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PubMed1987

Bovine IgM: does it fix guinea pig complement in the absence of bovine complement components?

Purified bovine isotypes IgM, IgG1, IgG2, and IgA (secretory), affinity purified with Brucella abortus, were tested in a complement fixation test (CFT) for their ability to activate guinea pig complement directly or in the presence of 'normal' bovine serum. Only IgG1 fixed guinea pig complement in the direct test and approximately 250 ng of antibody was required to activate 50% of 3 CH50 units with a standard amount of antigen. Addition of 'normal' bovine serum as an additional source of complement resulted in activation of guinea pig complement by IgM, IgG2 and secretory IgA at levels of approximately 1200, 700 and 2250 ng, respectively for 50% of 3 CH50 units. Addition of 'normal' bovine serum did not enhance complement activation by bovine IgG1.

Animals↗
PubMed2003

Combination effects of complement regulatory proteins and anti-complement polymer.

We previously reported the development of a "cytomedicine" that consists of cells trapped in alginate-poly-L-lysine-alginate (APA) microcapsules and agarose microbeads. The functional cells that are entrapped in semipermeable polymer are completely isolated from cellular immune system. However, the ability of cytomedicine to isolate cells from the humoral immune system, which plays an essential role in xenograft rejection, is low. Therefore, the goal of the present study was to develop a novel cytomedicine that could protect the entrapped cells from injury of the complement system. We investigated the applicability of the complement regulatory protein (CRP), Crry, to cytomedicine. Crry-transfected cells entrapped within agarose microbeads resisted injury by complement to a degree, while entrapment of Crry transfected cells within agarose microbeads containing polyvinyl sulfate (PVS), a novel cytomedical device with anti-complement activity, clearly protected against complement attack. These data indicate that the combination of a CRP and a cytomedical device with anti-complement activity is a superior device for cytomedical therapy.

Animals↗
PubMed2001

Enhancement of complement-mediated lysis by a peptide derived from SCR 13 of complement factor H.

Complement factor H (fH) is an important regulator of complement activation. It contributes to protection of cells against homologous complement attack. In this study we tested the effect of fH-depletion of normal human serum (NHS) on lysis of antibody-coated sheep and human erythrocytes (EshA and EhuA). In the absence of fH, lysis of sensitised Esh and Ehu was clearly increased. Addition of fH to fH-depleted serum re-established protection of cells against complement similar to that seen with NHS. A fH-derived peptide (pepAred), covering the N-terminal half of SCR 13 in fH, was able to enhance complement-mediated lysis of EhuA significantly. However, the oxidised form of this peptide (pepAox) had no effect. Biotinylated pepAred, but not pepAox, was able to directly bind to cells. Additionally, pepAred competed with direct fH-cell interaction which was observable only after treatment of purified fH with mercaptoethanol. Only pepAred increased the amount of C3 fragments and reduced levels of fH detectable on cells as shown by FACS analysis and radio-immuno assay. Furthermore, fH and factor I (fI)-mediated cleavage of agarose bound C3b into iC3b was decreased in the presence of pepAred. These data indicate that a fH-derived peptide can enhance complement-mediated lysis. We will continue to investigate whether the use of a fH peptide can be exploited for therapeutical purposes.

Amino Acid Sequence↗
PubMed1998

Complement-regulatory protein expression and activation of complement cascade on erythrocytes from patients with rheumatoid arthritis (RA).

It has been previously reported that the expression of the complement receptor, CR1, on erythrocytes is reduced in patients with RA and that the reduced expression of CR1 is related to disease activity. In this study we investigate the role of other regulatory proteins, i.e. decay-accelerating factor (DAF) and CD59 (membrane inhibitor of reactive lysis), in the pathogenesis of RA by checking the expression of DAF and CD59 on erythrocytes of RA patients to establish whether reduced expression of DAF and CD59 on erythrocytes could be related to increased ability of erythrocytes to activate complement in RA. Flow cytometry was used to measure the expression of DAF and CD59 on erythrocytes from RA patients as well as the deposition of C3 fragments occurring in vivo or after in vitro complement activation. Significantly reduced expression of DAF and CD59 was observed on erythrocytes of RA patients. A significant inverse relationship was observed between DAF expression and in vitro complement activation, whereas no significant relationship between CD59 and complement activation was observed. Finally, we demonstrated an inverse relationship between CH50 activity and DAF expression. Thus, determination of DAF on erythrocytes can emerge as an additional tool in the assessment of extent of complement activation in RA.

Adolescent↗
PubMed1976

Effect of sulfones on complement deposition in dermatitis herpetiformis and on complement-mediated guinea-pig reactions.

The role of complement and the mechanism of sulfone action in dermatitis herpetiformis (DH) have not yet been established; prior studies have presented conflicting data regarding the effect of sulfones on complement activation and deposition. Thirty-eight DH patients were studied. Twenty-four of 25 perilesional skin biopsies and 50 of 67 normal-appearing skin biopsies showed the third component of complement (C3) deposited in areas corresponding to those of IgA deposition. Nine of 10 patients with bound C3 in normal-appearing and perilesional skin during periods of active disease continued to have C3 in normal-appearing skin when treatment with sulfones kept them completely free of lesions for 2 to 8 weeks. When either Hartley-strain or C4-deficient guinea pigs were given up to 150 mg/kg sulfoxone (a water-soluble sulfone) intraperitoneally for 8 days before elicitation of active Arthus, reverse passive Arthrus reactions, or Forssman shock, there was no difference in time course, character, or intensity of reactions when compared to saline-treated control animals. We were therefore unable to demonstrate any effect of sulfones on complement deposition in DH skin or on complement activation in classical or alternate complement pathway-mediated guinea-pig reactions.

Animals↗
PubMed1998

Extracorporeal ("ex vivo") connection of pig kidneys to humans. III. Studies of plasma complement activation and complement deposition in the kidney tissue.

The complement system is one of the important factors involved in the hyperacute rejection of xenografts. This report deals with the activation of the complement system in a clinical trial where pig kidneys were extracorporeally connected to two volunteer dialysis patients who were pretreated with plasmapheresis in order to substantially reduce anti-pig xenoantibodies. The clinical data of the perfusion experiments and the patients humoral immune response to pig xenoantigens have been reported in detail (Xenotransplantation 1996; 3:328-339, 340-353). Three consecutive daily plasmapheresis treatments of the patients reduced the plasma complement protein (C3, C4, and C5) concentrations to 8-27% of the baseline values. The perfusion of the pig kidney connected to patient 1 was terminated at 65 min due to graft rejection and this patient was not hemodynamically affected by the experiment. The second experiment was terminated at 15 min due to an anaphylactic like reaction of the patient. In patient 1 a slight reduction of plasma C3, C4, and C5 and an increase of C5a and SC5b-9 occurred, while C3a decreased during the perfusion. Patient 2 had an increase of all complement parameters, most prominent for C4d and SC5b-9, which occurred concomitant with the appearance of the anaphylactic like side effects. In general, plasma levels of PMN elastase, IL6 and IL8 increased in both patients during the perfusion. Immunohistochemical investigation of the kidney tissues revealed deposition of human complement factors C1q, C4c, and C3c in a congruent pattern with the vasculature of the kidney in patient 1. In kidney 2 only trace amounts of C1q and C3c were found. Both kidneys were negative for properdin. Therefore, in this experimental set up with extracorporeal connection of pig kidneys to the human circulation the human complement cascade is activated mainly through the classical pathway.

Adult↗
PubMed1994

Soluble human complement receptor type 1 inhibits complement-mediated host defense.

Soluble complement receptor type 1 (sCR1) is a powerful inhibitor of complement activation. Because of this ability, sCR1 may prove to be an important therapeutic agent that can be used to block the immunopathologic effects of uncontrolled complement activation in a variety of clinically significant disorders. Although several previous studies have examined the ability of sCR1 to inhibit complemented-mediated immunopathologic damage, there is no information on its ability to interfere with the host's defense against infection. In the current experiments sCR1 exerted a concentration-dependent inhibitory effect on the phagocytosis of Streptococcus pneumoniae by human polymorphonuclear leukocytes in vitro. Not only di sCR1 inhibit complement-dependent opsonization of the pneumococcus but at higher concentrations it also inhibited the ingestion of bacteria which had been previously opsonized. Furthermore, when rats were injected with sCR1, it inhibited both their serum hemolytic activity and serum opsonic activity in a dose-dependent fashion. Finally, for rats treated with sCR1, the 50% lethal dose was S. pneumoniae and Pseudomonas aeruginosa. These data demonstrate that sCR1 significantly inhibits complement-mediated host against bacterial infection.

Animals↗
PubMed2003

Restoration of complement-enhanced neutralization of vaccinia virus virions by novel monoclonal antibodies raised against the vaccinia virus complement control protein.

The vaccinia virus complement control protein (VCP) is secreted by infected cells and has been shown to inhibit complement activation through interactions with C3b/C4b. It contains four short consensus repeat (SCR) domains. It has been suggested that all four SCRs are required for VCP's activity. To elucidate which SCR domains are involved in abolishing complement-enhanced neutralization of vaccinia virus virions, we generated and characterized a panel of mouse monoclonal antibodies (MAbs) raised against VCP. Ten MAbs were isolated and all recognized VCP on Western blots under reducing conditions as well as native-bound VCP in a sandwich enzyme-linked immunosorbent assay. Three of the 10 MAbs (2E5, 3D1, and 3F11) inhibited VCP's abolition of complement-enhanced neutralization of vaccinia virus virions. These MAbs blocked the interaction of VCP with C3b/C4b. The seven remaining MAbs did not alter VCP function in the complement neutralization assay and recognized VCP bound to C3b/C4b. To understand MAb specificity and mode of interaction with VCP, we mapped the MAb binding regions on VCP. The seven nonblocking MAbs all bound to the first SCR of VCP. One of the blocking MAbs recognized SCR 2 while the other two recognized either SCR 4 or the junction between SCRs 3 and 4, indicating that structural elements involved in the interaction of VCP with C3b/C4b are located within SCR domains 2 and 3 and 4. These anti-VCP MAbs may have clinical significance as therapeutic inhibitors of VCP's complement control activity and may also offer a novel approach to managing vaccinia virus vaccine complications that occur from smallpox vaccination.

Animals↗
PubMed1972

Role of antibody and complement in the immune clearance and destruction of erythrocytes. I. In vivo effects of IgG and IgM complement-fixing sites.

A model which permits evaluation in molecular terms of the role of antibody and of complement in the immune destruction of erythrocytes was established in the guinea pig. IgM and IgG immunoglobulins were isolated from rabbit anti-guinea pig erythrocyte antisera and were used to sensitize (51)Cr-labeled guinea pig erythrocytes. The average number of complement-fixing sites per erythrocyte formed by antibody was determined for each of the various preparations by the Cla fixation and transfer test. The rate of clearance and of organ localization was determined for cells sensitized with either IgM or IgG antibodies, and dose-response curves were established in normal guinea pigs and guinea pigs with a genetically controlled, complete absence of the fourth component of complement (C4). At least 60 complement-fixing sites per cell were required for accelerated clearance of IgM-sensitized erythrocytes. The bulk of cells with IgM sites were cleared by the liver within 5 min after injection and were then slowly returned to the circulation where they survived normally. There was no accelerated clearance whatsoever of IgM-sensitized erythrocytes in C4-deficient guinea pigs. As few as 1.4 IgG complement-fixing sites per cell resulted in decreased erythrocyte survival. There was no evidence of immediate tissue sequestration and release. Progressive trapping and destruction of erythrocytes by the spleen was responsible for most of the clearance of IgG-sensitized cells. Clearance of IgG-sensitized cells was markedly impaired in guinea pigs with C4 deficiency; however, there was some decrease over normal survival. The data indicate that IgG and IgM antibodies interact with complement in vivo by mechanisms which are qualitatively or quantitatively different and produce different biologic effects.

Anemia, Hemolytic↗
PubMed1980

Complement-independent adherence of Escherichia coli to complement receptors in vitro.

We studied adherence to human cells by a strain of Escherichia coli. Adherence to erythrocytes was assessed directly by phase-contrast microscopy and indirectly by hemagglutination; adherence to peripheral blood leukocytes, using radiolabeled bacteria and subsequent determination of leukocyte-associated radioactivity; and adherence to renal glomeruli, by microscopy of fluoresceinated bacteria and of Gram-stained nonfluoresceinated bacteria. In serum-free systems, E. coli of this strain adhered to human erythrocytes, which have surface receptors for the third component of complement (C3), but not to erythrocytes from species lacking this receptor. 1 mM trypan blue, a reagent that inhibits complement receptor function, inhibited adherence to human erythrocytes, as well as adherence to leukocytes and glomeruli. Preincubation of erythrocytes and leukocytes with complement-coated zymosan particles partially blocked subsequent bacterial adherence. Incubation of human erythrocytes with aging human serum, with trypsin-cleaved C3, or with C3 cleaved by the classical pathway convertase (EAC142)-all of which treatments deposited C3 on the erythrocyte surface, presumably at C3 receptors-inhibited subsequent E. coli adherence. Finally, incubation of E. coli with rabbit antiserum to human C3 blocked adherence to erythrocytes.Bacterial hemagglutination and erythrocyte adherence were not inhibited by mannose in concentrations up to 2.5%. And this strain of E. coli did not adhere to or agglutinate guinea pig erythrocytes, the usual test particle used for demonstration of common pili. Finally, electron microscopy of adherent bacteria showed only rare surface pili. In contrast, adherence to and agglutination of guinea pig erythrocytes by a stock piliated E. coli was inhibited by mannose but not by trypan blue. We conclude that organisms of this strain of E. coli adhere to human erythrocytes, leukocytes, and glomeruli at complement receptors. Complement is not required for this interaction. Adherence apparently involves a C3-like structure on the bacterial surface, but bacterial surface pili play no role. The physiological or pathological role of this adherence is not apparent, but study of this phenomenon may elucidate functions of complement receptors on various cells.

Animals↗
PubMed2005

Vaccinia virus complement control protein diminishes formation of atherosclerotic lesions: complement is centrally involved in atherosclerotic disease.

Complement is known to be activated in atherosclerotic lesions, but the importance of this event in disease pathology is a matter of debate. Studies of rabbits fed a high-fat diet have indicated complement activation as a rate-limiting step, whereas results from genetically modified mouse strains (ApoE-/- or LDLR-/-) have failed to support this finding. To resolve whether this reflects differences between species or between genetically driven and diet-induced disease, we studied the effect of a complement inhibitor, vaccinia virus complement control protein (VCP), on C57BL/6 mice, the background strain of ApoE-/- and LDLR-/- mice. Atherosclerosis was induced by a high-fat diet, and VCP (20 mg/kg) was injected once per week after the eighth week. Fatty streak development was monitored at 15 weeks by microscopic examination of oil red-O-stained sections from the root of the aorta. VCP injections led to significant (50%) reduction of lesion size (P = 0.004). Lesions were marked by gradual accumulation of lipids and macrophages but did not develop beyond the fatty streak stage. VCP activity disappeared from serum in 4 days, and the possibility therefore exists that a higher level of protection may be achieved by more frequent injections. We conclude that the development of fatty streaks in diet-induced atherosclerotic disease can be significantly retarded by prophylactic treatment with a complement inhibitor. These results support previous findings from complement-deficient rabbits and suggest that the pathogenesis of atherosclerosis in diet-induced disease differs from that induced by major defects in lipid metabolism.

Animals↗
PubMed1994

Tissue-specific Fc gamma and complement receptor expression by alveolar macrophages determines relative importance of IgG and complement in promoting phagocytosis of Pseudomonas aeruginosa.

Because the expression of IgG Fc receptors and complement receptors on macrophages may vary in a tissue-specific manner, we used monoclonal antibodies and flow cytometry to define the expression and function of opsonin receptors on fresh normal and cystic fibrosis (CF) bronchoalveolar lavage (BAL) macrophages. Using flow cytometry to separately analyze individual types of cells, we then determined the relative contributions of IgG and complement to phagocytosis of Pseudomonas aeruginosa by fresh BAL cells, avoiding alterations in receptor expression due to in vitro purification or culturing techniques. Neither normal nor CF BAL macrophages express appreciable amounts of the complement receptors CR1, CR2, or CR3. These results were confirmed by immunohistochemical staining of fixed lung sections. BAL macrophages express a high-affinity IgG receptor, Fc gamma RI, that is not found on neutrophils (PMN). In contrast, chemoattractant-stimulated blood PMN express large amounts of CR1 and CR3 but do not express Fc gamma RI. These results correlate with phagocytosis assays, which show that phagocytosis by macrophages is enhanced by relatively low concentrations of IgG but that the addition of complement does not further increase their phagocytosis. In contrast, low concentrations of IgG alone do not promote phagocytosis by PMN, whereas addition of complement markedly enhances phagocytosis by PMN. These results may explain the previously reported sensitivity of macrophages rather than PMN to the "blocking" effects of anti-Pseudomonas antibodies from CF patients, and emphasize the pathologic significance of interference with IgG and complement mediated opsonization in the lung in CF.

Adolescent↗
PubMed1995

Activation of homologous complement via the alternative complement pathway by quail cells transformed by Rous sarcoma virus.

After incubation of the cells with fresh quail serum, deposition of the third component of complement (C3) was demonstrated on the cell surface of various quail cell lines transformed by Rous sarcoma virus (RSV) as well as on that of primary quail embryo (QE) cells transformed by RSV. The C3 deposition occurred irrespective of virus production. On the other hand, the C-3 deposition was not observed on two quail cell lines transformed by a chemical carcinogen, QE cells infected with avian leukosis virus or normal QE cells. Moreover, QE cells infected with a temperature-sensitive mutant of RSV activated the complement at 37 degrees C but not at 41 degrees C. Since the progeny virus was generated even at 41 degrees C, viral molecules on the cell surface may not play an essential role for the activation. The activation of complement was blocked by EDTA but not by EGTA-Mg++. Therefore, the complement activation on the transformed cells appears to be mediated via the alternative complement pathway (ACP). Similar results were obtained with the complement consumption test; the residual cytolytic activity of fresh quail serum via ACP was markedly reduced by pre-incubation of the serum with transformed cells.

Animals↗
PubMed1999

[Complement activation in citrate plasma--inhibitory effect of anticoagulants on serum complement activation].

It is generally accepted that complement activation does not proceed in EDTA- and citrate-plasma because of calcium chelation by EDTA and citrate. However, there were several cases with low CH50 level in serum and citrate plasma and normal CH50 level in EDTA plasma, suggesting that complement might be activated in citrate-plasma but not in EDTA-plasma. The present study deals with the inhibitory effect of EDTA and citrate on complement activation. CH50 was assayed in serum or plasma containing various concentrations of EDTA or citrate after incubation with latex particles bearing immunoglobulin. It was revealed that complement activation proceeded in the presence of 2.0 mmol/l of EDTA but was inhibited in the presence of 2.5 mmol/l of EDTA, while blood coagulation was inhibited in plasma containing EDTA higher than 2.0 mmol/l. As to citrate, complement activation proceeded in the presence of 25 mmol/l of citrate but was inhibited in the presence of 50 mmol/l of citrate, while blood coagulation was inhibited in plasma containing citrate higher than 6.2 mmol/l. Thus, it was indicated that, as usual plasma in clinic contains 3.5 mmol/l of EDTA or 10.9 mmol/l of citrate, complement can be activated in citrate-plasma but not in EDTA-plasma. Similar conclusion was obtained by another experiment using ordinary vacuum-type blood collection tube for EDTA-2K plasma, EDTA-2Na plasma and citrate plasma.

Anticoagulants↗
PubMed2000

GluR3 autoantibodies destroy neural cells in a complement-dependent manner modulated by complement regulatory proteins.

GluR3 autoantibodies have been implicated in the development of Rasmussen's encephalitis, a rare neurodegenerative disease of humans characterized by epilepsy and degeneration of a single cerebral hemisphere. GluR3 autoantibodies are found in some Rasmussen's encephalitis patients, and GluR3 antibodies raised in rabbits destroy cultured cortical cells in a complement-dependent manner. In this study, the cellular targets of anti-GluR3 antisera-mediated cytotoxicity were examined in mixed primary neuronal-glial cultures of rat cortex. Unexpectedly, astrocytes were the principal target of the cytotoxic effects as assessed by immunohistochemistry and lactate dehydrogenase activity; neurons were destroyed to a lesser extent. Astrocyte vulnerability was rescued by transfection with complement regulatory proteins, and neuronal resistance was defeated by impairing complement regulatory protein function. Astrocyte death may occur in Rasmussen's encephalitis, and destruction of this cell type may play a critical role in the progression of this disorder. The present findings suggest complement regulatory protein expression may in part determine the nature and severity of Rasmussen's encephalitis and other complement-dependent nervous system diseases and thus underscore the need for a systematic investigation of the expression of all known complement regulatory proteins in healthy and diseased nervous system tissues.

Animals↗
PubMed1976

Erysipelas arthritis in swine: concentrations of complement and third component of complement in synovia.

Concentrations of hemolytic complement and of 3rd component of complement were determined in serums and in synovia of normal and arthritic joints in swine affected with arthritis experimentally produced by the inoculation of Erysipelothrix rhusiopathiae. Mean concentrations of complement in arthritic joints were increased from 24.7 to 37.5 50% hemolytic units of complement per milliliter. Third component of complement, expressed as a percentage of the serum concentration, was increased from a mean of 16.9 (normal joint synovia) to a mean of 27.1 (arthritic joint synovia). Also, fast-migrating conversion products of 3rd component of complement were not detected in synovia from arthritic joints. These results are interpreted as indicating a relatively less important role for immune complexes in the pathogenesis of erysipelothrix arthritis than is described for rheumatoid arthritis in persons.

Animals↗
PubMed1991

Complement and monocytes are essential for provoking glomerular injury in passive Heymann nephritis in rats. Terminal complement components are not the sole mediators of proteinuria.

Complement but not polymorphonuclear granulocytes (PMN) causes glomerular injury in passive Heymann nephritis in rats. We have now identified monocytes as another important mediator in this model. Passive Heymann nephritis was induced in Wistar rats by intravenous injection of sheep anti-rat Fx1A antiserum. Four groups (all receiving anti-rat Fx1A antiserum) were studied: (a) rats given normal sheep globulin (nephritic controls), (b) rats given sheep anti-rat PMN globulin (PMN-depleted), (c) rats given sheep anti-rat monocyte globulin (monocyte-depleted), (d) rats injected with cobra venom factor (complement-depleted). In vitro specificity controls for anti-cell antisera were made by cytotoxicity tests and inhibition of phagocytosis. In vivo specificity controls were performed in heterologous Masugi nephritis (PMN-dependent) and accelerated Masugi nephritis (monocyte-dependent). Complement and monocyte depletion significantly delayed the onset of proteinuria (p less than 0.001 versus nephritic controls on day 5), PMN depletion had no significant effect. Monocyte infiltration was seen in control nephritic rats, but monocyte depletion prevented this influx. In the monocyte-depleted group, no differences in glomerular deposition of C3, C9, and C5b-9 were seen in comparison to the nephritic control rats. Serum C3 levels were comparable in groups a, b, and c, the complement system was biologically active in the monocyte depleted-group (c), and the amount of anti-Fx1A antibody bound was the same in all groups. This shows that, besides complement, monocytes are required for induction of renal damage in passive Heymann nephritis. The concept of a sole role for complement in glomerular immune injury involving subepithelial immune deposits should be reconsidered.

Animals↗
PubMed1994

Effects of transfected complement regulatory proteins, MCP, DAF, and MCP/DAE hybrid, on complement-mediated swine endothelial cell lysis.

We established several swine endothelial cell (SEC) lines, expressing human MCP (CD46), DAF (CD55), and MCP/DAF hybrid by transfection of cDNA, and assessed the function of these transfectant molecules on complement-mediated cell lysis as an in vitro hyperacute rejection model of swine to human discordant xenograft. Discordant organ xenografts are hyperacutely rejected by complement activation. Amelioration of complement-mediated lysis by these transfectant molecules was tested in each SEC line by lactate dehydrogenase assay. Naive swine endothelial cells were markedly damaged by human complement mainly via the classical pathway, activating only minimally the alternative pathway of human complement. Both MCP and DAF protected SEC from human complement attack in parallel with the expression density, with DAF being more effective than MCP. The MCP/DAF hybrid was more effective than MCP alone, and as effective as DAF in this system. The results suggest that the transfection of DAF or the MCP/DAF hybrid cDNA into organs to be transplanted could protect against hyperacute rejection.

Animals↗