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PubMed1989

Complement activation in amyloid plaques in Alzheimer's dementia.

Amyloid plaques in Alzheimer's dementia contain complement factors C1q, C4 and C3. In the present study we demonstrate complement activation in amyloid plaques using immunoenzymatical techniques and specific antibodies against subunits of individual complement components and activated complement products. Amyloid plaques contain C1q and activated C3 fragments (C3c and C3d, g) but no C1s and C3a. These findings demonstrate that the complement components are not passively bound to the amyloid plaque structures but are the result of an activation process. The role of complement activation in the genesis of senile plaques is discussed.

Aged↗
PubMed1990

Regulation of proteolytic activity of complement factor I by pH: C3b/C4b receptor (CR1) and membrane cofactor protein (MCP) have different pH optima for factor I-mediated cleavage of C3b.

C3b/C4b receptor (CR1) and membrane cofactor protein (MCP) are integral membrane glycoproteins with factor I-dependent cofactor activity. They bind to C3b, allowing factor I to cleave C3b at two sites (first and second cleavage), which results in the generation of C3bi, a hemolytically inactive form which is a ligand for complement receptor type three (CR3). C3bi is further degraded by factor I and CR1 (third cleavage) to C3dg (a ligand for complement receptor type two, CR2) and C3c. Using two different substrates, fluid-phase C3b and cell-bound C3b, the cleavage of C3b by MCP and factor I was compared to that by CR1 and factor I under various conditions. The optimal pH for the first and second cleavage of either substrate was 6.0 for MCP and 7.5 for CR1. The third cleavage was mediated only by CR1 and factor I, the optimal pH being 8.0. Low ionic conditions enhanced the C3b binding and cofactor activity of both CR1 and MCP. The efficiency of binding C3b to CR1 or MCP was maximal at pH 6.2. The isoelectric point (pI) of MCP was acidic (approximately 4.0), while that of CR1 was 6.8. Therefore, compared to CR1, MCP possesses distinct functional profiles relative to C3b-binding and factor I-cofactor activity.

Antigens, CD↗
PubMed1987

Interactions of purified Serratia marcescens metalloproteases with fresh human serum and with purified human serum proteins.

Exposure of fresh human serum to two purified metalloproteases of S. marcescens strains SF 178 and SH 186 (both of serotype O6/O14:H12) at 35 degrees C, 3 h, resulted in altered electrophoretic mobility of the protease inhibitors alpha 1-antitrypsin and alpha 2-macroglobulin, alpha 2-HS-glycoprotein, and complement (C) components C1q, C1s, C3a, C3c, C4, C5, and C9, but not C6, C7, C8, and properdin, as determined with electroimmunoassays (Laurell technique). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) documented the partial degradation of the heavy (H) chain of purified human immunoglobulin IgG by the metalloproteases of S. marcescens strains SF 178 and SV O1 (serotype O13/O19:H1), but not by the metalloproteases of strains SH 186 and SE 182 (serotype O9B:H11) following extended incubation (35 degrees C, 22 h). Human IgA and IgM were refractory. Purified human C components, C3, C4, C5, C6, C7, C8, and C9, as well as purified human alpha 1-antitrypsin, alpha 2-macroglobulin, transferrin, and lactoferrin were attacked by the S. marcescens metalloproteases SF 178 and SH 186 at 35 degrees C for 5 h, as demonstrated with the SDS-PAGE procedure; haptoglobin and C-reactive protein were resistant.

Acute-Phase Proteins↗
PubMed1982

Breakdown of C3 after complement activation. Identification of a new fragment C3g, using monoclonal antibodies.

The physiological breakdown of C3 has been studied using monoclonal anti-C3 antibodies, and it has been found that the later stages of this process--the breakdown of C3bi--is more complex than had previously been recognized. C3bi is the reaction product produced from C3b by the action of factor I which, in the presence of factor H, produces a double cleavage in the alpha chain of C3b. It is here reported that, both on cells and in the fluid phase, the breakdown of C3bi in serum gives rise to two products: C3c and the product previously described as alpha 2D, which we now propose to designate C3d,g. Alpha 2D differs from C3d in that it contains an additional fragment of approximately 8,000 mol wt that carries the antigenic determinant for the clone 9 monoclonal anti-C3 antibody. C3g cannot be precipitated by anti-C3 antisera and therefore behaves as a uni- or bideterminant antigen. The cleavage of C3d,g to C3d and C3g does not occur in sterile serum. It is also still uncertain what enzyme cleaves C3bi to C3c and C3d,g in plasma. Plasmin can do so in vitro, but plasminogen-depleted serum can still produce the cleavage. The antigenic determinant recognized by clone 9 in C3 is not exposed in C3 or C3b, but appears as a neoantigen in C3bi (and in C3d,g). Anti-C3g therefore is a potentially useful ligand for detecting complement-activation products. C3g represents a new, highly anionic C3 fragment and seems not to be identical with the C3e fragment described by others.

Animals↗
PubMed1984

Cobra venom factor: structural homology with the third component of human complement.

The functional analogy between cobra venom factor (CVF), the complement-activating protein in cobra venom, and C3b, the activated form of the third complement component, prompted us to conduct a comparative analysis of structural properties of the two proteins derived from two phylogenetically distant species. We subjected CVF and human C3 and its physiologic cleavage products, C3b and C3c, to a variety of biochemical analyses. We report here structural similarities of these proteins, which include similarities in amino acid composition, far and near UV circular dichroism spectra, secondary structure, band patterns and pI values from isoelectric focusing, immunochemical cross-reactivity, ultrastructural morphology, and amino-terminal amino acid sequences. Analysis of these data reveals that, structurally, CVF resembles C3c more than C3b. We conclude that CVF is not the product of a convergent evolution, but is, in all likelihood, derived from a common C3 ancestor protein.

Amino Acid Sequence↗
PubMed1976

Purification and identification of a human-serum DNA-binding protein associated with malignant diseases.

A malignancy-associated human serum DNA-binding protein (C3DP protein), which was previously detected using dodecylsulfate gel electrophoresis, has been purified and characterized. This protein was isolated from human fetal cord serum by DNA-cellulose affinity chromatography, ammonium sulfate fractionations, DEAE-cellulose chromatography, and Sephadex gel filtration. The molecular weight of purified C3DP protein has been shown to be 135000 by ultracentrifugation, gel filtration, and dodecylsulfate gel electrophoresis. Dodecylsulfate gel electrophoresis following disulfide bond reduction has revealed that this protein is composed of three subunits having molecular weights of 74000, 40000 and 22000. Carbohydrate has been demonstrated to be attached to the 74000 and 22000 molecular weight components. Immunochemical studies have revealed that the C3DP protein is a fragment of human complement component C3, which closely resembles C3c.

Chromatography, Affinity↗
PubMed1991

[Immunological aspects of Menière's disease].

Among the various aetiopathogenetic hypotheses regarding Ménière's disease, the immunologic one has recently received a considerable amount of interest. Several studies have been performed using specific inner ear antigens (cell-mediated immunity) or by the evolution of circulating autoantibodies (i.e. against type II collagen or immune complex, etc...). We studied the immunological condition of 40 patients suffering from Ménière's disease, through the analysis of the following immunological blood tests: IgG, IgA, IgM, C3c, C4 and C-haemolytic complement level; circulating immune complexes, autoantibodies screening (Rheumatoid and antinuclear factors, mitochondrial smooth muscle and type II collagen antigens), cryoglobulins; T3, T4, T4/T8 monoclonal antibodies. Our results showed a rise in IgG levels in 6 patients (15%) and in IgA level, in 4 patients (10%). IgM blood level were abnormal in only one patient. Complement blood tests showed pathological results in 9 patients. All the patients had normal immunological tests regards to the autoantibody screening and T3, T4, T4/T8 monoclonal antibodies. The immunological results obtained in the patients suffering from Ménière's disease were compared with those of the control group (subjects suffering from vertigo by other causes than Ménière's disease); no significant difference was assessed between the two groups. The abnormal immunological pattern found in a few Ménière patients seems to be due to an aspecific response of the immune system, as the consequence of an alteration of the normal inner ear homeostasis.

Adult↗
PubMed1983

[Interaction of the 3rd component of complement (C3) with the surface of LS murine fibroblasts].

LS fibroblasts grown in suspension culture fix C3 on their surface when they are incubated with human or guinea pig complement as shown by reacting te cells with FITC-labelled anti C3c sera or immunoglobulins. At the same time the lytic activity of complement is lowered and aliquots of C3 are subtracted from the sera following incubation with the cells. EDTA - EGTA experiments and other observations suggest that C3 fixation requires activation, which proceeds via the alternative pathway, in much the same manner as it has been reported for limphoid cells and thymocytes.

Animals↗
PubMed2005

Structures of complement component C3 provide insights into the function and evolution of immunity.

The mammalian complement system is a phylogenetically ancient cascade system that has a major role in innate and adaptive immunity. Activation of component C3 (1,641 residues) is central to the three complement pathways and results in inflammation and elimination of self and non-self targets. Here we present crystal structures of native C3 and its final major proteolytic fragment C3c. The structures reveal thirteen domains, nine of which were unpredicted, and suggest that the proteins of the alpha2-macroglobulin family evolved from a core of eight homologous domains. A double mechanism prevents hydrolysis of the thioester group, essential for covalent attachment of activated C3 to target surfaces. Marked conformational changes in the alpha-chain, including movement of a critical interaction site through a ring formed by the domains of the beta-chain, indicate an unprecedented, conformation-dependent mechanism of activation, regulation and biological function of C3.

Complement Activation↗
PubMed1998

Mouse susceptibility to infection by the Salmonella abortusovis vaccine strain Rv6 is controlled by the Ity/Nramp 1 gene and influences the antibody but not the complement responses.

Early growth of Salmonella typhimurium in spleen and liver of mice is controlled by the mouse chromosome 1 locus Ity/Nramp 1. Genetic control of resistance to the attenuated vaccine strain Rv6 of Salmonella abortusovis was studied in mice infected by the intravenous route. Comparison of kinetics of bacterial colonization of spleen and liver in two congenic BALB/c-susceptible (Itys) and -resistant (Ityr) mouse lines showed that BALB/c mice (Itys) were significantly more susceptible to infection than C.D2 mice (Ityr) suggesting that infection by this vaccine strain is controlled by a gene which is close or identical to Ity/Nramp 1. Congenic mice also differed in their anti-Salmonella antibody response, measured by ELISA: susceptible mice had a significantly higher antibody level than resistant mice, whatever the immunoglobulin isotype (IgM, IgG1, IgG2a, IgG3, IgA, and total immunoglobulins). The two congenic BALB/c mouse lines had equal serum C3c levels in response to infection. However, we observed a highly significant difference according to the sex of mice, suggesting a role of sex hormones in the regulation of the level of some complement factors. These results, obtained with congenic mice, strongly suggest that the Ity/Nramp 1 locus controls susceptibility to infection by the S. abortusovis vaccine strain Rv6 and influences the antibody response.

Animals↗
PubMedDate not supplied

Freezing red blood cells prepared for quality control of antiglobulin sera.

A small-aliquot freezing technique was employed to store at -80 C red blood cells (RBC) prepared for quality control of antiglobulin sera. These RBC were used to test the specificity and potency of both polyspecific and monospecific antiglobulin sera on the day of use. Following deglycerolization, about 83 per cent of test RBC were recovered. They were then stored as 5 per cent suspensions in 0.9% NaCl at 4 C for up to two weeks and tested for specific agglutination. EIg (RBC sensitized with immunoglobulins) and EC4 (RBC sensitized with the fourth component of human complement) remained reactive for the two-week period. EC43 (RBC sensitized with both the fourth and third components of human complement) tended to lose reactivity only with anti-C3c antibodies following deglycerolization and storage. EC3d (RBC sensitized with the C3d fragment of the third component of human complement), produced in vivo as a result of Mycoplasma pneumoniae infection, remained reactive for the two-week period, whereas EC3d prepared by the alternative pathway of complement activation was useful only for one week. Use of deglycerolized test RBC improved quality-control procedures by saving materials and technician time as well as by providing a constant supply of uniformly prepared test RBC.

Complement C3↗
PubMed1993

[Correlation of hepatic necrosis and complement system activation in fulminant viral hepatitis].

The relationship between complement activation and hepatic necrosis was investigated in 110 cases of fulminant, acute or chronic viral hepatitis by examining plasma complement conversion products C3d and C4d and intact C3 and C4 molecules, as well as the local hepatic deposition of C3 IgG globulins in necrotic areas of the liver. The results revealed an excessive activation of plasma C3 in the fluminant hepatitis group. The C3d/C3 ratio was proved to be directly related to the severity of the clinical symptoms. C3 and IgG hepatic depositions in adjacent necrotic areas were found in over 85% of the fulminant hepatitis cases, as compared to 37.5% in cases of chronic active hepatitis. The conclusion was drawn that activation of the complement cascade is responsible for liver tissue damage, while the plasma complement activation represented by increased C3d and C3c fragment production might well reflect hepatic pathology. Therefore, the C3d/C3 ratio could serve as an index to aid clinical management, as well as pointing out a new therapeutic approach.

Complement Activation↗
PubMed1992

A phase I study of neuroblastoma with the anti-ganglioside GD2 antibody 14.G2a.

Nine patients with neuroblastoma stage IV were treated with the murine monoclonal antibody 14.G2a, directed against disialoganglioside GD2. The antibody was injected daily for 5-10 days and the total applied dosage ranged between 100 mg/m2 and 400 mg/m2. The peak serum levels of mAb 14.G2a ranged from 28 micrograms/ml to 61 micrograms/ml. Pharmacokinetic data obtained in three patients indicated that the serum elimination of mAb 14.G2a fits a two-compartment model, with an alpha-half-time (t1/2 alpha) between 0.66 h and 1.98 h and a beta-half-time (t1/2 beta) between 30.13 h and 53.33 h. All patients presented with a human anti-(mouse IgG) antibody response either during or shortly after therapy. Eight patients showed a continuous decrease in complement component C4 during therapy, as well as an initial decrease in C3c and an initial increase in C3a, all suggesting an activation of the complement cascade. Side-effects consisted of allergic reactions like pruritus, exanthema, urticaria and of severe pain, predominantly located in the abdomen and lower extremities, which required the use of continuous intravenous morphine. Four patients additionally developed a transient hypertension and one patient experienced a transient nephrotic syndrome. Three patients were treated in an adjuvant setting and are not evaluable for tumor response. Of the remaining six patients, two had a complete remission, two showed a partial remission, and two patients did not respond to treatment.

Antibodies, Anti-Idiotypic↗
PubMed1980

The complement system in hemolytic-uremic syndrome in childhood.

A dynamic estimation of the complement system was obtained by immunochemical estimation of C3, C4, C5, C1q, C3b + C3c, C3d, Ba in children with hemolytic-uremic syndrome. The presence of increased breakdown products of C3 (C3b + C3c, C3d) and of factor B (Ba) suggests an activation of the complement system possibly by the alternative pathway. No definite explanation for these complement abnormalities can be given.

Child↗
PubMed1998

Cerebrospinal fluid complement activation in neurological diseases.

Laser nephelometry (LN) is a rapid and very sensitive method for simultaneous determination of albumin, immunoglobulins, C3c and C4 in diluted serum and paired cerebrospinal fluid (CSF) samples. It is very useful in routine analyses. Determination of C3c and C4 covers classical as well as alternative pathways of complement activation. In CSF, they are mostly derived from and related to serum values. Under physiological conditions, the addition of intrathecal C4 synthesis is likely. The incidence of complement activation within CSF is also influenced by the method of choice (native molecules, activation products and complexes, inhibitors) and the mode of interpretation of results according to the functional state of the blood-brain barrier (BBB). Calculation of indexes and the modified Reiber's graph method are valid means of detection of complement activation within CSF. Complement activation within CSF was confirmed in 36% (111/302) of neurological patients examined; in 55% (48/87) of patients with inflammatory and demyelinating diseases, in 40% (37/94) of patients with CNS infections and complications, in 33% (4/12) of patients with motor neuron diseases, in 27% (11/40) of patients with spinal cord compression and sequelae, in 25% (8/32) of patients with neoplastic disease, and in 17% (6/37) of patients with cerebrovascular accidents.

Adolescent↗
PubMed1983

Role of human factor I and C3b receptor in the cleavage of surface-bound C3bi molecules.

Control of functions mediated by the third component of complement (C3) depends on the rate of generation and degradation of biologically active C3 fragments. To evaluate the mechanisms of degradation of active C3 fragments, the role of the control protein C3b/C4b inactivator (factor I) was investigated under conditions approximating those found in vivo, i.e. in the presence of plasma. The breakdown of human erythrocyte-bound C3bi molecules in serum or plasma was mediated only by factor I, since factor I-deficient or -depleted plasma was inactive until reconstituted with highly purified factor I. The rate of cleavage of C3bi bound to human erythrocytes by purified factor I was not affected by the presence or absence of beta 1H (factor H). The released breakdown product of C3bi has been shown to be C3c antigenically and on polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Two different monospecific antibodies to the human C3b receptor totally abrogated factor I-mediated cleavage of cell-bound C3bi, suggesting that the C3b receptor (but not factor H) is required as an obligate cofactor. The rate of this C3b receptor-dependent, factor I-mediated cleavage of bound C3bi is strongly regulated by the surface to which C3bi is bound. Whereas C3bi bound to particulate nonactivators of the alternative complement pathway such as human erythrocytes is rapidly degraded by this mechanism, the rate of cleavage of C3bi bound to activators is significantly slower. These data suggest a physiologic role of C3b receptors in the degradation of biologically active C3 fragments deposited on host tissues. They also suggest that C3bi molecules on restricted surfaces are relatively stable and can thereby interact with complement C3 receptors in vivo.

Animals↗
PubMed1980

[The effect of burns on the complement system].

Serum levels of total complement CH 50 and the complement components C1, C1 inactivator, C2, C4, C3c, and C3 activator were measured in 20 patients with burn injuries. The findings were assessed for any possible correlations between the results of serological investigations, severity of burns and clinical aspects of the patients.

Adolescent↗
PubMed2001

Renal involvement induced by human parvovirus B19 infection.

In an attempt to clarify the renal involvement induced by human parvovirus B19 (HPB19) infection, we investigated 6 adult patients with transient urinary abnormalities followed by erythema infectiosum. All patients had HPB19-specific IgM antibody and showed mild proteinuria of 0.2-1.2 g/day with or without microscopic hematuria. In 5 patients a decrease of complement was present, and in 2 the circulating immune complex levels were elevated. All patients showed mild or moderate endocapillary proliferation with leukocytic infiltrates in glomeruli and leukocytic infiltrates with edema around interlobular arteries and arterioles. Immunofluorescence microscopy revealed C3c deposits with immunoglobulins along the glomerular capillary walls and in the walls of small arteries and arterioles. Electron microscopic studies showed swelling of the endothelial cells and small electron-dense deposits in mesangium (in all 6 patients) and subendothelium (in 5 of 6 patients). However, HPB19 VP1 and VP2 capsid antigens were not demonstrated in the glomerulus or the vascular wall in any patient. These findings suggest that the renal lesions caused by an immune complex mediated phenomenon would be closely correlated with the HPB19 infection, although the precise mechanism is not entirely clear, and that in adults HPB19 should be thought of as a possible cause of acute postinfectious glomerulonephritis.

Adult↗