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PubMed1980

Cleavage of C4b by C3b inactivator: production of a nicked form of C4b, C4b', as an intermediate cleavage product of C4b by C3b inactivator.

We have investigated the mechanism of cleavage of C4b into C4c and C4d by the C3b inactivator (C3bINA) and revealed the formation of a nicked form of C4b as an intermediate cleavage product. The cleavage of C4b by the C3bINA was a two-step reaction. The first cleavage occurred on the alpha-chain (89,000 daltons) yielding two fragments, 73,000 daltons and 16,000 daltons. These fragments were bound to each other or to the beta or gamma chain through disulfide linkages. Therefore, an altered form of C4b, C4b', consisting of four disulfide-linked polypeptide chains with the same m.w. as C4b, was produced as an intermediate cleavage product. Subsequently, the second cleavage occurred on the alpha-chain fragment of 73,000 daltons to produce the two generally recognized fragments, C4c and C4d. In both cleavage reactions, a high m.w. cofactor protein, C4bC3bINACo, which is the same protein described as the C4 binding protein, was required, suggesting that both of the proteolytic processes are catalyzed by the C3bINA.

Complement C3b Inactivator Proteins↗
PubMed1999

Elastase and metalloproteinase activities regulate soluble complement receptor 1 release.

Complement receptor 1 (CR1) is cleaved from the surface of polymorphonuclear cells (PMN) in the membrane-proximal region to yield a soluble fragment (sCR1) that contains the functional domains. The enzymes involved in this cleavage are produced by the PMN itself, since in vitro stimulation of purified PMN is followed by sCR1 release. Purified human neutrophil elastase (HNE) cleaved CR1 from erythrocytes and urinary vesicles originating from podocytes and enhanced tenfold the cleavage of CR1 from activated PMN. The largest fragment released from PMN by HNE was identical in size to CR1 shed spontaneously. The CR1 fragments cleaved from erythrocytes were functional. The shedding of sCR1 by activated PMN was inhibited by phenylmethylsulfonyl fluoride (80 +/- 10%), alpha1-antiprotease (50 +/- 5%) and elafin (60 +/- 5%). Furthermore the cleavage was blocked by the metalloprotease inhibitor 1,10-phenanthroline (70 +/- 6 %) as well as by a monoclonal antibody against human neutrophil collagenase MMP8 (40 +/- 10%). Maximal inhibition of sCR1 shedding was obtained by a combination of 1,10-phenanthroline with elafin (86 +/- 6%). These inhibitors had no effect on L-selectin shedding, indicating that the cleavage of CR1 was specific. In conclusion, elastase or elastase-like activity may be responsible for the shedding of functional sCR1 in vivo, and this activity is controlled by the local release of PMN metalloproteases and alpha1antiprotease.

Complement C3b↗
PubMed1990

The iC3b receptor on Candida albicans: subcellular localization and modulation of receptor expression by glucose.

Patient isolates of Candida albicans from blood, urine, or mucosal sites express a surface receptor for C3 fragment iC3b that is recognized by monoclonal antibodies (MAb) directed against alpha-chain epitopes of the neutrophil iC3b receptor, also known as the type 3 complement receptor (CR3) or CD11b/CD18. Because 60% of these patients were hyperglycemic, the effect of glucose on receptor expression was investigated. As assessed by flow cytometry, yeasts grown in 20 mM D-glucose exhibited a four- to six-fold increase in receptor expression compared with yeasts grown in 20 mM L-glutamate. Receptor expression increased as glucose concentration rose from 0 to 20 mM (equivalent to plasma glucose concentrations of 0-360 mg/dl). Augmentation of receptor expression by growth in glucose led to significant inhibition of phagocytosis compared with that of organisms grown in equimolar L-glutamate. SDS-PAGE, Western blotting, and immunodetection of extracts of yeast cell wall, membrane, and cytosol disclosed a protein of 165 kDa in membrane and cytosolic extracts, consistent with the published Mr of the alpha-chain of neutrophil CR3. These studies provide a mechanism to explain the predilection of C. albicans to infect the hyperglycemic host.

Adolescent↗
PubMed1983

Interaction of phagocytes with other blood cells and with pathogenic and nonpathogenic microbes.

Owing to the high surface tension of blood cells and to the equally high surface tension of their liquid habitat, the Hamaker coefficients A131 of blood cells (subscript 1) in blood (subscript 3), are unusually small; they are of the order of 0.25 to 2.5 X 10(-16) ergs. The very small van der Waals attractions such low Hamaker coefficients give rise to, coupled to the medium low but still sizable negative xi-potentials (-11 to -18 mV) of the cells, which cause an appreciable mutual electrostatic repulsion between blood cells, have been used to elaborate potential energy vs. distance diagrams, which closely reflect the unusual stability of blood cells in blood. When bacteria find their way into the bloodstream, they initially form an almost equally stable suspension. However, relatively hydrophobic nonpathogenic bacteria quickly aspecifically adsorb immunoglobulin G (IgG) molecules from blood serum, whilst hydrophilic pathogenic bacteria sooner or later also become coated with specific antibody molecules of the IgG-class. Through receptor sites on the surface of phagocytic blood cells, which can specifically bind to the Fc tails of IgG molecules, bacteria are first bound and then removed from the blood circulation and surrounding tissues. These Fc-receptor bonds presumably also are of a combined van der Waals and electrostatic nature. Thus in the normal course of events and by purely physicochemical mechanisms, phagocytic leukocytes will neither interfere with other leukocytes nor with any other blood cells, whilst they specifically interact with microorganisms and other unwanted foreign particles via IgG-IgG-receptor interactions. Also discussed, in the light of the principles elaborated above, are: some of the antiphagocytic mechanisms developed by certain pathogenic bacteria; the phagocytic disposal of aged, weak, or abnormal blood cells; and the role played by immunoglobulins other than IgG, and by complement, in the removal of bacteria and viruses.

Adhesiveness↗
PubMed1976

Membrane receptors on neutrophils.

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

Antibody Specificity↗
PubMed2001

Accelerated Fas-mediated apoptosis of monocytes and maturing macrophages from patients with systemic lupus erythematosus: relevance to in vitro impairment of interaction with iC3b-opsonized apoptotic cells.

Impaired handling of apoptotic cells has been suggested as an important factor in the development of systemic lupus erythematosus (SLE), and a role for complement in the removal of apoptotic cells was shown recently. We studied the in vitro function of macrophages from 40 patients with SLE and their matched controls in the removal of heterologous apoptotic cells opsonized by iC3b. Interaction index of apoptotic cells opsonized by iC3b was significantly lower in patients with SLE and averaged 71% +/- 37 of that of healthy individuals (p < 0.002) and 69% +/- 35 of patients with rheumatoid arthritis (p < 0.007). SLE patients had increased apoptosis of both freshly isolated monocytes (p < 0.001) and maturing macrophages (p < 0.04) that led to decreased density of monocyte-derived macrophages. Apoptosis was inhibited by adding soluble Fas receptor indicating Fas-mediated apoptosis. As demonstrated in both healthy controls and patients with SLE, decreased macrophage density by itself caused significant decreased uptake of apoptotic cells by the remaining macrophages. Maintaining normal density in SLE patients either by an increased initial density or by using soluble Fas restored the interaction capacity of the individual macrophages in the majority of patients. We concluded that impaired in vitro interaction of iC3b-opsonized apoptotic cells with macrophages from patients with SLE was mainly associated with Fas-dependent accelerated apoptosis of the monocytes/macrophages. Accelerated apoptosis of phagocytes may represent a novel in vitro mechanism of impairment of interaction with apoptotic cells that, apart from reducing the number of professional phagocytes, alters the function of the remaining macrophages.

Apoptosis↗
PubMed1991

Low number of complement C3b/C4b receptors (CR1) on erythrocytes from patients with essential mixed cryoglobulinemia, systemic lupus erythematosus and rheumatoid arthritis: relationship with disease activity, anticardiolipin antibodies, complement activation and therapy.

Our aim was to assess whether the amount of complement C3b/C4b receptors (CR1) on erythrocytes shows a correlation to disease activity in various connective tissue diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and essential mixed cryoglobulinemia (EMC). Using an anti-CR1 monoclonal antibody, 26 patients with SLE, 34 with RA and 22 patients with EMC were investigated for erythrocyte CR1 expression. The control group consisted of 30 healthy individuals. The mean number of CR1/erythrocyte in the control group was 568 +/- 197 (range 174-1060), significantly higher than studied (EMC:379 +/- 248; p = 0.0005;SLE 147 +/- 56, p less than 0.0001; RA 298 +/- 177, p less than 0.0001). In patients with RA and in SLE, but not in patients with EMC, the number of CR1 numbers and anticardiolipin antibody (aCl) titers (r2 = 0.493; p = 0.034). A statistically significant correlation between CR1 numbers and CH50 values was found in patients with SLE, while in 3 patients with RA 4 months of therapy with cyclosporine A led to a further 30% reduction in CR1 number. Our conclusions are that (a) the decreased expression of erythrocyte CR1 is apparently a common feature of patients with various connective tissue diseases; (b) several acquired factors such as disease activity, complement activation, aCl and drugs may contribute to the loss of CR1 from erythrocytes; (c) in patients with RA and SLE, but not in patients with EMC, CR1 enumeration on erythrocytes may serve as a variable for clinical monitoring.

Adult↗
PubMed1980

Development of functional complement receptors during in vitro maturation of human monocytes into macrophages.

The development of Fc and C3 receptor function was evaluated during differentiation of human peripheral blood monocytes into macrophages in an in vitro culture system. At the time of isolation, monocytes formed rosettes with C3-coated erythrocytes (EIgMC) but did nt internalize them, whereas IgG-coated erythrocytes (EIgG) were both bound and ingested. During the first 24 hr in culture, IgG-mediated phagocytosis and C3-mediated rosette formation declined. After 7 days of in vitro differentiation, monocyte-derived macrophages were capable of ingesting 2 to 4 times as many EIgG as uncultured monocytes. In addition, macrophages demonstrated a new function--the ability to ingest C3-coated erythrocytes, as well as to efficiently bind them. The time course of the reappearance of receptor functions varied between different individuals, but by day 7, the activity of Fc and C3 receptors was vigorous for all individuals tested. Monocytes underwent differentiation whether they were cultured on glass coverslips or on a plastic surface. However, macrophages demonstrated C3-mediated ingestion earlier when cultured on plastic. Culturing monocytes on the different surfaces did not affect the time course of the reappearance of Fc receptor function, but did have a small effect on the magnitude of the response. These experiments demonstrate for the first time, that a defined population of human phagocytic cells can acquire the ability to mediate ingestion through their C3 receptors.

Cell Differentiation↗
PubMed1982

Differentiation of C3b receptors on human lymphocytes, phagocytes, erythrocytes and renal glomerulus cells by monoclonal antibodies.

C3b receptor protein was purified form human erythrocytes by 2 M KBr solubilization and affinity chromatography on C3-coated sepharose. This material served as antigen for raising monoclonal antibodies. To investigate the distribution and antigenetic relationship between the receptors for C3b on human erythrocytes, lymphoid and phagocytic cells, as well as kidney cells three monoclonal antibodies were selected which inhibited the binding of EAC14 degrees 23b to complement receptor-bearing cells. This could be shown for human erythrocytes by inhibiting the immune adherence reaction, for tonsil lymphocytes, Raji cells, and guinea-pig spleen cells by inhibition of rosette formation of these cells with EAC14 degrees 23b, and for human renal glomeruli by blocking of the the adherence of EAC14 degrees 23b to kidney sections. In contrast, these monoclonal antibodies were not capable of inhibiting rosette formation of human granulocytes and monocytes with EAC14 degrees 23b. The antibodies only interfered with the rosette formation, of EAC14 degrees 23bi and EAC14 degrees 23d with Raji cells and tonsil lymphocytes-if at all-at high concentrations, whereas the rosette formation of Raji cells and tonsil lymphocytes with EAC14 degrees 23b was influenced by supernatants of the selected clones up to a dilution of 1:10(3) to 1:10(5).

Animals↗
PubMed1983

Suppression of T lymphocyte functions by human C3 fragments. I. Inhibition of human T cell proliferative responses by a kallikrein cleavage fragment of human iC3b.

Cleavage of human iC3b by kallikrein isolated from human plasma generates a fragment, C3d-K, which is capable of inhibiting mitogen-, antigen-, and alloantigen-induced T lymphocyte proliferation. Native C3, C3a, C3b, and C3c-K had no effect on lymphocyte proliferative responses. In addition to being a potent suppressor of mitogen- and antigen-induced proliferation, C3d-K is capable of inducing leukocytosis in both mice and rabbits. Intravenous injection of C3d-K, but not C3, C3a, C3b, or C3c-K, results in a twofold to threefold increase in the number of circulating leukocytes. Thus, C3d-K exhibits two apparently independent functions, namely suppression of T cell proliferation and leukocytosis. Cleavage of iC3b by kallikrein results in the production of only two fragments. The larger fragment, C3c-K, is 144,000 m.w. and has a chemical structure analogous to that of C3c obtained from the cleavage of C3 by trypsin or elastase. The smaller fragment, C3d-K, is 41,000 m.w. and contains the metastable binding site of C3. It is through this site located in the C3d region of the molecule that C3 attaches covalently to target cells. Analysis of the amino terminal region of C3d-K provided a sequence that fails to overlap with any sequence yet reported for other characterized C3 fragments, including C3d originally obtained from elastase digestion. A revised model of the C3 molecule is proposed, with locations of the C3e and C3d fragments assigned on the basis of chemical analyses.

Adult↗
PubMed1979

Modulation of the properdin amplification loop in membranoproliferative and other forms of glomerulonephritis.

The mean serum concentrations of C3b inactivator (C3bINA) and beta1H globulin were measured in eighty-six sera (thirty-five membranoproliferative, thirteen membranous, thirty-one focal and seven minimal change) taken from seventy-five patients with histologically diagnosed glomerulonephritis. In none of the four groups of sera did the mean concentrations of both these proteins differ significantly from the mean levels in a group of fifty normal sera. However, in the membranoproliferative group, the mean level of C3bINA, but not beta1H, was significantly lower in the nephritic factor positive than in the nephritic factor negative group. When the eighty-six sera were considered together, serum concentrations of C3bINA and beta1H correlated with levels of C3, factor B, properdin and C4. When the membranoproliferative group was considered separately, C3bINA levels correlated with levels of C3, factor B, properdin and C4 and beta1H correlated with C3 and factor B, but not properdin or C4 in the nephritic factor negative group, but no such correlations were observed in the nephritic factor positive group. The significance of these findings is discussed in the light of current thoughts on the mechanisms of modulation of the alternative pathway.

Beta-Globulins↗
PubMed1996

High doses of immunoglobulin G attenuate immune aggregate-mediated complement activation by enhancing physiologic cleavage of C3b in C3bn-IgG complexes.

Intravenously applied human IgG has beneficial effects in treating inflammatory diseases, presumably because it has a complement attenuating role. This role of IgG was studied in vitro by following C3 activation and inactivation in sera that were supplemented with exogenous human IgG and incubated with immune aggregates. IgG added at 2 to 10 mg/mL stimulated the physiologic inactivation of C3b-containing complexes twofold to threefold in 20% sera. This, in turn, lowered the overall C3 activation by 28%, as new C3 convertases primarily assembled on C3b-containing complexes. Exogenous IgG (5 mg/mL) also stimulated inactivation of purified C3b2-IgG complexes, whereby their half-life dropped from 3-4 to 1.5 minutes in 20% serum. IgG appeared to act like a modulator of factor H and I because it did not stimulate inactivation of C3b-containing complexes in factor I-deficient serum. Thus, the known partial protection of C3bn-IgG complexes from inactivation by factor H and I was downregulated by high concentrations of IgG. The ability of high doses of IgG to stimulate complement inactivation is a novel regulatory role of IgG. This may be one of the molecular principles for its therapeutic efficacy in treating complement-mediated inflammations.

Antigen-Antibody Complex↗
PubMed1979

Relative importance of C3b inactivator and beta 1H globulin in the modulation of the properdin amplification loop in systemic lupus erythematosus.

Serum concentrations of C4, C3, factor B (B), properdin (P), C3b inactivator (C3bINA) and beta 1H globulin have been measured by radial immunodiffusion in sixty-two samples from thirteen patients with systemic lupus erythematosus (SLE). Significant reductions in the mean serum concentrations of C4 (classical pathway) B and P (alternative pathway) and C3 were found. In addition, the mean level of the control protein beta 1H, but not C3bINA, was reduced. Sera from thirteen patients taking during disease exacerbation (low C3) showed significantly lower levels of both C3bINA and beta 1H than sera taken from the same thirteen patients during disease remission (high C3). Serum concentrations of C3bINA correlated with B (P less than 0.005) but not C4, C3 or P, whereas levels of beta 1H correlated with C4 (P less than 0.01), B (P less than 0.005) and properdin (P less than 0.01). Serial measurements of the serum concentrations of C3bINA and beta 1H showed that levels of these protein fell during exacerbation, and such falls were more closely associated with diseases in the serum levels of the alternative pathways proteins than C4. It is concluded from these observations that serum concentrations of the control proteins C3bINA and beta 1H, especially the latter, control the extent of turnover of the alternative pathway in SLE. Metabolic studies are required to determine the causes of the decreased serum concentrations of these control proteins.

Complement Activation↗
PubMed1984

Defective in vivo Fc- and C3b-receptor function in IgA nephropathy.

Reticuloendothelial function was assessed in 17 patients with IgA nephropathy, using 99Tc-labeled autologous erythrocytes coated with either C3B or IgG. Results were compared with clearances in 14 normal control subjects and with a group of 14 patients with idiopathic mesangial proliferative glomerulonephritis without IgA deposition. The half-life of IgG-coated red cells in the IgA group was 69.8 +/- 32.5 minutes (control 42.2 +/- 9.0 minutes, P = 0.001). The half-life in the non-IgA mesangial proliferative group, 77.9 +/- 31.3 minutes, was not significantly different from that of the IgA patients. Clearance of C3b-coated cells, expressed as the percentage of cells cleared at 30 minutes, was 7.1% +/- 2.6% in the IgA patients, compared with 16.0% +/- 3.2% in control subjects (P less than 0.001) and 13.8% +/- 7.5% in the non-IgA mesangial proliferative group (NS). No statistical correlation was found between clearance results in individual patients and age, sex, weight, serum creatinine, or the severity of disease on clinical and pathological criteria. The severity of the defect in Fc- and C3b-receptor dependent clearances were not statistically correlated in individual patients.

Adolescent↗