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PubMed1981

Isolation and properties of a complement inhibitor from Naja haje venom, distinct from known anticomplementary factors in cobra venom.

A complement inhibitor (CI) has been isolated from cobra (Naja haje) venom which is distinct from the two known anticomplementary factors in cobra venom [1], in functional properties as well as structure. CI is a small (mol. wt 26,000, determined by sodium dodecyl sulphate gel electrophoresis), heat-labile glycoprotein; the amino acid composition is that of a globular protein. CI interferes at various steps of the complement sequence, including reactions of the classical and alternative pathway. No effect was observed on C4 fixation and on the assembly of the membrane attack complex from C6-9 (minor inhibiting effects, if present, have not been excluded). Initiation of the alternative pathway is inhibited by CI already at the stage of cleavage of factor B. CI binds to C4, C4b, C3 and C3b; since the major inhibitory action of CI is lost after washing of cell intermediates, complex formation and, as a consequence, steric hindrance may be responsible for the inhibiting effects of CI. CI also interferes with binding of C3b to C3b receptors on human erythrocytes. CI is non-toxic in mice when given intraperitoneally in doses of 5 microgram/g.

Amino Acids↗

PubMed1975

Stimulation of neutrophil oxidative metabolism by the alternate pathway of complement activation: a mechanism for the spontaneous NBT test.

The reduction of nitroblue tetrazolium dye by human neutrophils was measured in the presence of serum in which the complement system had been activated through the alternate pathway by interaction with inulin. Neutrophils incubated with serum inulin supernatants reduced the dye and showed a general increase in oxidative metabolism. The oxidation of glucose-1-14-C by supernatant prepared from selectively depleted sera indicated that the neutrophil-stimulating factor(s) was generated through the alternate pathway of complement activation. The possibility that inulun had been ingested as a particle was ruled out by light microscopy and radiolabeling studies. The failure of neutrophils stimulated by the serum-inulun supernatants to migrate after exposure to a chemotactic agent suggested that the site of neutrophil-complement interaction was on the cell membrane. It is concluded from these results that biologically active fragments generated through the alternative pathway of complement activation can stimulate neutrophil metabolism in the absence of phagocytosis. Interaction of such fragments with circulating neutrophils in vivo and the subsequent metabolic activation of these cells is one explanation for the spontaneous reduction of nitroblue tetrazolium dye in vitro by neutrophils from patients with certain infections and inflammatory disorders.

Absorption↗

PubMed1986

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↗

PubMed1979

Incompatibility between complement components C3 and C5 of guinea-pig and man, an indication of their interaction in C5 activation by classical and alternative C5 convertases.

The use of heterologous combinations of guinea-pig and human complement components for titration of C5 with convertases of the alternative and classical pathway has been investigated. In addition to the known unfavourable combination of C2hu with C4gp partial incompatibilities were detected between heterologous C3 and C5 as well as between CZhu and C5gp. The incompatibility between heterologous C3 and C5 is of special interest since it indicates an interaction of these two non-enzymic components. Concomitant binding studies have demonstrated that a reduced efficiency of C5 convertases correlates with decreased binding affinity of surface-fixed C3b for C5 when heterologous components are offered. Hence, the present studies give further evidence that surface-bound C3b has the function of a co-factor which binds C5; this interaction is required for C5 activation via the classical as well as the alternative pathway, i.e. by the C3/C5 convertases C42 and C3bB.

Animals↗

PubMed2003

Immunomodulatory activity and chemical characterisation of sangre de drago (dragon's blood) from Croton lechleri.

The immunomodulatory activity of the latex from Croton lechleri (sangre de drago) was determined by in vitro assays. Classical (CP) and alternative (AP) complement pathways activities were determined in human serum. Intracellular generation of reactive oxygen species (ROS) by human polymorphonuclear leukocytes (PMNs) and monocytes, and phagocytosis of opsonised fluorescent microspheres were measured by flow cytometry. Free radical scavenging activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH). Activity on proliferation of murine lymphocytes was also investigated. In addition, anti-inflammatory activity was assayed in vivo by carrageenan-induced rat paw oedema test. Some of the activities were compared with those of the isolated alkaloid taspine. Sangre de drago from Croton lechleri showed immunomodulatory activity. It exhibited a potent inhibitory activity on CP and AP of complement system and inhibited the proliferation of activated T-cells. The latex showed free radical scavenging capacity. Depending on the concentration, it showed antioxidant or prooxidant properties, and stimulated or inhibited the phagocytosis. Moreover, the latex has strong anti-inflammatory activity when administered i. p. Taspine cannot be considered the main responsible for these activities, and other constituents, probably proanthocyanidins, should be also involved.

Adjuvants, Immunologic↗

PubMed1999

C4, BF, C3 allele distribution and complement activity in healthy aged people and centenarians.

The aim of this study was to examine the complement system and the distribution of some human leukocyte antigen (HLA) class III alleles (C4, BF) in healthy aged people (77 centenarians and 89 elderly subjects). We have also studied the alleles of C3, a complement component genetically unrelated to HLA, the immunochemical levels of C4 and C3 and serum functional hemolytic activity for classical (CH50) and alternative (AP50) complement pathway. The levels of C3 and C4 and the CH50 and AP50 were found to be within the normal range. The frequencies of C3, BF, and C4A alleles were similar in the cohorts that have been studied. For C4B null allele (C4BQ0) a trend toward an increase in the older cohort was observed, although the differences were not significant after statistical correction. Our data suggest that the complement system is well preserved in centenarians and elderly subjects and class III HLA antigens are equally distributed in aged cohorts and in young healthy individuals.

Adult↗

PubMed1993

Hereditary properdin deficiency in three families of Tunisian Jews.

Hereditary properdin deficiency is a rare genetic disorder of the complement system. Three propositi and six additional family members with properdin deficiency have been found following analysis of the hemolytic activity of the classical (CH50) and the alternative (AP50) complement pathways in the sera of 101 survivors of meningococcal infections and 59 survivors of severe pneumococcal and Haemophilus influenza infections. All the properdin-deficient individuals had undetectable levels of properdin by radial immunodiffusion and by Western blotting. They belonged to three non-related families of Tunisian Jews who came from different parts of Tunisia. Two patients had a meningococcal infection at 15 and 16 years of age, respectively, and one had Haemophilus influenza meningitis at 1.5 years of age. In contrast to the fulminant and fatal course of meningococcal infection which was previously described in some properdin-deficient patients, our patients had a relatively mild disease. Properdin deficiency may not be as rare as previously thought. Analysis of AP50, in addition to CH50, in sera of patients who had meningococcal infection, will probably disclose many more cases of hereditary properdin deficiency. In addition, our findings indicate that, as in other complement abnormalities, hereditary properdin deficiency may also be associated with the ethnic origin of the patient.

Adolescent↗

PubMed1982

Complement-mediated inhibition of immune precipitation. II. Analysis by sucrose density gradient ultracentrifugation.

The factors influencing the ultracentrifugation characteristics of immune complexes generated in the presence of fresh normal human serum have been analysed. In the absence of alternative pathway factors B, D or Properdin, the size of complexes was increased. When classical pathway function was blocked, in C1q deficient serum or in the presence of Mg EGTA, although the proportion of complexes remaining in solution were reduced their size was similar to those formed in normal human serum. In C2 deficient serum, a heterogeneous population of complexes was generated. In all instances repletion with the appropriate missing complement component reversed the abnormality. We conclude that there is normally a rapid sequential process of classical followed by alternative pathway activation leading to stable soluble complexes. In the absence of C1 activation the alternative pathway process requires precipitation of the antigen-antibody aggregates whereas in normal serum these events occur in the fluid phase. We suggest that in C2 deficient serum the C1 and/or C4 reacted complexes fail to activate the alternative pathway efficiently.

Animals↗

PubMed1985

Depressed classical complement pathway activities in chronic lymphocytic leukaemia.

Haemolytic activities of the classical and alternative complement pathways, and levels of C1, C4, C3, factor B and C1 inhibitor (C1-INH) were measured in 85 serum samples from 46 patients with chronic lymphocytic leukaemia (CLL). Significantly decreased mean C1 and C4 levels were found, and the haemolytic activities of these components were low or low normal in more than 50% of the sera tested. In 15 sera from 5 patients a complement profile characteristic of acquired C1-IHN deficiency was observed. These results indicate that the depression of the activity of the classical complement pathway is a frequently occurring feature in CLL.

Antigen-Antibody Complex↗

PubMed1984

Activation of complement by tetrathyridia of Mesocestoides corti: enhancement by antibodies from infected mice and lack of effect on parasite viability.

Tetrathyridia of the cestode Mesocestoides corti were isolated from the peritoneal cavity of infected mice. The parasites activated guinea pig and mouse complement (C) in vitro by both the classical and alternative pathways as shown by quantitative C fixation and crossed immunoelectrophoresis. The ability of tetrathyridia to activate mouse C was enhanced by preincubating the parasites in serum obtained from mice infected with M. corti. Antibodies of the IgG1 class, an immunoglobulin found in profoundly increased amounts in mice infected with M. corti, as well as IgM and IgG2 antibodies, bound to cultured tetrathyridia and facilitated deposition of the third component of C (C3) from dilute mouse serum, presumably via classical pathway activation. The results demonstrate that mouse IgG1 antibodies do not prevent the activation of C by the tetrathyridia or by C-fixing antibodies of other classes which become attached to the tetrathyridia. The activation of C in vitro by tetrathyridia did not affect their ability to grow in mice, even though C3-derived polypeptides could be detected by immunofluorescence on the surface of the parasites.

Animals↗

PubMed1987

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↗

PubMed1998

Complementary recognition of alternative pathway activators by decay-accelerating factor and factor H.

The alternative complement pathway (ACP) functions as a surveillance mechanism by which microorganisms are opsonized with C3b in the absence of specific antibodies. The effectiveness of the ACP relies on its ability to distinguish self from non-self. This recognition function is mediated by C3 regulatory proteins including serum factor H, membrane cofactor protein (MCP), and membrane decay-accelerating factor (DAF). H activity against bound C3b can be increased by host components such as sialic acid and decreased by microbial polysaccharides. DAF and MCP may also recognize cell surface changes such as the presence of viral glycoproteins, since some virus-infected and tumor cells activate the ACP. In the present study, liposomes containing wild-type and mutant Salmonella minnesota lipopolysaccharide (LPS) were tested for ACP activation in serum. LPS-containing liposomes with bound C3b were then tested for their susceptibility to C3 convertase regulation by H and membrane DAF and for the sensitivity of their bound C3b to the cofactor activity of H. The results indicate that while the shortest mutant, Re595 LPS, did not induce ACP activation, R7 LPS containing an additional disaccharide did. This activation was poorly regulated by DAF but was inhibited by H. The regulatory activity of H for liposome-bound C3b, however, decreased when LPS of greater polysaccharide size was present in the membrane. In contrast the ACP activation induced by the phospholipid phosphatidylethanolamine was effectively inhibited by DAF but only poorly inhibited by H.

CD55 Antigens↗

PubMedDate not supplied

Echinoderm immunity and the evolution of the complement system.

Our understanding of inflammatory responses in humans has its roots in the comparative approach to immunology. In the late 1900s, research on echinoderms provided the initial evidence for the importance of phagocytic cells in reactions to foreign material. Studies of allograft rejection kinetics have shown that echinoderms have a non-adaptive, activation type of immune response. Coelomocytes mediate the cellular responses to immune challenges through phagocytosis, encapsulation, cytotoxicity, and the production of antimicrobial agents. In addition, a variety of humoral factors found in the coelomic fluid, including lectins, agglutinins, and lysins, are important in host defense against pathogens and other foreign substances. Recently, a simple complement system has been identified in the purple sea urchin that is homologous to the alternative pathway in vertebrates. The sea urchin [corrected] homologue of C3, is inducible by challenge with lipopolysaccharide, which is known to activate coelomocytes. Complement components have been identified in all vertebrate classes, and now have been characterized in protochordates and echinoderms indicating the primordial nature of the complement system. Because it is thought that the complement system evolved from a few primordial genes by gene duplication and divergence, the origin of this system appears to have occurred within the common ancestor of the deuterostomes.

Animals↗

PubMed2003

Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins.

Bone sialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP), enamelin (ENAM), matrix extracellular phosphoglycoprotein (MEPE), and osteopontin (OPN) are glycophosphoproteins expressed in bones and/or teeth. Direct comparison of their amino acid sequences do not suggest that they belong to a single genetic family, but a detailed analysis of their chromosomal location and gene structure does. Analysis of human brain mRNA by RT-PCR has led to the discovery of two additional exons thereby making it more convincing that MEPE is a member of the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family. We propose that the members of this SIBLING family are extended, flexible proteins in solution that can facilitate the formation of a number of different complexes. For example, OPN can bridge complement Factor H to either an RGD-dependent integrin or to CD44 forming a membrane-bound complex that actively suppresses the alternate complement pathway. Two possible mechanisms for inhibiting the lytic pathway of alternate complement are presented.

Animals↗

PubMed1982

Action of a new non-steroid anti-inflammatory drug, carprofen (Ro 20-5720) on activation of the complement system: an in vitro research.

Carprofen (Ro 20-5720), DL-6-chloro-alpha-methyl-carbazole-2-acetic acid, is a new non-steroid anti-inflammatory drug. We have studied the possible in vitro interference of the drug with the activation of human complement system. Carprofen exerts a constant inhibitory action of immunohaemolysis at a concentration of 4.5 X 10(-4)M. At the same concentration the drug is able to prevent the activation of the alternate pathway induced by insulin. Its specific site of action is on C1 and C3 components activation, according to the inhibiting activity on both classic and alternate pathway. However at a lower dosage (7.5 X 10(-6)M) carprofen is able to display an inducing action on the alternate pathway, thus confirming the complex in vitro interferences of the drug with the complement system.

Anti-Inflammatory Agents↗

PubMed1989

An affinity for complement C3 as a possible reason for the potency of naturally occurring antibodies in mediating tissue homeostasis.

Certain naturally occurring antibodies stimulate alternative complement pathway C3b deposition. We propose that only those IgG antibodies stimulate alternative complement pathway which have an affinity for C3. Their weak binding to C3 in plasma increases the probability that covalently linked C3b-IgG complexes are formed during C3 activation. Such complexes are known to be much more efficient than C3b in mediating positive feedback of C3 activation, since they are more stable against inactivation by factor I and H. The hypothesis is supported by functional properties of naturally occurring antibodies to erythrocyte band 3 protein. Their ability to stimulate alternative complement pathway C3b deposition increases the potency of these low titer antibodies as opsonins.

Antigen-Antibody Complex↗

PubMed1983

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↗

PubMed1978

Initiation of the alternative pathway of complement: recognition of activators by bound C3b and assembly of the entire pathway from six isolated proteins.

An intact alternative pathway of complement activation was assembled from six isolated proteins present at their respective physiological concentrations (C3, 1200 microgram/ml: factor B, 200 microgram/ml; factor D, 2 microgram/ml; beta1H, 560 microgram/ml; C3b inactivator, 34 microgram/ml; and native properdin, 20 microgram/ml). Initiation of the pathway required the presence of five of these proteins not including properdin. The initial C3 convertase of the system was shown to be a fluid-phase rather than a surface-bound enzyme. The ability of the pathway to discriminate between activator and nonactivator was found to reside in the bound C3b molecule. When bound to the surface of an activator through its labile binding site, C3b interacts with surface structures of the activator through another site on the molecule. This interaction results in diminished beta1H binding to C3b and thereby allows the bound C3b molecule to escape control and participate in C3 convertase formation. Thus, initiation of the alternative pathway is a two-step process, the first being non-specific and the second being discriminatory.

Binding Sites↗