes. Some serotypes of PPS reacted slowly with serum at 0 degrees C, diminishing its ability to support intracellular killing of pneumococci despite serum hemolytic complement activity. Phagocytosis was not inhibited. Specific antibody did not overcome inactivation. Different requirements for the inactivated factor among serotypes may be a characteristic related to organism virulence.

Blood Bactericidal Activity↗