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PubMed1985

Involvement of complement in atopic dermatitis.

There is little information about the role of complement in atopic dermatitis (AD). We studied the levels of both normal complement components and activation products in peripheral blood of patients with mild to intermediate disease. 35 patients had not received systemic or topical steroid therapy 6 weeks prior to blood collection. C3, C4 and C1 INA were determined in serum by radioimmunodiffusion. C3a and C5a levels were measured in EDTA plasma by radioimmunoassay. Compared to healthy non-atopic controls C3, C4 and C1 INA were found to be increased significantly. There was a tendency towards increased C3a levels but the difference was not significant. No measurable amounts of C5a were detected. Elevations of C3a were correlated with elevated levels of C3. The results suggest that the complement system participates in the inflammatory process in AD.

Adolescent↗
PubMed1985

On the kinetics of complement activation, leucopenia and granulocyte-elastase release induced by haemodialysis.

In order to elucidate the kinetics of haemodialysis-induced activation of complement, leucopenia and release of granulocyte-elastase, 10 patients (three females and seven males; mean age 47.8 years) were extensively studied during a 4 h haemodialysis treatment and for the following 24 h, and further compared with a healthy control group. Prior to dialysis patients had normal leucocyte count, plasma elastase bound to alpha 1-proteinase inhibitor (E-alpha 1P1) and total haemolytic complement, whereas plasma C3d was higher and plasma C5a lower than in controls. Haemodialysis induced initial leucopenia and subsequent rebound phenomenon lasting 24 h post treatment. These alterations were due to almost selective changes in neutrophile count as monocyte and lymphocyte counts, apart from decrease in the first 30 min, were unchanged. Total haemolytic complement decreased initially during dialysis and rose at the end. Generation of C5a within the dialyser was evident by demonstration of high levels of this anaphylatoxin in dialyser effluent plasma; maximal values observed coincided with the nadir of leukopenia. Plasma C3d and E-alpha 1P1 both progressively rose during dialysis. After termination of extracorporeal circulation the disappearance rates (T/2) were approximately 6 h and 2.5 h respectively. Haemodialysis thus induces changes in the complement and leucocyte system resembling an acute inflammation, which out-lasts the treatment period.

Adult↗
PubMed1988

Immunological analysis of a destructive pattern of intraocular tumor resolution.

Spontaneous rejection of syngeneic intraocular P91 mastocytoma occurred by a T cell-dependent immune process that produced extensive, irreparable damage to normal ocular tissue indicative of a delayed-type hypersensitivity (DTH) lesion. We investigated the contribution of other effector modalities in this tumor resolution. Antibody was not responsible for either tumor rejection of phthisis of the tumor-containing eye since passively transferred hyperimmune serum failed to produce either tumor rejection or the characteristic ocular lesions. Moreover, the destructive pattern of tumor rejection occurred in splenectomized hosts which had depressed anti-P91 serum antibody and in a congenic strain (B10.D2oSn) lacking the C5 complement component. The likelihood that tumor necrosis factor (TNF) was involved in this pathogenesis was also ruled out by the observation that P91 tumor cells were not susceptible to lysis by recombinant TNF. A different pattern of tumor resolution was observed when the opposite eye was challenged with tumor. In this case, the tumor was rejected without damaging any major ocular structures. Histological analysis demonstrated a mononuclear cellular infiltrate which was identified by immunohistology to be Thy 1+, Lyt 2+. Thus, although both forms of cell-mediated immunity are available to the host, only one predominated in each eye. These results suggest that unique immunological control mechanisms influence the outcome of tumor resolution in the eye.

Animals↗
PubMed1978

Neutrophil chemotaxis and serum chemotactic activity in systemic lupus erythematosus.

Neutrophil chemotaxis, random motility, serum chemotactic activity derived from complement activation by classical or alternative pathways, and the presence of serum inhibitors of chemotaxis were all studied in 24 patients affected by Systemic Lupus Erythematosus (SLE) and in an equal number of healthy control subjects. Statistical comparison between patients and controls indicated lower chemotactic activity in patient's serum when activated by the classical pathway, and the presence in some SLE patients of a heat-labile inhibitor of the chemoattractants. Low "classical pathway" chemotactic indexes were correlated with low C4 values, active nephritis and recurrent infections. The presence of heat-labile inhibitor was correlated with low values of C3. Our data suggest that defective neutrophil chemotaxis could be one of the mechanisms contributing to the high incidence of infections suffered by SLE patients. The importance of conducting separate studies on cell movement and on generation of serum chemotactic activities by classical and alternative pathways in SLE patients is discussed.

Adolescent↗
PubMed1976

Membrane receptors on neutrophils.

Neutrophils recognise humoral immunologic reactants through 'receptors' on their surface membrane. Most widely studied and probably of greatest biologic significance are the immunoglobulin (Fc), and complement (primarily C3b and C5a) receptors which enable the cell to ract with, and be stimulated by, antigen-antibody, or antigen-antibody-complement complexes and their products. This interaction with the putative receptors and the consequent cell activation occurs most optimally on surfaces and plays a critical role in the mammalian host defense system.

Antibody Specificity↗
PubMed1977

Complement receptors and cell associated complement components.

Membrane receptors for activated complement components are widely distributed amongst tissue cells of most mammalian species. Common amongst these are receptors for C3b which mediate many of the biological functions of C3. In addition, the genetic control of certain complement components is linked to the genes which code for the major histocompatibility complex. Many of these components are also present on cell surfaces. This suggests that the function of the complement system and the major histocompatibility complex may be related.

Animals↗
PubMed1997

C5b-7 and C5b-8 precursors of the membrane attack complex (C5b-9) are effective killers of E. coli J5 during serum incubation.

The finding that C9-deficient sera (C9D) can kill serum sensitive strains of Gram-negative bacteria by us and other investigators, questions the role of C9 in the membrane attack complex as necessary for cell death. In these studies we have demonstrated that C5b-8 complexes generated on E. coli J5 during incubation in C9-depleted and C9-neutralized sera are effective in killing Gram-negative bacteria. In the same study, we extended our investigations to show that the deposition of C5b-7 complexes (from C8-deficient [C8D], C8 depleted and C8-neutralized sera) is also effective in killing Gram-negative bacteria. In all cases, these studies demonstrated that when E. coli J5 was incubated with C8D, C9D and pooled normal human serum [PNHS], deposited C5b-9 complexes from PNHS produced more killing than C5b-7 or C5b-8 complexes alone. These experiments clearly demonstrated that C5b-7 and C5b-8 complexes are bactericidal and that multimeric C9 within C5b-9 is not an absolute requirement for inner membrane damage and cell death of Gram-negative bacteria.

Blood Bactericidal Activity↗
PubMed1986

In vitro C5a generation by synthetic vascular prostheses: implications for graft incorporation in vivo.

C5a, released during activation of the complement cascade, was measured by radioimmunoassay in human plasma incubated with Dacron, preclotted Dacron, glutaraldehyde treated human umbilical vein (HUV), polytetrafluoroethylene (PTFE), and Dacron-collagen composite vascular grafts. Expressed as percent of C5a in control plasma incubated without graft, C5a generation by preclotted Dacron, and by the HUV was similar to that by Dacron (941 +/- 206% S.E.M.), while that due to PTFE was markedly less (p = 0.005). The Dacron-collagen composite vascular graft also generated significantly less C5a than Dacron and was similar to PTFE in this respect. These results expand on previous work suggesting that lower C5a generation by PTFE explained the negligible polymorphonuclear infiltrate seen on its surface in vivo, allowing it to endothelialise as rapidly as Dacron despite poorer attachment of seeded endothelial cells. The role of complement as a factor limiting endothelialisation of synthetic vascular prostheses needs further investigation.

Blood Vessel Prosthesis↗
PubMed2000

Requirements for C5a receptor-mediated IL-4 and IL-13 production and leukotriene C4 generation in human basophils.

Anaphylatoxin derived from the fifth complement component (C5a) in the presence of IL-3 induces continuous leukotriene C4 generation and IL-4 and IL-13 expression in human basophils for a period of 16-18 h. This indicates that the G protein-coupled C5a receptor (C5aR) can induce long-lasting cellular responses. Using anti-N-terminal C5aR Abs, C-terminal C5a hexapeptide analogs, and pertussis toxin, we demonstrate that the putative activation site of the C5aR is both necessary and sufficient for these late cellular responses. Furthermore, continuous pertussis toxin-sensitive G protein-coupled receptor activation and receptor-ligand interaction is ongoing and required during the entire period of product release. However, the late basophil responses have a more stringent requirement for optimal receptor activation. Leukotriene C4 generation appears to be influenced mostly by the way the receptor is activated, because the most active hexapeptide is a superagonist for this response. By contrast, C5adesarg, lacking the C-terminal arginine, induces minimal lipid mediator formation but is fully active to induce IL-4 production and is even a superagonist for IL-13 release. Nevertheless, IL-4/IL-13 synthesis in response to C5adesarg could be blocked by both C-terminal antagonistic peptide as well as anti-N-terminal C5aR Abs, indicating only minor differences of ligand-receptor interactions between C5a and C5adesarg. Taken together, our data demonstrate that long-lasting and continuous signaling occurs through a limited activation domain of the C5aR, which can differentially promote separate basophil functions.

Antigens, CD↗
PubMed2002

Complement C2 receptor inhibitor trispanning and the beta-chain of C4 share a binding site for complement C2.

Complement C2 receptor inhibitor trispanning (CRIT) of the Schistosoma parasite binds human C2 via the C2a segment. The receptor in vivo functions as C2 decoy receptor by directly competing with C4b for binding to C2. As a result, CRIT is able to limit the extent of classical pathway (CP) C3 convertase formation. We report that the CRIT-extracellular domain 1 (ed1) peptide inhibits CP-mediated complement activation with an ICH(50) of approximately 0.1 microM, the C-terminal 11 aa of CRIT-ed1, named H17, even more effectively. The beta-chain region F222-Y232 of C4 shares 55% identity and 73% similarity with H17. Peptides based on this region also inhibit CP in a dose-dependent manner. As further evidence of C2 binding we showed CRIT-ed1 peptides and homologous C4 beta-chain peptides to inhibit complement in C2 hemolytic assays. We have predicted C4 beta-c F222-Y232 as a C2 binding site which we have termed the CRIT-ed1 domain, and the sequence [F/H]EVKX(4/5)P as a consensus C2-binding sequence. Anti-CRIT-ed1 cross-reacts with the C4 beta-chain and F222EVKITPGKPY232 appears to be the key epitope recognized by this Ab. Furthermore, anti-CRIT-ed1 was found to inhibit CP activation in a total hemolytic assay. We believe that Schistosoma CRIT-ed1, as well as C4 beta-chain peptides based on the CRIT-ed1 domain, function as interface peptides. These peptides, based on C2-binding sequences in CRIT, or C4, competitively inhibit the binding of C2 to C4b and thus limit the activation of C. The C4 peptides, unlike CRIT-ed1, did not inhibit the cleavage of C2 by C1s.

Amino Acid Sequence↗
PubMed2002

Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells.

C4b and C3b deposited on host cells undergo limited proteolytic cleavage by regulatory proteins. Membrane cofactor protein (MCP; CD46), factor H, and C4b binding protein mediate this reaction, known as cofactor activity, that also requires the plasma serine protease factor I. To explore the roles of the fluid phase regulators vs those expressed on host cells, a model system was used examining complement fragments deposited on cells transfected with human MCP as assessed by FACS and Western blotting. Following incubation with Ab and complement on MCP(+) cells, C4b was progressively cleaved over the first hour to C4d and C4c. There was no detectable cleavage of C4b on MCP(-) cells, indicating that MCP (and not C4BP in the serum) primarily mediates this cofactor activity. C3b deposition was not blocked on MCP(+) cells because classical pathway activation occurred before substantial C4b cleavage. Cleavage, though, of deposited C3b was rapid (<5 min) and iC3b was the dominant fragment on MCP(-) and MCP(+) cells. Studies using a function-blocking mAb further established factor H as the responsible cofactor. If the level of Ab sensitization was reduced 8-fold or if Mg(2+)-EGTA was used to block the classical pathway, MCP efficiently inhibited C3b deposition mediated by the alternative pathway. Thus, for the classical pathway, MCP is the cofactor for C4b cleavage and factor H for C3b cleavage. However, if the alternative pathway mediates C3b deposition, then MCP's cofactor activity is sufficient to restrict complement activation.

Animals↗
PubMed1976

Partial characterization of human C5a anaphylatoxin. I. Chemical description of the carbohydrate and polypeptide prtions of human C5a.

Human C5a was isolated from complement-activated serum and was characterized for protein and carbohydrate content. The purified C5a was judged to be homogeneous by both polyacrylamide gel electrophoresis and immunologic techniques. The polypeptide moiety of C5a contains 73 amino acid residues which represent a m.w. of 8,200. Analysis of the carbohydrate moiety in C5a indicated 4 moles of glucosamine, 3 to 4 moles os sialic acid, 4 moles of mannose and 2 moles of galactose. The total carbohydrate content in C5a, therefore, amounts to approximately 25% of the apparent m.w. of the anaphylatoxin molecule. The protein and carbohydrate portions of C5a together equal a m.w. of approximately 11,000 which is considerably less than the 15 to 16,000 indicated by physical measurements. Human C5a contains a COOH-terminal arginine which is essential for anaphylatoxin activity and a sequence of Gln-Leu-Gly-Arg-COOH at the COOH-terminus which compares favorably with that of human C3a (Gly-Leu-Ala-Arg-COOH). Additional similarities between the C3a and C5a molecules include length of the polypeptide chain, number of disulfide bonds and an absence of tryptophan residues. A major chemical difference does exist between these two human anaphylatoxins, namely that carbohydrate is associated with C5a but is absent in the C3a molecule. The partial NH2-terminal sequence of C5a was determined as NH2-Thr-Leu-Glx-Lys-Ile-Glx-Glx-Ile-Ala- and direct comparison with the known sequence of human C3a shows little homology.

Amino Acid Sequence↗
PubMed1999

Interaction between terminal complement proteins C5b-7 and anionic phospholipids.

We have recently shown that C5b-6 binds to the erythrocyte membrane via an ionic interaction with sialic acid before the addition of C7 and subsequent membrane insertion. In this study we assessed the role of anionic lipids in the binding of the terminal complement proteins to the membrane and the efficiency of subsequent hemolysis. Human erythrocytes were modified by insertion of dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylserine (DPPS), dipalmitoyl phosphatidylethanolamine (DPPE), or dipalmitoyl phosphatidic acid (DPPA). Lipid incorporation and the hemolytic assays were done in the presence of 100 micromol/L sodium orthovanadate to prevent enzymatic redistribution of lipid. We found that the neutral lipids, DPPC and DPPE, did not affect C5b-7 uptake or hemolysis by C5b-9. In contrast, the two acidic phospholipids, DPPS and DPPA, caused a dose-dependent increase in both lysis and C5b-7 uptake. We conclude that the presence of anionic lipids on the exterior face of the membrane increases C5b-7 uptake and subsequent hemolysis. It is known that sickle cell erythrocytes have increased exposure of phosphatidylserine on their external face and are abnormally sensitive to lysis by C5b-9. The data presented here provide a plausible mechanism for this increased sensitivity.

1,2-Dipalmitoylphosphatidylcholine↗
PubMedDate not supplied

[Complement system during hemofiltration in patients with multiple organ failure].

Nine patients (8 men and 1 woman) were treated. Sepsis was diagnosed in 7 of them. All patients were subjected to forced ventilation of the lungs, 6 were in need of inotropic support. The severity of clinical status was 31 +/- 0.8 according to APACHE II score. One patient survived. The main method of substitute renal therapy (SRT) was permanent hemofiltration with spontaneous arteriovenous perfusion. The results indicate manifest depletion of the complement system augmenting with the progress of multiple organ failure (MOF). Extracorporeal perfusion in SRT had no additional negative effects on the complement system damaged by disease. Nonselective penetration of individual complement fractions into the filtrate in the course of perfusion was noted. Therefore, the complement system is severely damaged in patients with MOF; it can modulate the SRT because of penetration of its individual fractions.

APACHE↗
PubMed1975

Hypochlorite-induced alterations to canine serum complement.

Changes in the concentration of the components of complement produced by NaOC1 both in vitro and in vivo are recorded. C1, C4 and C7 are particularly sensitive to this oxidizing agent, although all components decrease at high concentrations of NaOC1. Following oxidation, complement componenets return rapidly to normal. Data are presented to indicate that part of this repair mechanism is due to the action of reducing agents such as ascorbic acid and part is due to the synthesis of the individual components. The unique sensitivity of complement components to oxidation make this treatment of potential value in suppressing the inflammatory response.

Animals↗