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PubMed1988

Activation of the third complement component (C3) and C3a generation in cardiac anaphylaxis: histamine release and associated inotropic and chronotropic effects.

Activation of the complement system with generation of C3a and C5a anaphylatoxins occurs during immediate hypersensitivity reactions; furthermore, the administration of C3a and/or C5a into isolated hearts causes a dysfunction that closely resembles cardiac anaphylaxis. To determine whether complement is activated and anaphylatoxins are generated in the course of immediate hypersensitivity reactions of the heart, we have challenged presensitized isolated guinea pig atria and papillary muscles with the specific antigen in the presence of a source of complement. We have found that the anaphylactic reaction of these cardiac preparations is characterized by complement activation and C3a generation, as well as by histamine release and positive inotropic and chronotropic effects. The amounts of C3a generated and histamine released directly correlated with the extent of C3 consumption. Furthermore, when C3a and C5a inactivation by serum carboxypeptidase N was prevented by DL-2-mercapto-methyl-3-guanidino-ethylthiopropanoic acid, anaphylactic histamine release was enhanced, and chronotropic and inotropic responses were potentiated and prolonged. Notably, the administration of C3a to nonsensitized guinea pig atria and papillary muscles caused positive chronotropic and inotropic effects, which were associated with histamine release and were antagonized by the H2 receptor blocker cimetidine, thereby mimicking the effects of anaphylaxis. Our findings indicate that complement activation and anaphylatoxin generation are typical of cardiac anaphylaxis and suggest that anaphylatoxins function as mediator-modulators of immediate hypersensitivity reactions of the heart.

Anaphylaxis↗
PubMed2006

Modulation of the SDF-1-CXCR4 axis by the third complement component (C3)--implications for trafficking of CXCR4+ stem cells.

Several organs including hematopoietic ones may regenerate by attracting stem cells that are mobilized from their niches in response to stress related to tissue/organ damage and after mobilization circulate in the peripheral blood. The trafficking of these cells is regulated by alpha-chemokine stromal derived factor-1 (SDF-1) that is upregulated in damaged organs and binds to seven-transmembrane-span G-protein-coupled CXCR4 receptor that is expressed on circulating stem cells. In parallel, evidence has accumulated that the complement (C) system, which is part of innate immunity, may also orchestrate regeneration. C becomes activated with the release of the third complement component (C3) cleavage fragments (e.g., C3a, desArgC3a, and iC3b) during tissue/organ injury. Our recent work demonstrated that these fragments modulate responsiveness of CXCR4+ stem cells to an SDF-1 gradient. Thus the high concentration of both SDF-1 and C3 cleavage fragments in damaged organs results in the formation of an optimal gradient for chemoattracting circulating CXCR4+ stem cells. In this review we will focus on interactions between the SDF-1-CXCR4 axis and the C3 cleavage fragments in a model of mobilization, trafficking, and homing of hematopoietic stem/progenitor cells (HSPC).

Animals↗
PubMed2004

Evidence for a complex risk profile in obese postmenopausal Turkish women with hypertriglyceridaemia and elevated apolipoprotein B.

The aim of the present study was to examine possible pathophysiological relationships among a wide array of proatherogenic risk factors in postmenopausal women. Fasting lipids, apoB (apolipoprotein B), BMI (body mass index) and waist circumference were measured in 178 women (59.4+/-7.2 years) from the Turkish Adult Risk Factor Study. Fasting levels of complement C3, insulin, SHBG (sex hormone-binding globulin), cortisol, oestradiol, testosterone and DHEA-S (dehydroepiandrosterone sulphate) were also determined. This is the first study to examine the relationships of all these variables with apoB. In the first of two different approaches, three groups of obese women were compared. Group 1 comprised women who were normolipidaemic with normal apoB; group 2, women who were hypertriglyceridaemic, but with normal apoB; and group 3, women who were hypertriglyceridaemic with elevated apoB. Complement C3, fasting insulin and glucose were significantly higher and HDL-C (high-density lipoprotein-cholesterol) and SHBG levels were significantly lower in group 3 than in group 1. In the former group, the testosterone/SHBG ratio tended to be higher, indicating more free testosterone, than in group 1. The mean risk score in group 3 and the odds ratio for coronary disease by logistic regression analysis were significantly higher, 2.56 (confidence intervals, 1.12-5.85; P=0.026), compared with the two other groups combined. In examining the whole group, apoB levels correlated significantly with a wider array of pro-atherogenic risk factors than did LDL-C (low-density lipoprotein-cholesterol), particularly being linked to complement C3 and glucose, as well as the risk score. Complement C3 demonstrated the widest associations and was significantly linked with BMI, waist circumference, insulin, glucose, fibrinogen, triacylglycerols (triglycerides) and apoB and was inversely correlated with HDL-C and SHBG. SHBG was also correlated inversely with a wide spectrum of risk variables. In summary, in Turkish women, apoB was linked with a complex array of proatherogenic risk factors, and hypertriglyceridaemia with elevated apoB was associated with a higher risk of coronary disease.

Aged↗
PubMed1979

The immune complex pathogenesis of glomerulonephritis and pulmonary vasculitis in Behçet's disease.

A kidney and lung biopsy were performed on a patient with active Behçet's disease with renal and pulmonary involvement. Histologic, immunohistochemical and electron microscopic studies of the kidney biopsy specimen revealed a focal segmental necrotizing glomerulonephritis characterized by the presence of numerous subendothelial and occasional intramembranous deposits containing immunoglobulin G (IgG), the third component of complement (C3), the fourth component of complement (C4) and fibrin(ogen). Histologic and immunohistochemical studies of the lung biopsy specimen showed an acute venulitis and septal capillaritis associated with the presence of identical deposits within the walls of affected vessels. Circulating immune complexes were detected in the patient's serum by Raji cell assay. The findings indicate that the glomerulonephritis and pulmonary vasculitis occasionally occurring in Behçet's disease are due to the deposition of circulating antigen-antibody complexes. In addition, they strongly suggest that the majority of the major and minor manifestations of the disease, such as uveitis, cutaneous vasculitis, synovitis and meningoencephalitis, are a result of vascular immune complex deposition.

Behcet Syndrome↗
PubMed2005

Gene expression changes in rat prostate after activation or blocking of the androgen and estrogen receptor.

Several endpoints of different molecular complexity were studied in the Hershberger assay in order to evaluate the specificity and suitability of this test as a broad screening model. Androgen and estrogen receptors were activated or blocked, and expression of typical estrogen- or androgen responsive genes (complement C3, ERalpha, ERbeta, AR, TRPM-2, PBP C3, ODC, and IGF-1 mRNA) was analyzed in rat ventral prostate by real time RT-PCR. Administration of estradiol benzoate (EB) to castrated testosterone-treated rats had no effect on reproductive organ weights or gene expression levels and the anti-estrogen, ICI 182780, only affected ODC expression. Therefore, estrogenic or anti-estrogenic compounds would not be expected to seriously affect the outcome of a Hershberger test. However, EB given alone to castrated rats resulted in various effects. EB increased seminal vesicle weight, an effect reversed by ICI 182780, and affected TRPM-2, PBP C3, ODC, IGF-1, AR, and ERalpha mRNA levels. AR expression in the prostate seemed to be under regulation of both estrogens and androgens, as ICI 182780 inhibited the testosterone-induced AR expression, and flutamide inhibited the EB-induced AR expression. These data indicate that estrogens have various effects in castrated male rats and that expression of several genes is under multi-hormonal control in the ventral prostate. However, interactions between estrogens and androgens do not play a major role in the Hershberger assay, as simultaneous TP administration abolished the effects of EB. First choice of gene expression profiles in the Hershberger assay to study androgenic or anti-androgenic effects would be the traditional, TRPM-2 and PBP C3, supplemented with the new complement C3.

Androgen Receptor Antagonists↗
PubMed1988

Detection of native human complement components C3 and C5 and their primary activation peptides C3a and C5a (anaphylatoxic peptides) by ELISAs with monoclonal antibodies.

Monoclonal antibodies (mAbs) were raised against human C3a, C3b, C5a, and C5b after immunization of BALB/c mice with the native components C3 and C5. Using different combinations of these mAbs we have developed four sensitive sandwhich-enzyme-linked immunosorbent assays (ELISAs) for the detection of native C3 or C5 in samples with low concentrations of these proteins, e.g., in cell culture supernatants or synovial fluids and cerebrospinal fluids (CSF) and for the detection of the anaphylatoxic peptides (AT-peptides) C3a or C5a in human EDTA-plasma. The C3- and C5-ELISAs were found to be specific for the uncleaved complement proteins. Two different anti-C3a or anti-C5a mAbs were combined for the C3a- and C5a-ELISA. Before assaying a sample in the C3a- or C5a-ELISA a precipitation step to eliminate uncleaved C3 and C5 was necessary. The sensitivity and specificity of the four ELISAs were tested with purified antigens and EDTA-plasma or Cobra venom factor-activated EGTA-plasma samples as a source of C3a and C5a. The detection limits were 1 ng/ml for C3, 1 ng/ml for C3a, 2 ng/ml for C5, and 100 pg/ml for C5a. Plasma samples from patients undergoing cardiopulmonary bypass (CPB) surgery were used as a source of pathological material.

Anaphylaxis↗
PubMed1986

Flow cytometric analysis of immunoglobulin and complement component C3 on the surface of Trypanosoma lewisi.

We have reinvestigated whether surface immunoglobulin (sIg) on Trypanosoma lewisi is antibody directed toward parasite antigen by using flow cytometry to analyze parasites stained with fluoresceinated F(ab')2 fragments of antibodies to rat IgG and IgM. We have confirmed that IgG antibody to the parasites is present both in the serum of rats and on the surface of parasites between the fourth and twentieth days of infection, that the amount of sIg per cell increases as the infection progresses, and that considerably more IgG is present on parasites harvested from intact rats than on those from rats that had been immunosuppressed by whole body gamma-irradiation. In addition sIgM was detected on trypanosomes from intact, but not on parasites from irradiated rats. We have also made two observations suggesting that not all sIg is specific antibody made in response to T. lewisi. First, a low but significant amount of sIgG was detected on parasites throughout infection in irradiated rats; no sIgM was detected on these parasite. Second, when parasites harvested from immunosuppressed rats were incubated in normal rat serum, the amount of both sIgG and sIgM detected by flow immunofluorescence increased. Parasites harvested from intact animals bound IgM but not IgG from normal rat serum. These results suggest either that natural antibody to the trypanosomes is present in the serum of uninfected rats or that some rat immunoglobulins bind to structures on the trypanosome surface in ways that do not depend on usual antigen-antibody interactions. Finally, flow immunofluorescence was also used to detect complement component C3 on the surface of both intact and trypsinized bloodstream forms harvested from intact or immunosuppressed rats. The amount of sC3 per cell did not increase until late in the infection and consequently did not correlate with the increase of sIgG. Therefore, T. lewisi avoids destruction by the immune system although immune effector molecules, IgG, IgM, and C3, are on its surface.

Animals↗
PubMed1998

The covalent binding reaction of complement component C3.

The covalent binding of C3 to target molecules on the surfaces of pathogens is crucial in most complement-mediated activities. When C3 is activated, the acyl group is transferred from the sulfhydryl of the internal thioester to the hydroxyl group of the acceptor molecule; consequently, C3 is bound to the acceptor surface by an ester bond. It has been determined that the binding reaction of the B isotype of human C4 uses a two-step mechanism. Upon activation, a His residue first attacks the internal thioester to form an acyl-imidazole bond. The freed thiolate anion of the Cys residue of the thioester then acts as a base to catalyze the transfer of the acyl group from the imidazole to the hydroxyl group of the acceptor molecule. In this article, we present results which indicate that this two-step reaction mechanism also occurs in C3.

Amino Acid Sequence↗
PubMed2005

Complement in BuB/BnJ mice revisited: serum C3 levels and complement opsonic activity are not elevated.

With the exception of a few strains such as BuB/BnJ, complement activity in most inbred strains of mice is remarkably similar. The BuB/BnJ strain reportedly has high levels of complement activity and elevated serum levels of C3 and other complement proteins. However, we observed that BuB/BnJ mice have serum C3 levels comparable to those seen in C57BL/6, Balb/c and several other strains of inbred mice. More importantly, using bacteria as a substrate for activation and deposition of complement as a direct biological assay to assess serum complement opsonic activity, we found that BuB/BnJ mice do not have elevated complement activity compared to other inbred mouse strains. In contrast hemolytic assays indicate BuB/BnJ sera to be most active. These results indicate that accepted views regarding mouse serum complement activity need to be re-examined.

Animals↗
PubMed1984

The third complement factor (C3) and its in vivo cleavage products: interaction with lectins and precipitation with polyethylene glycol.

Five molecular forms of C3 expressing D but not C epitopes were identified following in vivo activation of the complement system. Examination of concanavalin A (Con-A) reactivity in crossed immunoelectrophoresis revealed that native C3, C3c and the beta mobile form 4 of C3d were completely precipitated by 100 micrograms Con A/cm2. The alpha-1 mobile form 1 of C3d did not interact with Con A, whereas the alpha-2 mobile forms 2 and 3 were retarded in electrophoretic migration by Con A. Native C3, C3c, and forms 4 and 5 of C3d were precipitated by 12% (w/v) polyethylene glycol (PEG). Form 1 of C3d was soluble in these PEG concentrations, whereas forms 2 and 3 were partially precipitated.

Antigen-Antibody Reactions↗
PubMed1986

Serum complement values (C3 and C4) to differentiate between systemic lupus activity and pre-eclampsia.

It is often difficult to differentiate between an exacerbation of systemic lupus erythematosus (SLE) and intercurrent pre-eclampsia in a patient with SLE since the manifestations of both entities include proteinuria and hypertension. This study was undertaken to determine wether serum C3 and C4 values can help distinguish SLE activity from pre-eclampsia. In 21 nonpregnant women of child-bearing age, the mean C3 level was 124 +/- 5 mg/dl and the mean C4 was 31 +/- 1 mg/dl. In 24 normal women in the third trimester of pregnancy, the C3 and C4 levels were elevated (165 +/- 4 mg/dl, p less than 0.001 versus nonpregnant control women; 37 +/- 2 mg/dl, p less than 0.01 versus nonpregnant control women, respectively). In 17 women in the third trimester of pregnancy with documented pre-eclampsia, the mean C3 level was 162 +/- 4 mg/dl, no different from that in normal pregnant women (p less than 0.001 versus nonpregnant control women; p = NS versus normal pregnant women), and the mean C4 was 29 +/- 3 mg/dl, lower than that found in normal pregnant women (p less than 0.02 versus normal pregnant women). Antinuclear antibody was absent at titers of less than 1:20 in all of these pre-eclamptic patients. In contrast, pregnant women with SLE has significantly lower C3 (103 +/- 13 mg/dl) and C4 (15.3 +/- 3.6 mg/dl) values during the third trimester of pregnancy than either normal pregnant women (p less than 0.001 for C3 and C4) or women with pre-eclampsia (p less than 0.001 for C3 and p less than 0.004 for C4) during the third trimester of pregnancy. Of the eight women with SLE in whom serial complement values were determined, three had falling C3 or C4 levels, and in each, there was a flare of SLE activity either during or immediately after pregnancy. None of the five patients with a rising C3 concentration had a flare of disease activity; however, pre-eclampsia developed in one of these patients, characterized by hypertension and proteinuria. Thus, measurement of serum C3 and C4 can help differentiate between SLE activity and pre-eclampsia, since both C3 and C4 are significantly lower in women with SLE than women with pre-eclampsia, and serum C3 and C4 concentrations rise during uncomplicated or pre-eclamptic pregnancy in women with SLE.

Adult↗
PubMed2001

Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie.

Following peripheral exposure to transmissible spongiform encephalopathies (TSEs), infectivity usually accumulates in lymphoid tissues before neuroinvasion. The host prion protein (PrPc) is critical for TSE agent replication and accumulates as an abnormal, detergent insoluble, relatively proteinase-resistant isoform (PrPSc) in diseased tissues. Early PrPSc accumulation takes place on follicular dendritic cells (FDCs) within germinal centers in lymphoid tissues of patients with variant Creutzfeldt-Jakob disease (vCJD), sheep with natural scrapie or rodents following experimental peripheral infection with scrapie. In mouse scrapie models, the absence of FDCs blocks scrapie replication and PrPSc accumulation in the spleen, and neuroinvasion is significantly impaired. The mechanisms by which the TSE agent initially localizes to lymphoid follicles and interacts with FDCs are unknown. Antigens are trapped and retained on the surface of FDCs through interactions between complement and cellular complement receptors. Here we show that in mice, both temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays the onset of disease following peripheral infection, and reduces the early accumulation of PrPSc in the spleen. Thus, in the early stages of infection, C3 and perhaps C1q contribute to the localization of TSE infectivity in lymphoid tissue and may be therapeutic targets.

Animals↗
PubMed1998

Kidneys derived from mice transgenic for human complement blockers are protected in an in vivo model of hyperacute rejection.

PURPOSE: The major obstacle to successful discordant kidney xenotransplantation is hyperacute rejection (HAR). Complement plays a key role in the induction of HRA, defined by endothelial cell activation, loss of vascular integrity, hemorrhage and thrombosis. The activation of complement is tightly controlled by a number of species-specific regulatory proteins which inhibit, at different points, the cascade of events leading to the formation of the membrane attack complex (MAC). We have tested the hypothesis that kidneys derived from transgenic mice expressing two human complement inhibitors, Decay Accelerating Factor (hDAF) and Membrane Cofactor Protein (MCP), could be protected from human complement-mediated damage. MATERIALS AND METHODS: Control and transgenic mice were perfused with human plasma by cannulation of the right jugular vein, at a perfusion rate of 10 microL./min. for two hours. Complement C3 deposition was detected on kidney sections by immunohistochemistry using specific FITC antibody. Complement-induced tissue damage was evaluated by histopathological examination. RESULTS: Heavy deposition of complement C3 was observed on kidneys derived from perfused control mice. This was associated with a characteristic HAR pathology of severe interstitial hemorrhage, inflammatory reaction, loss of glomerula and tubuli structure. Kidneys derived from mice transgenic for hDAF or hMCP were partially protected from both complement C3 deposition and tissue damage. The expression of both hDAF and hMCP in double transgenic mice significantly increases the protection from human complement-mediated damage. CONCLUSION: A novel model of in vivo perfusion with human plasma has been adopted to recreate the initial event of HAR. Our data show that this murine model could be very valuable to determine the effect of transgenic human molecules in protecting vascularized organs from human complement attack.

Acute Disease↗
PubMed1983

Non-enzymic activation of the covalent binding reaction of the complement protein C3.

The covalent binding of [3H]glycerol to C3 by the transfer of the acyl group of the internal thioester of C3 to the hydroxy group of glycerol can be activated either proteolytically by trypsin or by various chaotropes and denaturants. The activation of binding by trypsin or KBr showed similar dependence on the concentration of glycerol, indicating a similar activation mechanism. It is therefore concluded that the conformational change of the protein is the critical step in the binding reaction, and that the conversion of C3 into C3b under physiological conditions is only a means to induce the conformational change. Guanidinium chloride induces the binding of glycerol to C3 at concentrations of about 1 M. On increasing the concentration of guanidinium chloride the extent of binding declines and is accompanied by an increase in the autolytic cleavage reaction [Sim & Sim (1981) Biochem. J. 193, 129-141]. The autolytic cleavage reaction is therefore not independently activated with respect to the binding reaction. Its occurrence, however, is structurally restricted under physiological or limited denaturing conditions and is permissible only when C3 is brought to a higher denaturation state.

Complement Activation↗
PubMed1987

C3bi receptor (complement receptor type 3) recognizes a region of complement protein C3 containing the sequence Arg-Gly-Asp.

Human phagocytes express a receptor termed complement receptor type 3 (CR3) that recognizes the complement protein fragment C3bi. We show here that CR3 recognizes a region of C3 that contains the sequence Arg-Gly-Asp (RGD). CR3 is down-modulated upon spreading of macrophages on surfaces coated with a synthetic 21-residue peptide from C3 (residues 1383-1403). This peptide was also attached to erythrocytes by coupling myristic acid to its amino terminus and allowing the myristoylated peptide to bind to erythrocytes through hydrophobic interactions. Erythrocytes coated with this RGD-containing segment of C3 were bound by macrophages, and binding could be blocked by specific monoclonal antibodies against CR3. Since CR3 recognizes a peptide sequence that contains the RGD triplet, it appears to be a member of a larger family of adhesion-promoting receptors that recognize RGD-containing proteins. However, since CR3 does not recognize a hexapeptide containing RGD, we presume that residues beyond the RGD triplet contribute to binding. We have compared the RGD-containing region of fibronectin and vitronectin, proteins known to be recognized by means of their RGD-containing regions, with those in human and murine C3. A striking homology is observed over an approximately equal to 50 amino acid sequence present in all four proteins. We suggest that this extended region of homology contains a structure recognized by adhesion-promoting receptors.

Amino Acid Sequence↗
PubMedDate not supplied

The amyloidosis of juvenile rheumatoid arthritis - comparative studies in Polish and American children II. Serum immunoglobulins, kappa and lambda light chain and C3 levels.

The concentration of serum IgG, IgM, IgA, IgD, IgE and complement C3 as well as Kappa and Lambda free and bound light chains were determined in sera from 21 amyloidotic Polish children with juvenile rheumatoid arthritis (JRA), Polish and American children with JRA, and control children from a Polish population. Comparable concentrations of IgG, IgM, IgA, IgE and C3 were found in amyloidotic children when compared to Polish JRA children with active polyarticular disease. However, the amyloidotic Polish children with JRA had significantly higher levels of IgG, IgM, IgA, IgE and complement C3 fraction when compared to American JRA children. The levels of IgA and IgE were significantly elevated in amyloidotic and Polish JRA populations when compared to American JRA patients. Free immunoglobulin light chains were not found in the sera of any of the children tested in this study. However, in the patients with amyloidosis, significantly diminished levels of bound Kappa and Lambda light chains were found.

Amyloidosis↗