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PubMed1978

Binding of activated properdin to untreated erythrocytes: a new function of activated properdin.

Activated human properdin was found to be capable of binding to rabbit and sheep erythrocytes to form new intermediate cells of the alternative pathway of the complement system. The intermediate cells, termed EP, can react with B, D and C3 to form other intermediate cells, tentatively termed EPB(D)C3, which can be lysed by the subsequent action of six late-acting complement components, C3 to C9. The possibility of participation of C3, B, D or immunoglobulin in the formation of EP cells was neglected by the experiments in which the inhibition of the reactivities of P or EP by antisera to P, C3, B, D or immunoglobulins were investigated. The reduction in reactivities of P to E, or of EP to B, D and C3 was observed only when pretreated with antiserum to P. Furthermore, EP cells were agglutinated only by anti-P, not by antisera to C3 or IgG. The other possibility of participation of the classical complement components such as antibody, C1, C4 and C2 in the formation of EPB(D)C3 was excluded by the non-reactivities of EP with C4 and C2 and of EAC1 with B, D and C3. Thus, activated properdin is likely to function not only as modulator of preformed enzyme such as C3bBb but also as one of early-acting components of the alternative pathway.

Agglutination↗
PubMed1986

Alternative complement pathway activation by C4b deposited during classical pathway activation.

Sheep erythrocytes (E) sensitized with anti-E antibody (A) were reacted with guinea pig C1 (C1gp) and human C4 (C4hu) or guinea pig C4 (C4gp) to prepare EAC1, 4b. Treatment of the EAC1, 4b with a buffer containing EDTA removes C1rgp and C1sgp, resulting in the formation of EAC4b. EAC4b prepared in this way were found to be lysed by human or guinea pig serum in a gelatin Veronal-buffered saline containing 2 mM MgCl2 and 8 mM EGTA (Mg-EGTA-GVB). In the hemolytic sensitivity of EAC4bhu, essentially no difference was noted whether IgG or IgM antibodies were used for preparation of EAC4bhu. The extent of the hemolysis of EAC4bhu was dependent on the dose of C4bhu. Because EAC4bhu were lysed even by C2-deficient human serum, C3 convertase of the classical complement pathway would not be involved in the hemolysis of EAC4bhu. Furthermore, the reactivity of EAC4bhu with serum in Mg-EGTA-GVB remained even after treatment of the intermediate cells with 1 mM PMSF, indicating that any remaining C1gp was not responsible for the hemolysis. Therefore, the hemolysis of EAC4b by sera in Mg-EGTA-GVB was considered to be mediated via activation of the alternative complement pathway (ACP). Pretreatment of EAC4bhu with anti-C4hu antibody or C4-binding protein suppressed the hemolysis of EAC4bhu via the ACP activation. Furthermore, EAC4bhu were more sensitive to hemolysis by the reaction with a mixture of C3, B, D, and H followed by rat serum in EDTA-GVB than EAC1qgp were. These results indicate that C4b molecules on the cell membrane participate in the activation of ACP.

Animals↗
PubMed1987

Concentrations of C1q, factor B, factor D and properdin in healthy children, and the age-related presence of circulating C1r-C1s complexes.

The concentrations of C1q, factor B, factor D and properdin were determined in healthy children belonging to various age groups of one through five years of age. All concentrations were found to be age-dependent, though they varied from one component to another with regard to ontogenetic pattern. Thus, the concentrations of factor B were high, and those of factor D low throughout the age range studied. C1q and properdin levels were lowest in the younger children, who also showed a fairly high incidence of C1r-C1s complexes in excess of C1q. Since the concentrations of C1q are influenced by those of IgG, the presence of C1r-C1s complexes might partly have reflected maturation of immunoglobulin synthesis during ontogeny.

Age Factors↗
PubMed1990

Competition for binding sites on C3b by CR1, CR2, MCP, factor B and factor H.

The reaction of radiolabeled C3b-binding proteins with C3b-coated particles has been investigated. CR1 binding was inhibited by factor H and factor B (in the presence of properdin), but not by properdin alone. CR2 and MCP binding were also inhibited by factor H. Therefore factor H, factor B, CR1, CR2 and MCP probably comprise a group of mutually competitive proteins with similar or overlapping binding sites on C3b. These results correlate with their structural homology and suggest that they all evolved from a single C3b-binding molecule. Factor H, CR1 and MCP are also cofactors for the factor-I-mediated cleavage of C3b. A species incompatibility between rat factor I and human CR1 for the cleavage of human C3b suggests the possibility that cofactors may also function by interacting directly with factor I.

Animals↗
PubMed1985

In vivo modulation of rat complement activities by infusion of anti-H antibodies.

Regulation of the activity of the alternative pathway of complement occurs by the plasma proteins I and H. H is able not only to prevent formation of the amplification convertase C3bBb but also to cause the decay-dissociation of Bb from C3bBb. The present studies have investigated the role of H in vivo. Affinity-purified goat (Fab')2-anti H was infused intravenously in rats, and its effect on C4, C3 and CH50 activities was assessed. In addition, H, C3, C4 and B were quantitated by immunochemical methods. H depletion was dependent on the dose of anti-H, and maximal consumption in vivo occurred between 5 and 15 min. A maximum of 51% and 77% hemolytic C3-consumption was seen after 15 min with 3.8 and 8.4 mg anti-H, respectively. The injection of 6.3 mg affinity-purified goat IgG anti-rat H caused 96.8 +/- 0.7% and 85.0 +/- 1.4% consumption of CH50 and C3 hemolytic activity, respectively. Using this dose of IgG anti-rat H, it was found that the clearance in rats of rat erythrocytes sensitized with 8000 molecules of guinea pig IgG2 per E was impaired as compared to the clearance of these intermediates in control rats injected with a comparable dose of normal goat IgG. The results indicate that H functions as a potent regulator of C in vivo and that infusion of anti-H can be used as a method to achieve depletion of circulating complement components.

Animals↗
PubMed1991

Murine polymorphonuclear leukocytes synthesize and secrete the third component and factor B of complement.

Complement proteins in serum are synthesized mostly by hepatocytes and many other cell-types have also been shown to synthesize complement in various tissues. However, polymorphonuclear leukocytes (PMNs) have never been reported to secrete complement. This paper demonstrates the synthesis and secretion of C3 and factor B by murine peritoneal exudate PMNs elicited with OK432 (Streptococcus preparation). Using [35S]methionine incorporation and immunoprecipitation, C3 and factor B produced by PMN are found to be antigenically and physically identical to macrophage C3 and factor B. ELISA analysis reveals that culture supernatant of PMN--free of macrophage contamination--contains C3 antigen, and both flow cytometric analysis and immunoperoxidase staining also demonstrate the presence of intracellular C3 using special precautions to eliminate non-specific staining. The role of complement produced by PMN is currently unknown, but it is very important to take this new finding into consideration for further clarification of the roles of complement in extravascular inflammatory sites.

Animals↗
PubMed1989

Regulation of the human alternative complement pathway: formation of a ternary complex between factor H, surface-bound C3b and chemical groups on nonactivating surfaces.

Sephadex [alpha(1----6) cross-linked dextran] activates the human alternative pathway of complement. Substitution of hydroxyl groups of Sephadex with carboxymethyl groups (CM) results in a dose-dependent decrease of the activating capacity of the polymer in normal human serum. Sephadex bearing one CM group/glycosyl unit (CM-Seph 0.95) exhibited no activating capacity. CM groups did not interfere with the ability of the polymer to covalently bind C3b in the presence of purified alternative pathway proteins nor with the capacity of bound-C3b to form a C3 convertase in the absence of regulatory proteins. C3b that was bound to CM-Seph 0.95 was more susceptible to inactivation by factors H and I in serum than C3b bound to Sephadex. Binding studies using 125I-labeled H demonstrated that H bound with a similar affinity to the activating particle Sephadex, to Sephadex bearing C3b and to the nonactivating particle CM-Seph 0.95. However, factor H bound with a 5- to 7-fold higher affinity to CM-Seph 0.95 bearing C3b. These results demonstrate a requirement for both CM groups and C3b molecules in order for H to bind with high affinity to C3b on the non-activating surface, and indicate that H formed a ternary complex with surface-bound C3b and CM groups on CM-Seph 0.95. Using a chemically defined model system, the present study provides a molecular basis for the enhanced interaction between surface-bound C3b and factor H on nonactivators of the human alternative pathway.

Complement Activation↗
PubMed1978

A radial hemolysis method in agarose for the functional assay of properdin.

A simple one-step radial hemolytic assay for properdin has been devised. In this assay, the test material is introduced into a well in an agarose plate containing optimal concentrations of normal human serum immunochemically depleted of properdin (RP), EGTA, magnesium ions and unsensitized guinea pig erythrocytes. Following radial diffusion, the area of the hemolytic zones resulting from the activation of the alternative complement pathway and bystander lysis of guinea pig erythrocytes was directly proportional to the concentration of properdin in the test material. The assay is specific reproducible and sensitive and the correlation with the radioimmunoassay for properdin is very good. The assay has been used to measure properdin activity in animal sera.

Animals↗
PubMedDate not supplied

Complement C3: a molecular mosaic of binding sites.

Many of the biological activities of the complement system are mediated by C3, the third complement component, and its proteolytic fragments. At the same time, several of the molecules which regulate complement activation target their action at the C3 molecule. Accordingly, the C3 molecule is equipped with multiple binding sites for at least 14 other complement or complement-related proteins. As described in this review, major progress has been made recently in the identification of the C3 binding sites and the residues involved. Yet this has exposed only the "tip of the iceberg". A novel technique which may facilitate the elucidation of the active sites in C3 is presented. Finally, based on the current knowledge on the C3 molecule, a hypothetical model of the molecular organization of this molecule and its binding sites is presented.

Animals↗
PubMed1989

Complement abnormalities in multiple myeloma.

PURPOSE: Patients with multiple myeloma have been shown to have defective opsonization and C3 deposition. Previous studies have suggested that defective C3 deposition may be related to a failure of C3 activation in myeloma serum, the mechanism of which is unknown. We therefore decided to investigate the underlying mechanism responsible for the failure in C3 activation and deposition. PATIENTS AND METHODS: The study consisted of 10 patients from whom a total of 12 serum specimens were obtained. Normal serum was prepared from a pool of serum specimens in four healthy male donors. We evaluated, in vitro, the kinetics of C3 deposition onto zymosan using radiolabeled C3 under various conditions. We also measured the serum levels of a variety of complement components using standard methods. RESULTS: Five of 10 patients' sera demonstrated poor C3 deposition onto zymosan at all time points, whereas an additional two showed poor C3 deposition at early time points but a rebound to normal by 30 minutes. Multiple components of the classical and alternative complement pathways were decreased in many patients, with the most striking abnormalities occurring in those with the poorest C3 deposition. No single complement component abnormality was found to be common to the group. Elevations in Bb fragment concentration strongly suggest in vivo activation as the likely mechanism for depletion of alternative pathway components; the mechanism for classical pathway abnormalities is less clear. There was an inverse correlation between paraprotein concentration and abnormal C3 deposition (p less than 0.0001) and C3 (p less than 0.0005) and C4 (p less than 0.0001) concentrations. However, no consistent evidence of fluid-phase complement consumption was present. CONCLUSION: The defect in C3 activation and deposition in multiple myeloma cannot be explained on the basis of a single complement component abnormality but rather is due to a heterogeneous group of complement abnormalities. Although no correlation between in vitro abnormalities and clinical status was identified in this small group of patients, it is likely that the described complement defects play an important role in defective host defense in multiple myeloma.

Complement Activation↗
PubMed1988

Antiphagocytic activity of streptococcal M protein: selective binding of complement control protein factor H.

Isolated complement components were used to study the regulation of the alternative complement pathway C3 convertase (EC 3.4.21.47), also called C3b,Bb, on M protein-carrying (M+) and M protein-lacking (M-) streptococci. Neither M- nor M+ streptococci directly affected the formation or dissociation of the surface-bound C3b,Bb or the inactivation of surface-bound C3b by factor I. However, the activity of the serum control protein of the alternative complement pathway, factor H, in controlling streptococcus-bound C3b and C3b,Bb was 6-8 times stronger on M+ organisms than on M- organisms. Furthermore, M+ streptococci of different serotypes and purified streptococcal M6 protein were shown to selectively bind factor H, the dissociation constants ranging from 4.5 X 10(-6) M to 6 X 10(-7) M. We conclude that the antiphagocytic activity of streptococcal M protein may be due to complement inhibition mediated by the binding of factor H. Binding of a regulatory protein appears to be a previously unrecognized route by which a pathogen is able to evade alternative pathway activation.

Antigens, Bacterial↗
PubMed1992

Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis.

Immunopathological evidence suggests that activation of the alternative pathway of complement (AP) is involved in membranoproliferative glomerulonephritis (MPGN) and in immunoglobulin A nephropathy. In this report we describe an AP dysfunction-associated factor that was isolated from the serum and urine of a patient with hypocomplementemic MPGN. Extensive glomerular deposits of C3, properdin, and of the terminal complement components were observed in the kidney of the patient. In her serum the AP hemolytic activity was virtually absent. When mixed with fresh normal serum, the patient's serum induced a 96% C3 conversion during a 30-min incubation at +37 degrees C. This activity was found to be due to a circulating factor that by immunochemical characterization proved to be a 46-kD monoclonal immunoglobulin lambda light (L) chain dimer (lambda L). Purified lambda L, but not control lambda or kappa L chains from patients with L chain disease, activated the AP in a dose- and ionic strength-dependent manner. Functionally, lambda L was differentiated from C3 nephritic factor (an autoantibody against the AP C3 convertase, C3bBb) by its inability to bind to and stabilize the C3bBb enzyme. Instead, lambda L was observed to interact directly with the AP control factor H. Thus, lambda L represents a novel type of immunoglobulin-related AP-activating factor with the capacity to initiate alternative complement pathway activation in the fluid phase.

Antibodies, Monoclonal↗
PubMedDate not supplied

The properdin system: composition and function.

This article summarized the physicohemical data on the factors which compose the properdin system in guinea pig and man. The following other topics are discussed: (1) Activation of the properdin system; (2) Formation of the initiating and amplification C3 convertases; (3) Formation of the C5 convertase, and (4) Regulatory control mechanisms of the properdin system.

Animals↗
PubMed1986

Serum profiles of the regulatory complement proteins during the progression of renal damage in human glomerulonephritis.

Persistent activation of the complement system after escape from control by the regulatory proteins results in an excessive release of split products with inflammatory properties. Serum levels of the regulatory proteins of the complement system (Cl-INH, H, I and AT III) were assayed by the radial immunodiffusion technique in 521 serum samples from 124 patients with idiopathic chronic glomerulonephritis divided into two groups: 81 cases with normal renal function (NRF), and 43 cases with deteriorated renal function (DRF). Significant high mean levels of Cl-INH, H, I and AT III were found in patients with NRF, when they were compared with DRF patient groups. Positive correlations between the regulatory proteins and the corresponding complement components were found in patients with NRF, whereas they were reduced considerably in patients with DRF. Serial measurement of the control proteins showed a decay of the levels of Cl-INH, H and I in patients with progressive impairment of renal function. The presence of high levels of regulatory proteins suggest that a control mechanism may occur in patients with NRF; measurement of these proteins could, therefore, be of prognostic value, as the presence of high levels are indicative of a block of the complement system.

Antithrombin III↗