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PubMed1991

Exogenous C1q reconstitutes a secondary deficiency of C5-deficient AKR mouse macrophages for FcR-dependent cellular cytotoxicity and phagocytosis.

Studies originally designed to assess the putative role of endogenous C5 in macrophage activation for antibody-dependent cellular cytotoxicity (ADCC) yielded unanticipated results. Resident and inflammatory peritoneal macrophages from C5-deficient AKR mice were found to have significantly lower capacity for FcR-dependent ADCC activation and phagocytosis of IgG-opsonized SRBC targets than did C5-competent C3HeB/FeJ (C3H) mice. Reconstitution of the ADCC response of AKR macrophages was accomplished initially with C5-sufficient C3H mouse serum, which suggested that endogenous C5 may be required for ADCC activation. However, further investigation largely eliminated C5 involvement in that a heat-labile component of C5-deficient AKR serum was shown to be active in the reconstitution of ADCC activation of AKR macrophages. Macrophages from AKR mice were found to have significantly lower levels of C1q mRNA synthesis, endogenous C1q levels, and C1q secretion than did C3H mouse macrophages as determined by Northern blot, Western blot, and presynthetic radiolabeling analysis, respectively. The addition of purified exogenous C1q to IgG-opsonized SRBC targets fully reconstituted ADCC activation for AKR inflammatory peritoneal macrophages to levels of normally FcR-responsive C3H macrophages. Similarly, exogenous C1q augmented FcR-dependent phagocytosis of AKR macrophages but had no effect on macrophages from responsive C3H mice. Our results indicate that AKR mice have a deficiency for FcR-dependent cellular cytotoxicity and phagocytosis that is related to their low potential for C1q synthesis and secretion rather than to their established genetic deficiency for C5 synthesis. We tentatively conclude that endogenous C1q is required as an accessory molecule for macrophage FcR-dependent effector functions and that C5 is not a prerequisite for ADCC activation.

Animals↗

PubMed1992

Hagfish humoral defense protein exhibits structural and functional homology with mammalian complement components.

A genomic clone and cDNA fragment encoding a portion of a humoral recognition molecule from the hagfish were isolated and sequenced. The serum protein has previously been described as having structural features that are immunoglobulin-like. Amino acid sequence obtained from the 77-kDa H1 heavy chain facilitated the isolation of a genomic clone containing at least two coding regions. Through use of primers derived from the genomic sequences, a 231-base-pair cDNA fragment was obtained by PCR from liver RNA. Comparison of the deduced 120-amino acid sequence from the N terminus of H1 with known protein sequences revealed substantial sequence similarity with the beta chain of the murine fourth complement component C4 and with the related third and fifth complement molecules C5 and C3 and the major histocompatibility complex-encoded sex-limited protein. Observation of structural and functional similarities associated with the sequence similarity indicate that these molecules share an evolutionary relationship: the polypeptide chain structure of hagfish complement-like protein (CLP) resembles that of C4; CLP contains a hidden thioester group on the 70-kDa chain; CLP binds to streptococcal cells and enhances the phagocytosis of yeast by hagfish leukocytes. These data suggest that CLP forms part of a non-clonally-derived complement-related humoral defense system in the hagfish.

Amino Acid Sequence↗

PubMed2001

Structural studies on the cobra venom factor: isolation, purification, crystallization and preliminary crystallographic analysis.

Cobra venom factor (CVF) is the complement-activating protein in cobra venom. It is a three-chain glycoprotein with a molecular weight of 149,000 Da. In serum, CVF forms a bimolecular enzyme with the Bb subunit of factor B. The enzyme cleaves C3 and C5, causing complement consumption in human and mammalian serum. CVF is frequently used to decomplement serum to investigate the biological functions of complement and serves as a tool to investigate the multifunctionality of C3. Furthermore, CVF bears the potential for clinical application to deplete complement in situations where complement activation is involved in the pathogenesis of disease. CVF was isolated from Indian cobra (Naja naja naja) venom. The protein was crystallized at room temperature using the sitting-drop vapour-diffusion technique. The crystals diffract to 2.7 A resolution and belong to the tetragonal space group P4(1), with unit-cell parameters a = b = 62.7, c = 368.1 A.

Animals↗

PubMed1984

Anti-complement activity in a series of substituted 2-aryl-1,3-indandiones; absence of correlation with the anti-carrageenan oedema effects.

It was found that a number of substituted 2-phenyl-1,3-indandiones possesses a considerable inhibitory effect on the classical pathway of complement. Furthermore it appeared that in this series a reasonable correlation (r = 0.86) exists between this anti-complement effect and the inhibition of the prostaglandine biosynthesis. A quantitative structure-activity relation study revealed that both the electronic sigma parameter of the substituent involved and the lipophilicity of the corresponding compound are important for anti-complement activity. Mainly the C5 step in the complement process is inhibited by these compounds. The complement-inhibiting phenylindandiones also inhibit the alternative pathway. This effect may also be due to an inhibition of C5, as C5 is common to both pathways. Remarkably, the 2-(3,5-dichlorophenyl)-1,3-indandione, which is most active in the anti-complement test, showed no reduction of the carrageenan-induced oedema in the rat after both oral and local application. Possibly the absence of this anti-inflammatory effect is caused by the pharmacokinetic profile of the compound.

Animals↗

PubMed2005

IgG Fc receptor polymorphisms and association with autoimmune disease.

The aim of this study was to investigate whether a genetic polymorphism of Fc gammaRIII exists in mice, which could explain the different susceptibility to pathogenic IgG anti-collagen type II (CII) antibodies in mice carrying the collagen-induced arthritis (CIA)-susceptible H-2q haplotype. The gene for Fc gammaRIII was sequenced in 11 common mouse strains, and the results revealed three different haplotypes of mouse Fc gammaRIII: Fc gammaRIII:V, Fc gammaRIII:H and Fc gammaRIII:T. To study the consequences of this polymorphism, we generated mice carrying the Fc gammaRIII:H haplotype from the CIA-susceptible, H-2q-positive DBA/1 mouse or the Fc gammaRIII:V haplotype from the CIA-resistant, H-2q-positive SWR mouse. After CII immunization or transfer of IgG anti-CII antibodies, Fc gammaRIII:H-expressing mice, but not Fc gammaRIII:V-expressing mice, developed progressively severe arthritis. We also investigated if C5, in addition to Fc gammaRIII polymorphism, could affect the susceptibility to the pathogenic IgG anti-CII antibodies in H-2q-positive mice. Here we show that SWR mice, naturally deficient in C5, can develop CIA when supplemented with C5 and that anti-C5 antibody treatment of Fc gammaRIII:H-expressing mice inhibits arthritis development. These data demonstrate for the first time a genetic polymorphism of Fc gammaRIII in mice that may, together with C5, regulate induction of autoimmune disease.

Amino Acid Sequence↗

PubMed1987

Leukocyte C5a receptor modulation during hemodialysis.

Exposure of blood to hemodialysis (HD) membranes results in the activation of the complement system. In this study, flow cytometry was used to analyze the binding of fluoresceinated chemotactic factors (C5a, f-Met-Leu-Phe-Lys [fMLPL], and casein) and aggregated IgG to PMN and monocytes isolated from normal whole blood following passage through a hemodialyzer. Analysis of ligand binding by these PMN and monocytes showed no difference in the binding of casein, fMLPL, or aggregated IgG throughout the 45 minute procedure. In contrast, a progressive decrease in the binding of C5a by PMN and monocytes occurred. By 45 minutes, the average percentage of PMN binding C5a had dropped from 95 to 61% and monocytes from 73 to 40%. In additional studies, blood samples were obtained from chronic renal failure patients undergoing hemodialysis at four different time intervals during dialysis. Total white blood cell (WBC) counts showed that the mean WBC count at 30 minutes dropped to 60.9% of the predialysis WBC count, and rebounded to 133.8% by two hours and 128.2% by four hours. Analysis of the binding of C5a, casein, fMLPL, or aggregated IgG by PMN or monocytes from HD patients indicated there were no significant differences at the four time intervals studied. When blood samples from normal subjects or chronic hemodialysis patients were incubated in vitro with dialysis membrane fibers, a loss of identifiable C5a receptors was observed on PMN from normal blood, while PMN from HD patients showed no significant change in the percentage of C5a-receptor-positive cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement C5↗

PubMed1993

Recurrent meningococcal infections in a patient with congenital C5 deficiency.

A congenital C5 deficiency was the cause of recurrent meningococcal disease in a 27-year-old man. The lack of serum bactericidal activity accounts for the higher incidence and the different course of Neisseria infections in patients with a deficiency of the late complement components. Early antibiotic treatment and vaccination with a capsular polysaccharide meningococcal vaccine (A,C,Y,W-135) should be considered.

Adult↗

PubMed2000

Butyrylcholinesterase and C5+ variant in a Javanese ethnic group in Indonesia.

OBJECTIVE: This study was designed to investigate the butyrylcholinesterase (BChE) and C5 variant phenotypes in a Javanese ethnic group in Indonesia. BLOOD-DONORS, MATERIALS AND METHODS: Random blood samples from a Javanese ethnic group were obtained from the Indonesian Red Cross Service. The donors were 40.09 +/- 9.53 years old, consisting of 358 (89.45%) males and 42 females (10.55%). The plasma content of BChE was determined spectrophotometrically using benzoylcholine as substrate, and phenotyping of BChE was performed using the inhibitors 10 microM dibucaine and 50 microM sodium fluoride. Phenotyping of the C5+ variant was carried out by means of polyacrylamide gel electrophoresis using a 7.5% (w/v) acrylamide slab gel and a 3% (w/v) acrylamide stacking gel, and stained with fast red azo dye. RESULTS: The results show that of 398 samples studied, the average activities of BChE are 1.00 +/- 0.22 U/ml. 377 individuals (94.72%) show normal activities, whereas 21 individuals (5.78%) are below normal (< 0.690 U/ml). The mean +/- SD of dibucaine number (DN) is 83 +/- 5 and the fluoride number (FN) is 66 +/- 6. From this population we identified one individual with UA phenotype (total activity: 0.310 U/ml, DN: 62, and FN: 50). The frequency of C5+ variant in the population as detected by acrylamide electrophoresis is 21%. CONCLUSION: Our data indicate that the atypical allele of BChE is rare and that the C5+ variant is detected in high frequency in the ethnic Javanese of Indonesia.

Adult↗

PubMed1979

Transcutaneous leukocyte migration in vivo: cellular kinetics, platelet and C5a dependent activity.

A simple quantitative method for the measurement of leukotaxis in vivo is described. Duplicate skin chambers are placed over tape-stripped skin with 50% autologous serum--50% Hank's balanced salt solution as the attractant. Neutrophils predominate throughout 24 hr in this method with no change to mononuclear cells. A recommended modification of our original method is that chambers are sampled and removed after 8 hr rather than 24 hr since the majority of leukocyte migration occurs within the first 8 hr. Analysis of serum factors showed that heat-inactivation of the serum (56degreesC for 30 min) had no effect. However, depleting platelets or C5 from the serum removed approximately 90% of chemotactic activity for human neutrophils in vivo. Platelets, presumably through activity of their granules, enzymatically cleaves C5a from C5 in plasma. We conclude that C5a, after cleavage from C5, accounts for the majority of chemattractant activity in vivo.

Blood Platelets↗

PubMed1981

Chemotaxis under agarose utilizing human serum depleted of C-5 derived peptides.

An immunoabsorbent column was made with antibody to trypsinized human C5. This column removed the chemotactic activity from zymosan-activated serum as well as from C5a des-arg-enriched fractions. Anti-trypsinized C5-absorbed human serum was substituted for unabsorbed human serum in the chemotaxis under agarose system. This resulted in significantly reduced random neutrophil migration with a negligible effect on C5a des-arg or FMLP-directed migration. The results indicate that much of the random migration observed in the chemotaxis under agarose system is due to C5-derived peptides present in normal human serum.

ABO Blood-Group System↗

PubMed1983

Mechanism of complement-induced stimulation of prostacyclin production by isolated rabbit peritoneum.

The interaction between the complement system and prostaglandin synthesis has not thoroughly been explored, although both mediators are known to be involved in inflammatory reactions and endotoxic shock. When rabbit peritoneum, a rich source of prostacyclin forming activity was incubated in serum in which the complement system was activated (CVF, LPS, zymosan), the tissue produced significantly more PGI2, when compared with appropriate controls, indicating that by activation of the complement, factors were generated that stimulated PGI2 biosynthesis. Further results indicated that tryptic cleavage products of complement factor C3 and C5 also led to the appearance of PGI2 releasing principles with a molecular weight of about 7000-11000. The stimulation of PGI2 biosynthesis was explained by enhanced release of AA, and not due to increased activity of cyclo-oxygenase or PGI2 synthetase. Our results suggest that complement-derived products may promote the supply of prostaglandins at the site of inflammation.

6-Ketoprostaglandin F1 alpha↗

PubMed1991

Production of 13 plasma proteins by human testicular yolk sac tumor transplanted into nude mice.

Thirteen human proteins were found in plasma and cystic fluid of mice bearing human testicular yolk sac tumor. Six of them, alpha-fetoprotein, prealbumin, albumin, alpha 1-antitrypsin, hemopexin and transferrin, had been previously demonstrated to be produced by yolk sac tumors. The syntheses of the remaining seven, namely apolipoprotein A1, retinol-binding protein, alpha 2HS-glycoprotein, haptoglobin, apolipoprotein B, C5 component and anti-hemophilic factor, have been demonstrated for the first time.

Adult↗

PubMed1999

Elucidation of the early events contributing to zymosan-induced multiple organ dysfunction syndrome using MIP-1alpha, C3 knockout, and C5-deficient mice.

Using a zymosan-induced mouse model of multiple organ dysfunction syndrome (MODS), it has been shown that the absence of MIP-1alpha increased mortality fourfold, whereas the absence of C5 decreased mortality fourfold. The purpose of the present study was to determine the early events following zymosan injection in MIP-1alpha knockout and C5-deficient mice. B10.D2/nSnJ (C5-sufficient) and B10.D2/0SnJ (C5-deficient) and genetically matched MIP-1alpha +/+ and MIP-1alpha -/- mice were divided into 3 groups: Group1 received no injection, Group 2 received intraperitoneal saline injection (1.0 mL), and Group 3 were given intraperitoneal zymosan (1 mg/gm, 1.0 mL). Two hours, 24 h, and 48 h after injection, peritoneal exudate leukocyte counts, total WBC count, lung MPO levels, and organ histology were examined for signs of changes in cellular infiltration. An acute local and systemic inflammatory response characterized by an increase in the peritoneal leukocyte count, total WBC counts, and circulating neutrophil levels was observed within 2-48 h of zymosan injection. Lack of MIP-1alpha attenuated local recruitment of phagocytes into the peritoneal cavity, and absence of MIP-1alpha or C5 caused a decrease in circulating neutrophil levels. The presence or absence of either C5 or MIP-1alpha did not affect early pulmonary neutrophil sequestration. Organ histopathology suggested early neutrophil infiltration in the lung and spleen within 48 h. These studies indicate that MIP-1alpha and C5 play a critical role in modulating cellular changes associated with lethality in a zymosan model of MODS.

Animals↗

PubMed2002

Essential role for the C5a receptor in regulating the effector phase of synovial infiltration and joint destruction in experimental arthritis.

A characteristic feature of rheumatoid arthritis is the abundance of inflammatory cells in the diseased joint. Two major components of this infiltrate are neutrophils in the synovial fluid and macrophages in the synovial tissue. These cells produce cytokines including tumor necrosis factor alpha and other proinflammatory mediators that likely drive the disease through its effector phases. To investigate what mechanisms underlie the recruitment of these cells into the synovial fluid and tissue, we performed expression analyses of chemoattractant receptors in a related family that includes the anaphylatoxin receptors and the formyl-MetLeuPhe receptor. We then examined the effect of targeted disruption of two abundantly expressed chemoattractant receptors, the receptors for C3a and C5a, on arthritogenesis in a mouse model of disease. We report that genetic ablation of C5a receptor expression completely protects mice from arthritis.

Animals↗

PubMed2000

The role of complement anaphylatoxin C5a in neurodegeneration: implications in Alzheimer's disease.

There is evidence that the complement system, a major component of inflammatory responses, may play an important role in neurodegenerative conditions such as Alzheimer's disease (AD). Work from our lab demonstrated that mice genetically deficient in the complement component C5 are more susceptible to hippocampal excitotoxic lesions (Pasinetti et al., 1996) and that the C5-derived ana;hylatoxin C5a may protect against excitotoxicity in vitro and in vivo (Osaka et al., 1999). Potential mechanisms identified in C5a-mediated neuroprotection include activation of mitogen activated protein (MAP)-kinase (Osaka et al., 1998; Osaka et al., 1999). This novel neuroprotective role of C5a complicates current theories that complement proteins augment beta-amyloid (Abeta) toxicity in AD. In view of the fact that the complement system represents a target for therapeutic interventions in AD, further characterization of the complex role of complement proteins is essential. Towards this aim, we have characterized a transgenic C5a receptor (C5aR) knockout (KO) mouse. Recent studies in the lab using C5aR-KO mice show that disruption of C5aR alters calcium calmodulin kinase (CaM-KII) signal transduction in brain cells. We are presently using C5aR-KO mice to study the role of C5a in caspase mediated apoptotic neuronal death. In this review we will attempt to delineate possible neuroprotective roles for C5a in mechanisms of neurotoxicity pertaining to AD.

Alzheimer Disease↗

PubMed1987

Induction of acute pulmonary inflammation. A differential effect of C5 and the 200,000 molecular weight form of trypsin-activated C5 (C5').

A series of studies was performed in which Syrian golden hamsters were injected intratracheally with 25 to 200 micrograms of highly purified human C5 or the 200,000 molecular weight form of trypsin-activated C5 (C5'). Bronchoalveolar lavage (BAL) was performed 4 h after intratracheal injection, the recovered white cells were counted and differentiated, and the BAL fluid was assayed for in vitro neutrophil chemotactic activity. A significant increase in BAL neutrophils and total BAL cell numbers was evident at 4 h after C5' instillation. In contrast, highly purified native C5 induced no evidence of pulmonary inflammation, even at the highest injection doses studied. Kinetic experiments indicated that hamsters receiving an intratracheal injection of 60 micrograms of C5' per animal demonstrated rapid pulmonary neutrophil infiltration that persisted for 120 to 168 h. Control hamsters receiving intratracheal injections of phosphate-buffered saline (PBS) or 60 micrograms of highly purified C5 did not demonstrate significant neutrophil infiltration. Lung pathology studies revealed neutrophilic alveolitis with intraalveolar and intracapillary neutrophil infiltration in the C5'-treated animals. The BAL fluid obtained from C5'-treated, but not from C5-treated or control hamsters, contained chemotactic factors for neutrophils, which appeared to be unrelated to C5. From these studies we conclude that C5', the 200,000 molecular weight form of protease-activated C5, is capable of mediating an acute inflammatory response in the hamster lung in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1982

Defects of serum chemoattraction and polymorphonuclear leucocyte movement in patients with primary hepatocellular carcinoma.

Movement of polymorphonuclear leucocytes to the site of tumour cells may be an important stage in host defences against tumours in a variety of organs. In this study, sera from 29 of 30 patients with primary hepatocellular carcinoma had reduced ability to stimulate the movement in vitro of normal polymorphonuclear leucocytes. The serum defect was more severe in 11 patients with underlying cirrhosis but was not related to abnormalities of tests of liver function, levels of serum alphafetoprotein, or deficiency of complement factors C3 and C5. Serial studies showed that the defect was persistent and progressive in patients in whom the tumour did not respond to treatment. In 35% of patients, mainly those with cirrhosis, the sera contained antagonists to normal serum chemotactic factors which were heat stable and dialysable, but could be distinguished by their effect on complement factor C5a. A heat labile dialysable antagonist(s) was found in sera from 28% of the patients (mainly those without cirrhosis) which antagonized the movement of normal polymorphonuclear leucocytes (cell directed antagonism). In addition to these serum defects, polymorphonuclear leucocytes from two of seven patients studied had reduced movement which was not related to the presence in the serum of cell directed antagonists. These serum and cellular defects have not been reported previously in patients with primary hepatocellular carcinoma, and could compromise the body's defences against the tumour.

Adolescent↗

PubMed1991

Cytokine regulation of C3 and C5 production by human corneal fibroblasts.

Recent investigations have suggested that cytokines play important roles during inflammation and host defense, primarily by regulating the diverse functions of immunologic cells (e.g. lymphocytes and monocytes). However, much less is known about the capacity of cytokines to also regulate the functions of resident tissue cells. We hypothesize that during inflammation, cytokines (e.g. monokines and lymphokines) directly regulate the expression of inflammatory precursors and mediators, such as the third and fifth complement components, by resident ocular cells and are therefore important in the local regulation of ocular inflammation. To test this hypothesis we developed an in vitro culture system utilizing isolated human corneal fibroblasts and examined the effects of specific cytokines, i.e. interleukins and interferons, on the production of the third and fifth components of the complement system. Human corneal fibroblasts were cultured in the presence of varying concentrations (1-500 U ml-1) of interleukin 1 alpha, interleukin 1 beta, interleukin 2, interferon alpha and interferon gamma for 48 hr at 37 degrees C, 5% CO2. The supernatants were then evaluated for antigen levels for the third and fifth components of complement using specific enzyme-linked immunospecific assays. These studies revealed that both interleukin 1 alpha and interleukin 1 beta induced seven to tenfold increases in the levels of the third component. Similarly interferon alpha and interferon gamma stimulated an approximate four and ninefold dose-dependent increase, respectively, in the production of the third component. Analysis of the effect of interleukin 2 on third component production demonstrated that higher concentrations (100 U ml-1) were required to induce a fivefold increase in the production of the third component.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗