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PubMed1984

Macrophages release arachidonic acid, prostaglandin E2, and thromboxane in response to late complement components.

Rat peritoneal macrophages released arachidonic acid, prostaglandin E2, and thromboxane B2 when treated with normal rabbit or C6-deficient rabbit complement in vitro. Normal rabbit complement, however, was more efficient, which indicates that late complement components, in addition to the known effects of C3a and C3b, were responsible for an enhanced arachidonic acid turnover. Indeed, in the absence of the C3 cleavage products, the purified late complement components C5b6, C7, C8, and C9 stimulated the arachidonic acid, as well as the prostaglandin E2 and thromboxane B2 release. Incubation of C5b6, C7, C8, and C9 for 1 hr at 37 degrees C before addition to the macrophages abolished the stimulatory activity, being in complete agreement with the fact that a fluid phase-formed complex of C5-9 loses its membrane-binding capacity. Although the mechanism by which C5b-9-membrane interaction affects the arachidonic acid metabolism remains unclear, the data describe a new function of the late complement components.

Animals↗
PubMed1978

Activation of complement by radiographic contrast media: generation of chemotactic and anaphylatoxin activities.

Iodinated radiographic contrast media such as methylglucamine diatrizoate and sodium ioglycamate activate serum complement in vitro. This was shown by a dose-, time-, and temperature-dependent decrease of total hemolytic complement activity in normal human serum, consumption of C4 and C6 activity, conversion of C3 to C3b, and generation of C5-derived chemotactic and smooth muscle contracting activity. Complement activation was achieved even in sera depleted of immunoglobulin and properdin, which may indicate that contrast media induce complement activation by mechanisms different from the classical or alternative pathway.

Anaphylatoxins↗
PubMed1976

Absence of the sixth component of complement in a patient with repeated episodes of meningococcal meningitis.

A previously healthy 6-year-old boy who presented with meningococcal meningitis responded favorably to ampicillin, but suffered two and possibly three repeat attacks in the ensuing month. No abnormality of the otolarynx, skin, or neuroskeleton was found. The infecting strain, Neisseria meningitidis, Group Y, Type IV, was sensitive to the therapeutic agents used, and antibiotic levels were adequate. Serum bactericidal antibody titers against autologous meningococci were high. Serum complement hemolytic bactericidal activities, however, were entirely lacking, and this was attributable to a complete deficiency of C6. Measurements of the remaining complement components, C-dependent chemotaxis and opsonization, neutrophil function, specific immunity, and the coagulation system, were normal. The parents had half-normal C6 levels. Recurrence of meningitis in this patient supports the concept that complement plays a role in resistance to certain microorganisms and emphasizes the need for complete evaluation of the complement system in individuals with unexplained repeated infections.

Child↗
PubMed1979

Familial herpes simplex infection associated with activation of the complement system.

A patient with severe recurrent herpes infection was evaluated for immunologic analysis including a profile of complement components. The peripheral blood lymphocytes from the patient responded by proliferation to herpes simplex antigen but failed to produce leukocyte migration inhibition factor. Herpes simplex antibody titers increased during active infection. Total hemolytic complement (TCH50), the third (C3), fifth (C5), sixth (C6) and seventh (C7) components of complement, and factor B were dramatically reduced; the first (C1), second (C2) and fourth (C4) components of complement were within normal limits. In family members with a history of recurrent herpes simplex, one or more of the later complement components (C5, C6 or C7) was reduced. This study demonstrates the activation of complement in these serums via the alternative pathway.

Adult↗
PubMed1979

Delayed rejection of cardiac xenografts in C6-deficient rabbits.

Puppy hearts were engrafted to C6-deficient rabbits, and also to complement-sufficient animals in order to determine the influence of the sixth component of complement on xenograft rejection. Delayed rejection was observed in the puppy hearts engrafted to the C6-deficient animals indicating that complement sufficiency of C6 is required for hyperacute xenograft rejection.

Animals↗
PubMed1997

The role of CD11b/CD18 mediated neutrophil adhesion in complement deficient xenograft recipients.

Hyperacute rejection (HAR) of discordant xenografts is dependent on local complement activation. The formation of a functional complex of the complement components C5b-9 (membrane attack complex, MAC) causes endothelial injury and activation leading to coagulation and inflammation. In PVG rats which selectively lack the C6 component of complement, the MAC complex is not formed, whereas early split products of the complement cascade are produced normally. We reported previously that HAR is averted in C6 deficient xenograft recipients, and that subsequent accelerated acute rejection (AAR) can be delayed by inhibition of CD11b/CD18 (Mac-1) dependent neutrophil adhesion using leumedin, a member of a novel class of anti-inflammatory agents. Here we report the in vivo effects of a dose-response study using 2 new members of another class of Mac-1 directed agents designated nactins. Discordant cardiac xenografts from Hartley guinea pigs were heterotopically grafted into PVG(C6-) and PVG(C6+) rats. Experimental animals were divided into 3 groups receiving leumedin (group 1) or nactin (groups 2 and 3). Control animals received intravenous saline solution only. All C6(+) rats rejected their grafts hyperacutely within 10 to 15 min, irrespective of mode or dosage of treatment. C6 deficient controls rejected grafts within 17.7 +/- 3.5 h (n = 10). Treatment with leumedin/nactin prolonged graft survival up to 61.0 +/- 4.7 h (n = 4-6), with dose dependent differences in effectiveness among the 3 compounds tested. Histology showed that treatment was associated with less edema, hemorrhage, and neutrophil infiltrate at 2, 6, and 12 h. The marked decrease in hemorrhage seen in nactin-treated animals may reflect an interaction of Mac-1 with blood coagulation factors. Our data confirm that the neutrophil adhesion pathway is involved in AAR, especially when complement mediated injury due to MAC is restricted.

Acute Disease↗
PubMed1977

Haemolytic assays in agarose plates for components of the classical complement pathway: interference by the alternative pathway.

It has been observed that when serum C6 is measured by the haemolytic radial diffusion technique a heat labile factor limits the size of the haemolytic rings. This reduction is haemolysis has been shown to be due to alternative pathway activation of C6 in the agarose plate; and that the heat labile factor is Factor B of the alternative pathway. This phenomenon is of practical importance when assaying for C6; however, it does not explain the observations of a C6 inactivator reported by Nelson & Biro (1968).

Antigen-Antibody Complex↗
PubMed1973

A new complement-mediated cytolytic mechanism--the C1-bypass activation pathway.

A new cytolytic pathway is described whereby cells sensitized with cytotoxic antibody can be specifically lysed in the complete absence of intact, classical complement pathway function. Evaluation of this model with sera deficient in the 4th (C4), 2nd (C2), and 6th (C6) components of complement has revealed that this new lytic mechanism, termed the C1-bypass activation pathway, is initiated by the antibody-mediated activation of C1. Utilizing components of the previously described alternate complement pathway, this pathway bypasses C4 and C2 to activate the third to ninth components of complement (C3-9) with induction of membrane damage.

Animals↗
PubMed1990

Role of the terminal complement pathway in accelerated autologous anti-glomerular basement membrane nephritis.

The terminal complement pathway (C5b to C9) has been demonstrated to have an important role in the mediation of glomerular immune injury in various models of experimental glomerulonephritis. In the present studies, the role of the terminal complement pathway in the accelerated autologous phase of anti-glomerular basement membrane (GBM) nephritis in the rabbit was investigated. Normocomplementemic rabbits and rabbits deficient in C6 (C6D) who are therefore unable to form the terminal complement pathway were immunized with sheep immunoglobulin G (IgG) before being injected with a subnephrotoxic dose of the gamma 2 fraction of sheep anti-rabbit GBM. C6D animals had a delay in the onset of the glomerular injury, as manifested by proteinuria. At 72 hours, controls had a greater degree of proteinuria (15.2 +/- 8.8 mg protein/mg creatinine vs. 2.6 +/- 2.1, P = 0.197), but at 120 hours there were no differences in proteinuria between C6D and control animals (11.1 +/- 3.6 mg protein/mg creatinine vs. 12.2 +/- 6.2, P = 0.89). Light microscopy demonstrated more severe glomerular injury in C6D animals with marked cellular proliferation and large areas of glomerular necrosis. Interestingly, C6D animals had significantly higher levels of sheep IgG remaining in their glomeruli at 120 hours (0.95 +/- 0.12 micrograms sheep IgG/1 x 10(4) glomeruli, N = 11, vs. 0.57 +/- 0.07, N = 11, P = 0.014) and 72 hours (1.22 +/- 0.25 micrograms, N = 3, vs. 0.60 +/- 0.15, N = 3, P = 0.104) compared with 24 hours when there was no difference (1.25 +/- 0.22 micrograms, N = 7, vs. 1.08 +/- 0.14, N = 7, P = 0.53). C6D rabbits had a greater rise in serum creatinine at 120 hours (2.3 +/- 0.5 mg/dl vs. 1.3 +/- 6.4, P = 0.132). We conclude that in C6D animals, the persistence of glomerular immune deposits is responsible for more severe renal injury and renal failure.

Animals↗
PubMed1989

Hereditary factors in Takayasu disease. III. Polymorphism of human complements.

Genetic polymorphisms in C2, C4, C6, C7 and BF alleles of human complement were studied in 80 Japanese patients with Takayasu disease, and compared with those of 433 normal Japanese. Statistically significant high frequencies of C4A2 (chi 2: 27.2; p less than 0.01) and C4BQ0 allotype (chi 2: 8.7; p less than 0.01) were found in patients with Takayasu disease. Furthermore, all patients carrying C4A2 were found to be associated with C4BQ0. In addition, patients with HLA Bw52 were strongly associated with C4A2BQ0. In 5 patients homozygous C4BQ0 was found. These data suggest that some genetic factor(s) may contribute to the pathophysiological condition of Takayasu disease, which is strongly associated with the complotype of HLA Bw52-C4A2BQ0.

Adult↗
PubMed1977

C6: synthesis by the liver in vivo.

The allotype of the sixth component of complement was determined in a patient before and after liver transplantation. The C6 phenotype changed from A before transplantation to B (the donor phenotype) within 10 days of the transplant and remained wholly of the donor phenotype at 17 wk. This demonstrates that the liver is the exclusive or predominant site of C6 synthesis in vivo in man.

Blood Transfusion↗
PubMed1976

Immunoglobulins and complement in pleural effusions associated with bronchogenic carcinoma.

Levels of IgG, IgA, IgM, the total haemolytic complement (CH50), and the individual components C1q, C3, C4, C6, and C7 were measured in 29 pleural effusions. Of these, 18 were associated with carcinoma of the bronchus and 11 were non-malignant effusions including empyemas. The level of IgG was significantly lower in the malignant group when compared with non-malignant effusions. The usefulness of measurements of IgG with respect to malignant effusions associated with carcinoma of the bronchus requires an expanded study to show whether it has any real diagnostic value. There were no significant differences in other immunoglobulins, the CH50, and individual complement components between the two groups. The identification of total haemolytic activity in the majority of effusions in both groups indicates that all nine components of the classical pathway of complement, including macromolecules such as C1, can be present in pleural fluids.

Carcinoma, Bronchogenic↗
PubMed1990

Membrane attack complex of complement in Henoch-Schönlein purpura skin and nephritis.

The present study using direct immunofluorescence with monoclonal antibodies to C5b-9 complex-related antigens was undertaken to determine whether complement activation in Henoch-Schönlein purpura (HSP) causes assembly of the membrane attack complex of complement (MAC) in skin and nephritis lesions. The deposition of C5, C6, C7, C8, C9, and C5b-9 neoantigens was noted in the vascular walls of papillary dermis and/or subpapillary dermal plexus of the vessels in 11 out of 15 patients with HSP. Their presence in vessel walls indicates complement activation which leads to terminal complement activation. There were small deposits of S protein at the same sites in three of the 11 skin specimens. Thus, the majority of C5b-9 demonstrated in HSP skin was the cytolytically active C5b-9 complex, MAC. Granular deposits of C5b-9 related antigens without S protein were also found in the capillary walls and mesangium of the glomeruli of two out of four specimens from patients with HSP nephritis; in the other two S protein was colocalized with the deposition of C5b-9. The results of the present study indicate that complement activation leading to generation of MAC may possibly be involved in the pathogenesis of vascular injury in a significantly large number of skin lesions and of HSP nephritis.

Antibodies, Monoclonal↗
PubMed1981

Human complement in the arachidonic acid transformation pathway in platelets.

Arachidonate-mediated release of 14C serotonin and thromboxane B2 (TXB2) is significantly enhanced in the presence of complement. Only purified complement components C5, C6, C7, C8, and C9 are required for this reactivity. No known activating mechanism of the classical or alternative pathway is required, nor is C3. In the absence of exogenously added complement, platelet membrane-bound complement components play an essential role in modulating arachidonate-mediated serotonin release. Incubation of platelet membranes with arachidonate and C5--C9 led to the production of dimers of the membrane attack complex (C5b--9) on the platelet surface. These macromolecular complexes were eluted from the platelet membrane and were identified physicochemically and morphologically. The possibility arises that C3 in association with C5--C9 is required for mobilization of the arachidonic acid from the phospholipid of the platelet membrane. Once the arachidonic acid is mobilized, C3 is no longer required, C5--C9 being sufficient to modulate this pathway leading to enhanced production of TXB2.

Animals↗
PubMed1990

Study of genetic polymorphism of seventh complement component in two families with hereditary deficit.

The results of an allelic segregation of C6 and C7 were studied in two Spanish families that have members with C7 deficiency. Absence of C7 in the affected siblings and half of the normal values in their parents were found in both families. The variant responsible for the deficiency (C7Q*0) follows a codominant autosomic inheritance pattern. Establishing allotypes of C6 and C7 by isoelectrofocusing followed by electrophoretic immunoblotting allowed haplotype assignments. In both families the haplotype form responsible for the deficiency seemed to be related to the C6B allotype.

Alleles↗
PubMed1975

Complement-mediated bactericidal system: evidence for a new pathway of complement action.

The early components of human complement (C1, C4, and C2) plus certain serum euglobulins will kill pathogenic strains of Shigella sonnei. Serum from patients with hereditary C3 deficiencies and specific antiserums to C3, C5, and C6 were utilized to demonstrate the absence of requirements for late-acting complement components in this unusual bactericidal system.

Antibodies, Bacterial↗
PubMed1994

Genomic structure of the human complement protein C8 gamma: homology to the lipocalin gene family.

Human C8 is one of five complement components (C5b, C6, C7, C8, C9) that interact to form the cytolytic C5b-9 complex on target cells. It contains three subunits (C8 alpha, C8 beta, C8 gamma) which are encoded in separate genes. In relation to other proteins of the complement system, C8 gamma is unusual in that it is not structurally related to any other component nor does it have an obvious function. Based on weak but significant sequence similarity, it is proposed to be a member of the lipocalin family of widely distributed proteins that bind and transport small hydrophobic ligands. In this study, the human C8 gamma gene has been characterized and found to contain seven exons spanning approximately 1.8 kb. S1 nuclease and anchored PCR were used to identify the transcription initiation site. This site is preceded by putative regulatory elements that include two SP1 binding sites, several glucocorticoid response elements, and two SV40 enhancer core consensus sequences. A comparison to genes of other lipocalins reveals a remarkably close correlation in exon number, lengths, and phases. A close correspondence in exon boundaries is also observed and suggests that C8 gamma contains the same discrete structural elements that define the characteristic beta-barrel shape of the lipocalins. These results establish that C8 gamma is indeed ancestrally related to the lipocalin family and strengthens the likelihood that its role in the complement system is to bind an as yet unidentified ligand.

Amino Acid Sequence↗