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PubMed2000

Control of the classical and the MBL pathway of complement activation.

The activation of complement via the mannan-binding lectin (MBL) pathway is initiated by the MBL complex consisting of the carbohydrate binding molecule, MBL, two associated serine proteases, MASP-1 and MASP-2, and a third protein, MAp19. In the present report we used an assay of complement activation specifically reflecting the physiological activity of the MBL complex to identify biological and synthetic inhibitors. Inhibitor activity towards the MBL complex was compared to the inhibition of the classical pathway C1 complex and to a complex of MBL and recombinant MASP-2. A number of synthetic inhibitors were found to differ in their activities towards complement activation via the MBL pathway and the classical pathway. C1 inhibitor inhibited both pathways whereas alpha2-macroglobulin (alpha2M) inhibited neither. C1 inhibitor and alpha2M were found to be associated with the MBL complex. Upon incubation at 37 degrees C in physiological buffer, the associated inhibitors as well as MASP-1, MASP-2, and MAp19 dissociated from MBL, whereas only little dissociation of the complex occurred in buffer with high ionic strength (1 M NaCl). The difference in sensitivity to various inhibitors and the influence of high ionic strength on the complexes indicate that the activation and control of the MBL pathway differ from that of the classical pathway. MBL deficiency is linked to various clinical manifestations such as recurrent infections, severe diarrhoea, and recurrent miscarriage. On the other hand, impaired control of complement activation may lead to severe and often chronically disabling diseases. The results in the present report suggests the possibility of specifically inhibiting of the MBL pathway of complement activation.

Animals↗
PubMed1986

Interaction of bovine complement with Fasciola hepatica.

The host-parasite relationship of Fasciola hepatica in cattle was characterized by determining the effects of the parasite on the bovine complement system. Phosphosaline extracts of F. hepatica adults inhibited both the classical and alternative pathways of complement activation in normal bovine and human sera in a protein dose-dependent manner. The in vitro reaction of viable newly excysted juveniles (NEJ) with bovine serum (NBS) and with bovine serum containing antibodies specific to F. hepatica (IBS) resulted in no detectable changes in serum hemolytic complement activity for either pathway. This lack of complement consumption occurred even though these same flukes incubated in IBS for at least 24 h developed a precipitate that adhered to the parasite tegument, a feature that may reflect antibody--antigen reactions.

Animals↗
PubMed1980

Receptors on guinea-pig erythrocytes specific for cell-bound fourth component of human complement (C4).

Guinea-pig erythrocytes have receptors for heterologous (human and rabbit) complement activated by the classical pathway on cell surfaces. This was shown in the present study by rosette-forming reactions of guinea-pig erythrocytes and human lymphocytes or sheep erythrocytes pre-treated with antibody and human R3 complement. The binding is temperature-dependent and is enhanced by treating the guinea-pig erythrocytes with neuraminidase. The receptors were shown to be specific for C4 by inhibition tests employing a range of anti-human complement antibodies (including anti-Clq, -Cl inhibitor, -C4, -C2, -C3 and -C3b inactivator). Of these reagents, only anti-C4 inhibited the receptor activity, indicating that the guinea-pig erythrocyte C4-receptors differ from those on lymphocytes, monocytes, polymorphonuclear leucocytes and human erythrocytes which are reported to react with both C3b and C4b. In contrast to the strong affinity observed for heterologous C4, guinea-pig erythrocytes appear to react very weakly, if at all, with homologous C4.

Animals↗
PubMed1984

Studies of complement autoactivatability in hereditary angioedema: direct relationship to functional C-1-INA and the effect of classical pathway activators.

It has been observed earlier that the hemolytic complement in diluted sera obtained from patients with hereditary angioedema (HAE) undergoes spontaneous decay when incubated at 37 degrees C. Employing individual serum from patients at different stages of this disease it was demonstrated that this spontaneous loss of hemolytic complement also occurs without dilution and is directly linked to the absence of functional C-1-INA. Incubation of HAE serum resulted in a loss of activity which appears to be dependent upon the concentration of functional C-1-INA. While C-1-INA levels less than 50 micrograms/ml lead to rapid depletion with time, reconstitution of deficient sera with highly purified C-1-INA or of undiluted NHS inhibited spontaneous activation. Furthermore, NHS was rendered susceptible to autoactivation when its C-1-INA was depleted by passage over an anti-C-1-INA Sepharose 4B affinity column in the presence of 10 mM EDTA, indicating that in the absence of functional C-1-INA, C1 undergoes an uninhibited spontaneous autoactivation which leads to the consumption of C4 and C2 but not C3. Consumption of C3 was observed, however, in HAE sera that contained a significant amount of immune complexes. Incubation of HAE sera with highly purified Hageman factor fragment (5 micrograms/ml), or aggregated IgG (2 mg/ml) was found to accelerate the rate of decay when compared to untreated samples while sera from patients under treatment with Danazol or Stanozolol failed to autoactive. These results suggest that, the absence of C-1-INA, may, by itself trigger the dissociation and autoactivation of C1 in the sera of such patients; however, the presence of other complement activators accelerates the reaction. This inherent property of HAE sera, i.e., spontaneous autoactivation at 37 degrees C, may be a useful screening test but direct determination of C-1-INA activity is required to establish the precise diagnosis.

Angioedema↗
PubMed1984

Pathogenetic mechanisms of Mycoplasma mycoides subsp. mycoides septicemia in goats.

The variant best known as the large-colony type of M. mycoides subsp. mycoides is responsible for severe outbreaks of septicemia with coagulopathy in goats. Our objective was to study aspects of the pathogenesis that might explain the coagulopathy, the persistence of mycoplasmas in the blood of septicemic goats, and the host specificity. The endothelial cells of caprine aorta tissue cultured in vitro and exposed to the M. mycoides underwent severe ultrastructural damage. There was no evidence of cytotoxicity to 51Cr-labeled adherent cells from peripheral blood of goats. Complement from goat, sheep, calf and guinea pig was activated by the mycoplasma, resulting in consumption of complement and lysis of mycoplasmas. Goat complement had the poorest mycoplasmacidal effect, whereas guinea pig complement had the highest cidal activity. Complement was activated through the classical pathway, since selective chelation of Ca++ inhibited activation, and serum from C4-deficient guinea pigs was not mycoplasmacidal. Complement activity was restored in chelated serum of sheep, calf and guinea pig after Ca++ supplementation, but not in goat serum, suggesting a difference in the classical pathway activity between these species. Activation of complement may be an important generator of inflammation in this disease. However, species variation in mycoplasmacidal efficiency of complement cannot wholly explain why goats and sheep are susceptible to septicemia and calves and guinea pigs are not. Both endothelial damage and complement activation may be important features of the pathogenesis of tissue damage, and may help explain the coagulopathy in this disease.

Animals↗
PubMed2003

Inhibition of complement activation decreases airway inflammation and hyperresponsiveness.

Studies in murine models have suggested the involvement of the complement anaphylatoxins (C3a and C5a) in the development of allergic asthma. We investigated the effects of inhibiting complement activation after sensitization but before allergen challenge on the development of allergic airway inflammation and airway hyperresponsiveness. To prevent complement activation, we used a recombinant soluble form of the mouse membrane complement inhibitor complement receptor-related gene y (Crry) fused to the IgG1 hinge, CH2 and CH3 domains (Crry-Ig), which has decay-accelerating activity for both the classic and alternative pathways of complement as well as cofactor activity for factor I-mediated cleavage of C3b and C4b. C57BL/6 mice were sensitized (Days 1 and 14) and challenged (Days 24-26) with ovalbumin. Crry-Ig was administered after allergen sensitization either as an intraperitoneal injection or by nebulization before allergen challenge. Crry-Ig significantly prevented the development of airway hyperresponsiveness, decreased airway and lung eosinophilia as well as the numbers of lung lymphocytes, decreased levels of interleukin (IL)-4, IL-5, and IL-13 in bronchoalveolar lavage fluid and decreased serum ovalbumin-specific IgE and IgG1. These results suggest that prevention of complement activation may have a therapeutic role in the treatment of allergic airway inflammation and asthma in sensitized individuals.

Animals↗
PubMed1983

Regulation of immune complex-mediated complement activation by autoantibodies (F-42) isolated from sera of patients with systemic lupus erythematosus.

Sera of some patients with systematic lupus erythematosus (SLE) contain IgG autoantibodies (F-42) which have been shown to stabilize the cell bound classical pathway C3 convertase of complement, C42. C42 is susceptible to inactivation by the plasma protein C4bp while stabilized C42 is relatively resistant to C4bp. The present study demonstrates that F-42 by itself does not induce activation of the classical pathway in vitro but that it is able to modulate the immune complex-induced consumption of C2 and C3 in whole serum. Incubation of incremental concentrations of F-42 with normal human serum (NHS) for 30 min at 30 degrees C did not result in detectable consumption of C1q, C4, C2 and C3. However, when soluble immune aggregates or immune complexes were incubated in NHS together with 100 u/ml of F-42, a significant increase in consumption of C3 was seen as compared to the reaction mixture containing immune complexes or F-42 alone. In addition the presence of F-42 during the immune complex mediated consumption of complement was associated with relative protection of C2 consumption. (Fab)'2 and Fab' fragments of F-42 behaved as intact F-42, except that their activities on a molar basis were less than that of intact F-42. The results presented in this paper suggest that F-42 may play a regulatory role in the immune complex-mediated consumption at C2 and C3 in vivo.

Antigen-Antibody Complex↗
PubMed1994

The synthesis of a water soluble complement activating polyacrylic acid-IgG polymer.

Polyacrylic acid-IgG polymer (PAA-IgG) activates the classical and alternative pathway of complement as shown by specific Clq-(IgG-PAA) interaction and the generation of C4d, Bb, C3b, C3a and C5a. This water soluble and stable PAA-IgG polymer represents a model substance for the study of humoral and cellular inflammatory mechanisms, mediated by the complement system.

Acrylic Resins↗
PubMed1977

Host serum proteins in Echinococcus multilocularis: complement activation via the classical pathway.

The presence of host serum proteins, including IgG and IgM, within the cyst membranes and on the surface of protoscoleces of Echinococcus multilocularis was demonstrated by the use of HRPO-conjugated purified antisera. Viable protoscoleces incubated either in EDTA- or EGTA-fresh human sera were not lysed; the addition of calcium restored the protoscolecidal activity of the EGTA serum. It is concluded that the complement-mediated lysis of this metazoan organism proceeds via the classical pathway of complement activation. The results are discussed in relation to the ability of this parasite to survive in the immunologically hostile environment of the host.

Animals↗
PubMed1992

A single arginine to tryptophan interchange at beta-chain residue 458 of human complement component C4 accounts for the defect in classical pathway C5 convertase activity of allotype C4A6. Implications for the location of a C5 binding site in C4.

In general, C4A allotypes of human C4 show one-fourth to one-third the hemolytic activity of C4B allotypes. An exception to this rule is C4A6 which is almost totally deficient in hemolytic activity. Previous studies have localized the defect in C4A6 to the C5 convertase stage. Of the two critical events required for C5 cleavage, namely formation of a covalent adduct between C3b and the C4b subunit of the C3 convertase (C4b2a), and binding of C5 to this C4b-C3b complex, it is a defect in the latter step that accounts for the aberrant activity of C4A6. DNA sequencing studies described in a companion paper have suggested that the sole C4A6-specific difference was a Trp for Arg replacement at beta-chain residue 458. To directly ascertain whether this single substitution was responsible for the hemolytic defect in C4A6, we have used site-directed mutagenesis to introduce this change into both C4A and C4B cDNA expression plasmids. We found that the R to W replacement totally abrogated hemolytic activity. However, irrespective of the amino acid at residue 458, the mutant proteins behaved like their wild-type counterparts with respect to covalent binding to C1-bearing targets, i.e., the C4B recombinants displayed higher binding to sheep and human red cells than did the C4A counterparts. Furthermore, the mutants were able to form covalent C4b-C3b adducts. There was, however, substantially less C5 cleavage produced by cell-bound C4boxy23b complexes made with R458W mutant C4B than with wild-type C4B. These results are consistent with the sole defect in the mutants being at the C5 binding stage and strongly suggest that Arg 458 of the C4 beta-chain contributes to the C5 binding site of the molecule.

Complement C1↗
PubMedDate not supplied

[The state of classical and alternative complement activation pathways in persons who participated in the cleanup of the aftereffects of the accident at the Chernobyl Atomic Power Plant].

The levels of T-cell activation through classical and alternative pathways were studied in persons participated in cleaning-up operations at Chernobyl N. P. P. Proliferation response of T-cells on the action of monoclonal antibody anti-CD3 (classical activation) as well as response on phytohaemagglutinin was partially decreased just as response on autologic erythrocytes in combination with phorbol 12-myristate-13 acetate (CD2-dependent alternative activation) was completely suppressed in all affected persons. Addition of interleukin 2 did not restore T-cell responses on both anti-CD3 and alternative stimulation. The different degree of decrease of T-cell responses on anti-CD3 and CD2-dependent alternative stimulation is not a result of respective alterations of cell surface CD3 and CD2 expression.

Cells, Cultured↗
PubMed1985

Activation of complement pathways by univalent antibody derivatives with intact Fc zones.

The ability of two univalent antibody derivatives to invoke complement-mediated lysis of guinea-pig L2C leukemic lymphocytes was investigated. The derivatives were Fab/c from rabbit IgG antibody, in which only one Fab arm is removed from the parent molecule and FabFc in which Fab gamma, from peptic digestion of sheep IgG antibody, is disulfide-bonded to the Fc gamma yielded by papain digestion of an arbitrary IgG. Antibody activity was directed against surface IgM on the target cells. Both derivatives could invoke lysis via the classical pathway in the presence of rabbit complement. Exposure of the cells to the derivatives at 37 degrees C before introducing complement yielded no protective antigenic modulation. At low complement concns the derivatives were more efficient than the parent antibodies at invoking lysis, apparently due to the fact that the derivatives do not cause modulation: it appears that cells can undergo a useful degree of modulation when confronted simultaneously by bivalent antibody and low levels of complement. The Fab/c preparations were also able to invoke lysis by guinea-pig complement. Lysis occurred under conditions where activation took place only via the classical pathway (in dilute complement) or only via the alternative pathway (in the absence of calcium ions, or in C4-deficient guinea-pig serum). The results demonstrate that there is no need for two antigen-binding Fab arms in antibody activation of either the classical or alternative complement pathways. They favour models requiring clustering of Fc regions rather than steric changes which might follow binding of antigen.

Animals↗
PubMed1994

Isolation, partial characterisation and complement inhibiting activity of a new glycoprotein from Cuscuta europea.

A new complement inhibiting factor (CIF) was isolated from the seeds of Cuscuta europea parasitic plant. When activated via both classical and alternative pathway, the complement activity was completely depleted by CIF at a concentration of 0,25 mg per ml serum. Studies concerning the precipitation showed that CIF developed one or two precipitin bands against human sera. It was established that the precipitation is as a result of the specific association of CIF to the C3 component of complement. A partial characteristic of the CIF was carried out. It is a glycoprotein with molecular weight between 27000 and 28000 Da. Its molecule consists of one polypeptide chain.

Chromatography, Affinity↗
PubMed1993

Complement (C3, C4) and C-reactive protein responses to cardiopulmonary bypass and protamine administration.

Complement activation has been deemed responsible for the damaging effects of cardiopulmonary bypass (CPB) in patients undergoing open heart surgery. We studied C3, C4 and C-reactive protein (CRP) in 22 patients undergoing CPB. In Group 1 (11 patients), protamine was given intravenously and in Group 2 (11 patients), via the aortic root after CPB. Significant decreases were observed in C3 and C4 during CPB in both groups indicating complement activation primarily by the classic pathway. Protamine did not lead to further activation of the complement system. In both groups, C3 levels gradually returned toward baseline within 24 hours but C4 levels were still lower than baseline 24 hours postoperatively. CPB and protamine administration did not cause any significant changes in CRP levels, but CRP increased abruptly 24 hours after operation. Although activation of complement system during CPB is expected to invoke an acute phase response, we conclude that this period is not long enough to induce an increased production of CRP in response to tissue injury or inflammation.

Adult↗
PubMed1987

Inherited deficiency of properdin and C2 in a patient with recurrent bacteremia.

A nine-year-old white boy with recurrent pneumococcal bacteremia is described. His serum had no hemolytic activity in either the classic or alternative complement pathways. Absence of classic pathway activity was secondary to a homozygous deficiency of C2. The parents had half-normal levels of C2, compatible with an autosomal recessive mode of inheritance. Measurement of serum properdin levels by radial immunodiffusion and enzyme-linked immunoabsorbent assay revealed a profound deficiency in the patient, normal levels in the father, and half-normal levels in the mother, suggesting X-linked inheritance of the deficiency. Addition of purified properdin to the patient's serum fully reconstituted the alternative pathway function. This patient's unique combination of inherited deficiencies of properdin and C2 is a likely explanation for his susceptibility to bacterial infection.

Child↗
PubMed1976

Alternative complement pathway: activity levels in allogeneic pregnancy.

Classical and alternative complement pathway activities have been evaluated in sera of women in progressive stages of gestation and in pregnant mice belonging to outbred or inbred matings, as compared to suitable controls. While classical C pathway was found to be unmodified, the alternative one attained in pregnancy significantly higher activity levels. Results are discussed in the light of mother-conceptus relationships.

Animals↗
PubMed2002

C1-inhibitor for prophylaxis of xenograft rejection after pig to cynomolgus monkey kidney transplantation.

BACKGROUND: Early rejection of discordant porcine xenografts in primate recipients is initiated by the intragraft binding of either preformed (hyperacute xenograft rejection) or induced (acute vascular rejection) antiporcine recipient antibodies with subsequent complement activation via the classical pathway. We have investigated the efficacy of the supplemental administration of C1-inhibitor (C1-INH), a specific inhibitor of the classical complement activation pathway, for prophylaxis of xenograft rejection in a pig to primate kidney xenotransplantation setting. METHODS: Based on the results of pharmacokinetic studies performed in two nontransplanted monkeys, supplemental C1-INH therapy was administered daily to three Cynomolgus monkeys receiving a life-supporting porcine kidney transplant together with cyclophosphamide-induction/cyclosporine A/mycophenolat-mofetil/steroid immunosuppressive therapy. RESULTS: In the three monkeys receiving porcine kidney xenografts and continuous C1-INH treatment none of the grafts underwent hyperacute rejection; all xenografts showed initial function. Recipient survival was 13, 15, and 5 days. No graft was lost due to acute vascular rejection. All animals died with a functioning graft (latest creatinine 96, 112, and 96 micromol/liter) due to bacterial septicemia. CONCLUSION: We conclude that, in our model, supplemental C1-INH therapy together with a standard immunosuppressive regimen can be helpful for prevention of xenograft rejection in a pig to primate kidney xenotransplantation setting. The optimal dose and duration of C1-INH treatment, however, has yet to be determined.

Acute Disease↗
PubMed1986

Opsonization of Listeria monocytogenes type 4b by human adult and newborn sera.

We studied the requirements for opsonization of Listeria monocytogenes type 4b with chemiluminescence and bactericidal assays and electron microscopy. Preopsonization with 3% adult serum had good opsonic activity (27,300 +/- 11,000 [standard deviation] counts, chemiluminescence assay), while 3% newborn cord serum was not opsonically active (820 +/- 530 counts, P less than 0.001 versus adult serum). In addition, organisms opsonized with cord serum were not killed (0% bacterial killing) and were less frequently visualized intracellularly on electron micrographs (0 to 4 bacteria per cell) than organisms opsonized with adult serum (70% killing and 10 to 20 bacteria per cell). Opsonic requirements for L. monocytogenes type 4b at low concentrations of serum were studied in detail with Sepharose-protein A-treated adult serum to obtain immunoglobulin G (IgG) and IgM fractions and zymosan-absorbed and C4 inactivator-treated serum to obtain alternative and classical complement pathway-deficient sera, respectively. In the presence of complement, IgM was opsonically active (59% of control) while IgG was not (6% of control). In addition, classical complement activity was required for efficient opsonization (greater than 100% of control) while the alternative complement pathway was unnecessary (3% of control). Since IgM is absent and classical complement activity is low in neonatal serum and at the common sites of neonatal Listeria infection, the requirement for IgM and classical complement activity for efficient opsonization of L. monocytogenes type 4b at low serum concentrations may be a factor in the pathogenesis of neonatal disease.

Blood Bactericidal Activity↗