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PubMed1984

Initiation of complement activation.

The complement system is an excellent one to look at as an example of a triggered enzyme system. It is found to use almost all the strategies of enzyme cascades and for initiation which were discussed in the introduction. The classical pathway is a fine example of an active zymogen form of activation and the alternative pathway is the canonical example of a tickover. Both may also be activated by exogenous enzymes from other systems. The strategies of enzymes waiting for substrates, of substrates waiting for enzymes, and of both waiting for modifying proteins are all seen in various stages of the reaction. There is an association of a linear cascade with the positive feedback amplification loop. This degree of evolutionary adaptation is not only aesthetically pleasing but must be taken to mean that the system is of considerable biological importance and has been over a long evolutionary time span.

Complement Activation↗
PubMedDate not supplied

Role of humoral factors in host resistance to the Bacteroides fragilis group.

The alternative complement pathway and antibody play an important role in host resistance to members of the Bacteroides fragilis group. Clinical isolates of the B. fragilis group are typically resistant to the bactericidal action of serum. Naturally occurring antibodies in serum directed against these bacteria belong primarily to the IgM class. These antibodies are not required for activation of the alternative pathway by the bacteria but rather potentiate alternative pathway activation. Activation of the alternative pathway by the bacteria leads to the generation of chemotactic activity for neutrophils and to C3 deposition on the bacterial surfaces. Both iC3b, the predominant molecular form of the bacteria-bound C3, and IgM antibody are necessary for phagocytosis and killing of the bacteria by neutrophils. IgM acts synergistically with iC3b to facilitate adherence of the bacteria to the neutrophils. Certain Bacteroides strains require additional as yet uncharacterized auxiliary opsonins for maximal adherence to neutrophils.

Antibodies, Bacterial↗
PubMed1987

The effects of immunoglobulin isotype and antibody affinity on complement-mediated inhibition of immune precipitation and solubilization.

We have studied complement-mediated prevention of precipitation (PIP) and solubilization of immune complexes (IC) formed with DNP19-BSA and murine monoclonal antibodies (MCAs) of different isotypes and affinities. PIP was effective for IC formed with IgG1 and IgM antibodies, but not for IgA MCA. For IgG1 MCAs, affinity appeared to exert a minor effect on PIP, and IC formed in antibody excess or at equivalence were retained in solution more readily than those formed in antigen excess. For IgM MCAs affinity and antigen-antibody ratio did not affect PIP. As PIP did not occur in Mg-EGTA, it was concluded that PIP was entirely classical pathway dependent. Solubilization of IC containing IgG1 MCAs occurred more rapidly and to a greater extent with low affinity antibodies and an inverse relationship between affinity and the extent of solubilization was observed. Complexes formed with IgG1 MCAs were solubilized relatively poorly when formed in antigen excess. In contrast, affinity and antigen-antibody ratio did not influence the rate and extent of solubilization of IC containing IgM MCAs. IC formed with IgG2b were solubilized rapidly whereas those formed with IgG2a or IgA were solubilized poorly. The relative contributions of the classical and the alternative pathways to solubilization varied with each antibody and the effect of antigen-antibody ratio on these relative contributions was inconsistent.

Antibodies, Monoclonal↗
PubMed1990

Inherited complement deficiency states: implications for immunity and immunological disease.

The study of complement deficiency states and their influence on immune function has generated new insights and still provides a challenge to continued investigation. The association of classical pathway deficiencies (C1, C4, C2 or C3) with immunological diseases such as SLE and glomerulonephritis has contributed to current knowledge concerning complement-dependent immune complex handling and elimination. Susceptibility to systemic infection with encapsulated bacteria is encountered in most forms of inherited complement deficiency. Recurrent neisserial infection is the only clinical manifestation clearly associated with defects of the membranolytic sequence C5-C9, while deficiency of properdin, a component of the alternative activation pathway, appears to predispose to nonrecurrent meningococcal disease. Inherited complement deficiency is rare, but the perspective is widened by the more common occurence of acquired defects in immunological diseases, and the apparent requirement for efficient complement recruitment in host defense. Another aspect is the possibility that complement deficiency might alleviate or prevent inflammatory symptoms. Notably, complement deficiency has not been reported in classical rheumatoid arthritis. Considerations of this kind would be refuted or modified by findings of complement deficiency in single patients.

Animals↗
PubMed1985

[Chemotaxis defect and recurrent E. coli meningitis].

The increased susceptibility to bacterial infections due to a decreased chemotaxis of neutrophil granulocytes was investigated in a premature small for gestational age baby, who such suffered from recurrent E. coli-meningitis. Causes as anatomic lesions, brain abscess, septic granuloumatosus disease and the Chédiak-Higashi-anomaly were ruled out. At the age of 9 and 13 weeks chemotaxis function compared to age-matched and adult controls was diminished. Addition of serum from healthy adults increased directed migration without reaching normal levels. The study of the complement status revealed a diminution of CH50, the alternate pathway components and C6-C9. Thus, decreased chemotaxis is believed to originate from a combined intrinsic-extrinsic defect. No relapses of infection were observed during prophylactic treatment with ascorbate and cotrimoxazole. Intrinsic as well as extrinsic chemotaxis became normal at the age of 7 months. Simultaneously, complement status was found to approach normal levels. The relevance of haematologic-immunologic evaluation in cases of relapsing severe bacterial infections in preterm newborns is discussed.

Chemotaxis, Leukocyte↗
PubMed1998

Soluble mannan and beta-glucan inhibit the uptake of Malassezia furfur by human monocytic cell line, THP-1.

The uptake of live and heat-killed Malassezia furfur HIC 3321, HIC 3343 and Candida albicans ATCC 10231 by human monocytic cell line, THP-1, was examined. THP-1 was differentiated by PMA for 7 days before use. The uptake of these yeasts by THP-1 was increased in a concentration-dependent manner of yeasts, and the uptake reached plateau level at the E/T (yeast/THP-1) ratio 5. In addition, a higher percentage of heat-killed cells than live cells was taken in THP-1. Yeast mannan and beta-1,3-glucan, random coiled conformer, inhibited the uptake of live and heat-killed M. furfur by THP-1, though dextran T-250, that is alpha-glucan, and schizophyllan (SPG), triple helix conformer of beta-glucan, did not. Interestingly, mannan inhibited the uptake of both types, live and heat-killed, of C. albicans, however, laminaran inhibited the uptake of heat-killed C. albicans alone. Opsonization of these yeasts with normal human serum enhanced the uptake of yeasts, although opsonization with heat-inactivated serum, the treatment at 56 degrees C for 30 min, did not enhance. These results suggested that live and heat-killed M. furfur was recognized by THP-1 through mannose receptor, beta-glucan receptor and complement receptor type 3 via the activation of alternative pathway of complement.

Candida albicans↗
PubMed1985

Deposition of C3b and iC3b onto particulate activators of the human complement system. Quantitation with monoclonal antibodies to human C3.

Monoclonal antibodies were used to determine the number and molecular form of C3 bound to particulate activators of the complement (C) system by human serum. Sheep erythrocytes (E) coated with IgM (EIgM) and IgG (EIgG) were used to study activation of the classical pathway (CP). Yeast (Y), rabbit erythrocytes (ER), and five species of bacteria (Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae type 3, Streptococcus pyogenes, and Hemophilus influenzae type b) were used to study activation of the alternative pathway (AP). The deposition of C3b onto EIgM and EIgG incubated in C7-deficient human serum was dependent on the serum concentration. At all serum concentrations tested, there was complete conversion of C3b to iC3b. Kinetic analysis of C3b deposition and conversion to iC3b indicated that these events occurred almost simultaneously; the reaction was completed by 15 min. The deposition of C3 onto the AP activators ER and Y was also dependent on serum concentration, and ER, but not Y, required the presence of Mg-EGTA and thus the activation of only the AP. C3b deposition and conversion to iC3b on Y was complete in 15 min, with 82% of bound C3 converted to iC3b. For ER, maximum C3 deposition required 30 min in both the presence and absence of Mg-EGTA. However, after 1 h of incubation, 74% of bound C2 was iC3b in the absence of Mg-EGTA, compared with only 52% in the presence of Mg-EGTA. Thus, even on AP activators, a large portion of C3b may be converted to iC3b, and this conversion is probably controlled by elements on the particle's surface. Studies with the five species of bacteria yielded similar results. Approximately 3-5 X 10(4) molecules of C3 were bound per microorganism, with opsonization being completed in 30 min. Remarkably, only 16-28% of bound C3 was in the form of iC3b, even after 2 h of incubation. The presence or absence of Mg-EGTA, or the addition of purified CR1 to the reaction mixture, did not significantly effect the ratio of C3b to iC3b. Finally, SDS-PAGE and autoradiography of particle-bound 125I-C3 fragments confirmed that there was no conversion of iC3b to C3d,g or C3d. The data obtained about the opsonization of bacteria suggest that the predominant form of C3 that is encountered by inflammatory phagocytes may be C3b.

Animals↗
PubMed1984

Complement activation via the alternative pathway by purified Salmonella lipopolysaccharide is affected by its structure but not its O-antigen length.

Salmonellae, the lipopolysaccharide of which differ in the chemical structure of their O-antigenic side chains, were previously shown to activate C3 at differential rates via the alternative pathway. We wanted to test whether lipopolysaccharide isolated from these strains yields identical results, and also the effect of the polysaccharide chain length, which varies from 0 to 40 or more repeating units in a single strain. Lipopolysaccharide was purified from the above strains, hydrolyzed (0.1 N NaOH, 56 degrees C, 30 min), and used to coat sheep erythrocytes to different densities, and C3 activation in C4-deficient guinea pig serum was measured. C3 activation was proportional to lipopolysaccharide density and time, and the relative rates and extents of activation by this bacteria-free system were the same as for the original bacteria. Activation was reduced 10 to 15% when the serum was preabsorbed with strains either containing or lacking O-antigen side chain, suggesting augmentation by antibody; however, even after multiple absorptions, activation varied with O-antigen structure as expected. This differential activation was not due to differences in the average length of the O-antigenic polysaccharide chains, because the size was similar for all three lipopolysaccharides. Moreover, the extent of activation by lipopolysaccharide that had been fractionated on a column of Sephadex G-200 was independent of the polysaccharide chain length for lengths greater than 3 repeating units. The results prove that C3 activation by lipopolysaccharide via the alternative pathway is sensitive to slight variations in the chemical structure, but not to large variations in length of the O-antigen polysaccharide side chain of lipopolysaccharide.

Animals↗
PubMed1983

Synthesis of complement by macrophages and modulation of their functions through complement activation.

During the last decade considerable progress has been made to characterize intimate functional links between macrophages, a major cellular component of immunoinflammatory responses, and the complement system representing the major humoral mediator of inflammation. Macrophages of various species and tissue sites have been shown to synthesize and release most of the complement components providing these cells with their own "pericellular" complement system. Circumstantial evidence for the assembly of both classical and alternative pathway convertases has been adduced. An intricate network of feedback loops involving endogenous and extrinsic factors operates to adjust complement production to acute requirements, for example augmenting production in the face of accelerated turnover at sites of inflammation, and returning it to baseline levels once the inflammatory stimulus has subsided, in order to maintain a fine-tuned balance. The molecular mechanisms underlying regulation of complement synthesis by macrophages are beginning to be elucidated by use of gene technology. On the other hand, complement activation products exert a number of effects on macrophages via specific surface receptors causing internalization of offending agents, microbes, and immune complexes, promotion of intracellular killing, controlling migration behavior, inducing release of potent biologic substances such as lysosomal enzymes, arachidonic acid metabolites, and interleukin 1. In these interactions, two important humoral mediator systems of inflammation, the complement system and the arachidonic acid cascade, are functionally linked at the level of the macrophage. Stimulation of the release of immunomodulating compounds from macrophages invoke a role for complement in immune regulation. This multifaceted interplay is of particular importance considering the mobility of macrophages that allows them to gain almost unrestricted access to sites of ongoing immunoinflammatory responses. The time seems to have come to abandon the petrified thinking in socalled systems as, for instance, humoral versus cellular, specific versus unspecific, and to proceed to interlocking functions guided by physiology proper.

Anaphylatoxins↗
PubMed2003

Excessive matrix accumulation in the kidneys of MRL/lpr lupus mice is dependent on complement activation.

Complement receptor 1-related gene/protein y (Crry) in rodents is a potent membrane complement regulator that inhibits complement C3 activation by both classical and alternative pathways. Complement inhibition with Crry as the recombinant protein Crry-Ig has been demonstrated to prevent MRL/MpJ-Tnfrsf6(lpr) (MRL/lpr) mice from developing proteinuria and renal failure. Crry-Ig-treated mice also showed less glomerulosclerosis compared with control MRL/lpr mice. To clarify how complement inhibition with Crry might affect renal scarring in lupus nephritis, gene transcript profiling was performed comparing Crry-Ig-treated MRL/lpr mice to control-treated MRL/lpr mice as well as to the MRL/+ strain control. Altered gene expression was confirmed by quantitative PCR, and protein quantity with either immunoblotting or immunofluorescence microscopy. Collagens I, III, IV, and VI were overexpressed in control MRL/lpr mice, whereas complement inhibition with Crry reduced the overexpression of these extracellular matrix components toward normal. Plasminogen activator inhibitor 1, connective tissue growth factor, and TGF-beta1 were upregulated in MRL/lpr mice compared with MRL/+ mice and were normalized by Crry-Ig treatment, suggesting that the product of these genes may contribute to the progressive glomerulosclerosis in MRL/lpr mice in a complement-dependent fashion. Thus, complement inhibition with Crry has a prominent effect on matrix-related genes and proteins, which translates into improvement in functional renal disease.

Animals↗
PubMed1981

Augmentation of human monocyte opsonin-independent phagocytosis by fragments of human plasma fibronectin.

Human plasma fibronectin isolated by gelatin-affinity chromatography increases in a dose-dependent fashion the number of human monocytes that ingest particulate activators of the human alternative complement pathway in a fully synthetic medium. The fibronectin effect is selective for these particulate activators, does not extend to particles whose ingestion is dependent upon opsonization with IgG, and is not observed with pretreatment of the monocytes. Affinity chromatography with monoclonal antibody to plasma fibronectin of 440,000 daltons reveals that only 12-53% of the protein in a phagocytically active gelatin-affinity-purified fibronectin preparations is bound to the antibody. The protein eluted after affinity chromatography with monoclonal antibody of active preparations, which represented 10-43% of the protein applied, exhibits a 2- to 10-fold increment of activity per microgram of protein above the starting gelatin-affinity-purified material. Thus, the activity that augments the percent of human monocytes ingesting particulate activators of the alternative pathway is antigenically defined as plasma fibronectin. Preparations containing only intact 440,000-dalton fibronectin are also bound to and eluted from the monoclonal antibody, but they fail to augment phagocytosis. When inactive 440,000-dalton plasma fibronectin is subjected to limited trypsin cleavage, phagocytosis-enhancing activity develops that is bound to and elutes from the affinity column prepared with monoclonal antibody, thereby indicating that the enhancing activity of plasma fibronectin resides in cleavage fragments.

Clone Cells↗
PubMed1978

Alternate pathway activation of complement in a Proteus mirabilis ulceration of the cornea.

A 63-year-old patient had an extensive infiltration, ulceration, and eventual perforation of the cornea caused by Proteus mirabilis. Histopathological examination of corneal tissue that was obtained at keratoplasty disclosed that the stroma was ulcerated with a diffuse infiltration of polymorphonuclear leukocytes. Immunopathological examination of the cornea revealed prominent and diffuse staining for properdin and C3 complement. There was an absence of staining for IgG, IgA, IgM, IgE, and C4 complement. These findings suggest that the alternate pathway of complement was activated in this ulcerated cornea and that immunopathological phenomena contribute to the polymorphonuclear infiltration found with Gram-negative ulcerations of the human cornea.

Complement C3↗
PubMed1985

Influence of different immunoglobulin G preparations on phagocytosis of Pseudomonas aeruginosa by polymorphonuclear granulocytes.

Commercially available immunoglobulin products suitable for intravenous application in humans are made by enzymatic or chemical modification of the IgG molecule. In order to examine, to which extent in vitro biologic functions of the IgG molecule are preserved in such preparations, specific antipseudomonal IgG from the rabbit was modified according to some of these procedures. The opsonizing activity of the different IgG preparations was evaluated in an in vitro system measuring the phagocytosis of Pseudomonas aeruginosa by rabbit granulocytes. The results demonstrated that the product Fab/Fc, which is made by papain or plasmin degradation of the IgG molecule, was still able to enhance phagocytosis but not to activate complement. The smaller papain- or plasmin-derived fragments Fab and Fc had no opsonizing activity. The pepsin-derived product F(ab')2 which possesses a divalent antigen binding site but lacks the Fc part, only enhanced phagocytosis when complement concentrations of more than 20% were present in the phagocytic system. Since the F(ab')2 fragment is not able to interact with Fc receptors or to activate complement via the classical pathway, the phagocytosis-enhancing activity of this molecule must be attributed to alternative complement pathway activation. In contrast to the enzymatically derived IgG preparations, a newly developed S-sulphonated IgG product was as efficient as unmodified IgG both in Fc- and complement-mediated opsonization.

Animals↗
PubMed1989

[Activation of complement by hemodialysis membrane].

Incubation of normal human serum with hemodialysis membranes in vitro resulted in conversion of C3 which was detected by crossed immunoelectrophoresis. In addition, formation of C3d was also observed, as was detected by double-decker rocket immunoelectrophoresis. Furthermore, breakdown products of complement (iC3b, C4d & Bb) in plasma samples were measured by ELISA. The microassay plates were coated with monoclonal antibodies which bind specifically to human iC3b, C4d and Bb, respectively, while the plasma samples were drawn from five polycystic kidney patients during initial hemodialysis. As a result, the iC3b and Bb levels in plasma were seen to increase during hemodialysis but the C4d levels revealed no significant changes. It was also observed that the Bb levels in patients undergoing hemodialysis were significantly higher than those in various renal and collagen diseases. Terminal complement complex (TCC) was not present in detectable amounts in normal human serum when measured by ELISA. However, incubation of normal human serum with hemodialysis membranes in vitro resulted in detection of TCC. TCC was present in the same plasma samples drawned from the five polycystic kidney patients during initial hemodialysis. It is suggestive that activation of complement by hemodialysis membrane is predominantly mediated through the alternative pathway and products such as TCC and anaphylatoxin are formed by this activation.

Complement Activation↗
PubMed1976

Analysis of complement-dependent antibody-mediated lysis of target cells acutely infected with measles.

A sensitive assay for the detection of complement-dependent cytolytic measles-antibodies in monkey and human sera is described. The high sensitivity of the technique is dependent upon the use of Vero or MA-104 cells acutely infected with a high-titered, non-syncitiogenic strain of attenuated measles virus. Cytolytic antibody titers of serum can be determined either by endpoint dilution in the presence of a standard dilution of heterologous (guinea pig) complement or by percentage of lysis of a specific number of target cells at a standard dilution of immune serum (1:32). The latter technique proved expedient in the comparison of cytolytic activities of large numbers of serum samples. Clearly, the alternative complement pathway is effective in lysis of these cells, but neither the classical nor the alternative pathway alone appears to be as effective as both pathways combined. No prozone effect occurred with homologous complement, and inhibition of lysis was eliminated by washing sensitized cells before addition of heterologous complement. Lysis of measles-infected cells untreated with measles antibody occurred in the presence of both normal and C4-deficient guinea pig serum at high concentrations, but no such activity occurred with non-immune human or rhesus serum. Antibody-mediated complement-dependent lysis of measles-infected cells may be an important immune defense against acute measles infection.

Animals↗
PubMedDate not supplied

Complement activation via the alternative pathway in a patient with insulin-dependent diabetes mellitus.

A 41-year old male with insulin-dependent diabetes mellitus previously unsuccessfully treated with a controlled diet and glibenclamide, and subsequently with increasing insulin doses (5 and 20 IU/day) experienced polyuria, glycosuria and loss of weight. On admittance to hospital serum C3 concentrations were found to be depressed. The insulin dose was further increased to 30 IU/day and the patient was also treated with 20 mg nafamostat mesylate given intravenously twice daily for 6 days. On completion of nafamostat mesylate treatment serum C3 concentrations were increased but after 17 days they started to decrease again.

Adult↗
PubMed2001

Complement activation in factor D-deficient mice.

To assess the contribution of the alternative pathway in complement activation and host defense and its possible role in the regulation of systemic energy balance in vivo, factor D-deficient mice were generated by gene targeting. The mutant mice have no apparent abnormality in development and their body weights are similar to those of factor D-sufficient littermates. Complement activation could not be initiated in the serum of deficient mice by the alternative pathway activators rabbit erythrocytes and zymosan. Surprisingly, injection of cobra venom factor (CVF) caused a profound and reproducible reduction in serum C3 levels, whereas, as expected, there was no C3 reduction in factor B-deficient mice treated similarly. Studies of C3 and factor B activation in vitro by CVF demonstrated that in factor D-deficient serum the alpha chain of C3 was cleaved gradually over a period of 60 min without detectable cleavage of factor B. CVF-dependent C3 cleavage in the deficient serum required the presence of Mg(2+), whereas in normal mouse serum the presence of divalent cations was not required. These results suggest that in mouse proteolytic cleavage of factor B by factor D is not an absolute requirement for the zymogen to active enzyme conformational transition of CVF-bound factor B. Kinetics of opsonization of Streptococcus pneumoniae by C3 fragments was much slower in factor D-deficient serum, suggesting a significant contribution of the alternative pathway to antibacterial host defense early after infection.

Animals↗