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At least 307 records · Page 17Linked to original sources
PubMed1995

G alpha-16 complements the signal transduction cascade of chemotactic receptors for complement factor C5a (C5a-R) and N-formylated peptides (fMLF-R) in Xenopus laevis oocytes: G alpha-16 couples to chemotactic receptors in Xenopus oocytes.

The human leukocyte chemoattractant receptors for complement factor C5a (C5a-R) and N-formylated peptides (fMLF-R) are important members of the superfamily of G-protein coupled receptors (GPCR). Uniquely among the GPCR, these two receptors cannot be expressed in a functionally active form in the oocytes of the frog Xenopus laevis, but require substitution of total RNA of the myelomonocytic U-937 or HL-60 cell lines, respectively. Recently, it was reported that the C5a-R may couple to the alpha subunit of G-16. We have tested this G-protein for its ability to complement the signal transduction cascade of the C5a-R and fMLF-R in Xenopus oocytes. Injection of cRNA for the C5a-R in combination with G alpha-16 led to expression of a functional C5a-R as measured by ligand-induced whole cell current. In contrast to a previous report, the fMLF-R exhibited some residual functional activity when transiently expressed in Xenopus oocytes the extent of which could, however, substantially be increased by coexpression of G alpha-16. Thus, G alpha-16 complements the signal transduction cascade of both receptors in Xenopus laevis oocytes and is most likely the complementing factor present in the U-937 and HL-60 cell lines.

Animals↗
PubMed1990

Complement-mediated antibody-dependent enhancement of HIV-1 infection requires CD4 and complement receptors.

In this study it is demonstrated that complement-mediated antibody-dependent enhancement (C'-ADE) of HIV-1 infection in vitro is blocked by murine monoclonal antibodies to CD4 and complement receptor type 2 (CR2) while HIV-1 infection in the absence of C'-ADE is blocked by anti-CD4 but not anti-CR2 monoclonal antibodies. The anti-CR2 murine monoclonal antibody, OKB7, blocked C'-ADE of HIV-1 infection at concentrations greater than 1 microgram/ml. The anti-CD4 monoclonal antibody, OKT4a, but not OKT4f blocked C'-ADE at concentrations greater than 0.06 microgram/ml. HIV-1 infections were quantitated by cytopathic effect, indirect immunofluorescence, and reverse transcriptase release. It appears from these in vitro studies that C'-ADE of HIV-1 infection requires both CD4 and complement receptors while HIV-1 infection in the absence of antibody and complement requires only CD4.

Antibodies, Monoclonal↗
PubMed2005

Investigation of the role of complement and complement receptors in the modulation of B cell activation by a Paracoccidioides brasiliensis cell wall fraction.

F1 fraction from Paracoccidioides brasiliensis is a potent activator of the complement system. Considering that complement receptors CR1 and CR2 are involved in the regulation of B cell response, we evaluated the in vitro effect of the F1 in the activation of B lymphocytes, as well as the participation of complement receptors in this process. Murine splenocytes were cultured in order to evaluate the expression of CD40, CD45RB and CD69 on B lymphocyte, and IgG and IgM were quantified in the culture supernatant. F1 participated in the activation of B cells, showing a positive modulation effect on all markers analyzed. An increase in the production of IgG was detected in the supernatants when the opsonized F1 fraction was present. Complement receptor blockade with monoclonal antibodies led to a partial reduction in immunoglobulin secretion, suggesting that these receptors, especially CR2, play a role in modulating the function of B lymphocyte stimulated with the opsonized F1 fraction. These results may contribute for a better understanding of the B cell activation and differentiation processes in response to the F1 fraction from P. brasiliensis.

Animals↗
PubMed2006

Compstatin inhibits complement activation by binding to the beta-chain of complement factor 3.

Compstatin is a peptidic complement inhibitor that prevents the cleavage of complement factor 3 (C3) by C3 convertase. Compstatin differs from other C3-regulatory proteins, such as complement receptor (CR) 1 and decay-accelerating factor (DAF), in that it binds native as well as activated C3 fragments and acts through mechanisms that do not involve the destabilization of the C3 convertase or the accelerated degradation of C3b. Compstatin's activity most likely relies on its affinity for native C3 and the conformational change that results upon binding with C3. Although the intermolecular interactions between compstatin and C3 have been studied, the identity of the targeted region on C3 is still elusive. To address this issue, we synthesized a photo-crosslinking compstatin analog and used it to probe C3 for sites of interaction. We identified a 40-kDa region at the C-terminus of the beta-chain of C3 that included the binding site of the compstatin analog. The specificity of the binding was confirmed by inhibition studies, which showed reduced crosslinking signal after pre-incubation of C3 with compstatin but not with various inactive analogs. Binding studies performed with a recombinant homolog of the 40-kDa region confirmed these findings. Five smaller recombinant proteins corresponding to various overlapping regions of the 40-kDa fragment did not bind compstatin, suggesting that a proper protein conformation, only found in larger fragments, is required for compstatin binding. The identified region on the beta-chain has, thus far, not been implicated in C3 cleavage or interactions with other proteins. Therefore, further research on this part of the C3 molecule may have implications for studies on the regulation of C3 cleavage, as well as for complement-based drug design.

Binding Sites↗
PubMed1999

Systemic lupus erythematosus and complement deficiency: clues to a novel role for the classical complement pathway in the maintenance of immune tolerance.

Complete deficiency of C1q, the first component of the classical pathway of complement activation, is almost invariably associated with the development of systemic lupus erythematosus. Understanding why complement deficiency results in the specific autoimmune phenotype of SLE may provide valuable clues to the role of complement in the maintenance of immune tolerance. The following review will focus on the characteristics of complement-deficient SLE and the experimental evidence in support of our hypothesis that C1q may critically influence the immune response to self-antigen contained within surface blebs generated by apoptotic cells.

Animals↗
PubMed1992

Levels of complement receptor type one (CR1, CD35) on erythrocytes, circulating immune complexes and complement C3 split products C3d and C3c are not changed by short-term physical exercise or training.

The effect of heavy short-term physical exercise on the levels of complement receptor type one (CR1, CD35) on erythrocytes, the concentrations of circulating immune complexes (IC), and the complement C3 split products C3c and C3d were examined in young healthy males. Fourteen untrained volunteers underwent a 60-min bicycle exercise test at 75% of maximal oxygen uptake (VO2max). Six of the volunteers were exercised twice with an interval of at least one month. Before the second bicycle test they received oral indomethacin. With an interval of at least 1 week, 6 also went through a 60-min back-muscle exercise at up to 30% of VO2max. Blood samples were collected before and during the last few minutes of exercise as well as 2 h and 24 h afterwards. The same parameters were examined once in 29 highly trained racing cyclists. There were no consistent or significant exercise-induced changes in the levels of erythrocyte CR1, circulating IC, C3c nor C3d as measured by an enzyme-linked immunosorbent assay, polyethylene glycol precipitation complement consumption method, and by intermediate gel rocket immunoelectrophoresis, respectively. Neither did these parameters differ from controls in the highly trained group. The results indicate that CR1 on erythrocytes, circulating immune complexes and complement cleavage products C3c and C3d in healthy subjects remain unaffected by short-term heavy physical activity and training.

Adult↗
PubMed1995

Studies of group B streptococcal infection in mice deficient in complement component C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity.

Group B streptococci (GBS) cause sepsis and meningitis in neonates and serious infections in adults with underlying chronic illnesses. Specific antibodies have been shown to be an important factor in protective immunity for neonates, but the role of serum complement is less well defined. To elucidate the function of the complement system in immunity to this pathogen, we have used the approach of gene targeting in embryonic stem cells to generate mice totally deficient in complement component C3. Comparison of C3-deficient mice with mice deficient in complement component C4 demonstrated that the 50% lethal dose for GBS infection was reduced by approximately 50-fold and 25-fold, respectively, compared to control mice. GBS were effectively killed in vitro by human blood leukocytes in the presence of specific antibody and C4-deficient serum but not C3-deficient serum. The defective opsonization by C3-deficient serum in vitro was corroborated by in vivo studies in which passive immunization of pregnant dams with specific antibodies conferred protection from GBS challenge to normal and C4-deficient pups but not C3-deficient pups. These results indicate that the alternative pathway is sufficient to mediate effective opsonophagocytosis and protective immunity to GBS in the presence of specific antibody. In contrast, the increased susceptibility to infection of non-immune mice deficient in either C3 or C4 implies that the classical pathway plays an essential role in host defense against GBS infection in the absence of specific immunity.

Animals↗
PubMed1991

Alternative complement pathway activation by HIV infected cells: C3 fixation does not lead to complement lysis but enhances NK sensitivity.

HIV infected T and monocytic cell lines could activate and fix C3 fragments when incubated in human serum under conditions allowing for activation of the alternative complement pathway. Normal T lymphocytes incubated with HIV could also activate and fix C3. This activity was, at least in part, the property of the virus itself since cell-free HIV could efficiently activate C3. The C3 activating HIV infected cells were resistant to complement-mediated lysis, even after prolonged incubation periods. However, their sensitivity to cell-mediated natural killing increased, presumably due to their interaction with complement receptor bearing NK lymphocytes. The results suggest that the alternative complement pathway may contribute to the depletion of CD4+ T lymphocytes during HIV infection in vivo.

Cell Line↗
PubMed1998

Complement and complement inhibitors: their role in autoimmune and inflammatory diseases.

The role of complement in the pathogenesis of renal injury is now being confirmed with the use of knockout technology and specific inhibitors. Chronic injury, particularly of the tubules and interstitium, and local complement synthesis are emerging as potential additional targets for complement-based therapy. Strategies are being developed to prevent complement-induced injury both in transplant and in native kidneys.

Animals↗
PubMed2003

Chronic progression of tubulointerstitial damage in proteinuric renal disease is mediated by complement activation: a therapeutic role for complement inhibitors?

The mechanisms by which increased urinary protein concentrations lead to nephrotoxic injury are certain to be multifactorial and involve complex interactions between numerous pathways of cellular damage mediated by both cellular and humoral pathways. These may include a major role for the podocyte in glomerular diseases leading to chronic renal failure, the loss of microvascular endothelium, the albumin-induced upregulation of renal cytokines and growth factors that promote tubulointerstitial injury by inflammation and fibrogenesis, and the role of complement-mediated tubulointerstitial injury due to proteinuria. This review will focus on the last mechanism, and emphasize recent studies implicating a primary role for activation of complement in proteinuric urine as the principal mediator of tubulointerstitial damage and progressive renal disease in various experimental animal models of nephrosis. It will be our contention that intraluminal activation of the terminal complement cascade leading to the formation of the C5b-9 membrane attack complex is the principal mediator of chronic progressive interstitial damage and progressive renal failure irrespective of the type of primary glomerular injury. This paradigm has important implications for the potential therapeutic role of complement inhibitors that are currently being developed.

Chronic Disease↗
PubMed1995

The complement control protein homolog of herpesvirus saimiri regulates serum complement by inhibiting C3 convertase activity.

The herpesvirus saimiri genome encodes a complement control protein homolog (CCPH). Stable mammalian cell transfectants expressing a recombinant transmembrane form of CCPH (mCCPH) or a 5'FLAG epitope-tagged mCCPH (5'FLAGmCCPH) conferred resistance to complement-mediated cell damage by inhibiting the lytic activity of human serum complement. The function of CCPH was further defined by showing that the mCCPH and the 5'FLAGmCCPH transfectants inhibited C3 convertase activity and effectively reduced cell surface deposition of the activated complement component, C3d.

Amino Acid Sequence↗
PubMed2004

Kinetic analysis of the interactions between vaccinia virus complement control protein and human complement proteins C3b and C4b.

The vaccinia virus complement control protein (VCP) is an immune evasion protein of vaccinia virus. Previously, VCP has been shown to bind and support inactivation of host complement proteins C3b and C4b and to protect the vaccinia virions from antibody-dependent complement-enhanced neutralization. However, the molecular mechanisms involved in the interaction of VCP with its target proteins C3b and C4b have not yet been elucidated. We have utilized surface plasmon resonance technology to study the interaction of VCP with C3b and C4b. We measured the kinetics of binding of the viral protein to its target proteins and compared it with human complement regulators factor H and sCR1, assessed the influence of immobilization of ligand on the binding kinetics, examined the effect of ionic contacts on these interactions, and sublocalized the binding site on C3b and C4b. Our results indicate that (i) the orientation of the ligand is important for accurate determination of the binding constants, as well as the mechanism of binding; (ii) in contrast to factor H and sCR1, the binding of VCP to C3b and C4b follows a simple 1:1 binding model and does not involve multiple-site interactions as predicted earlier; (iii) VCP has a 4.6-fold higher affinity for C4b than that for C3b, which is also reflected in its factor I cofactor activity; (iv) ionic interactions are important for VCP-C3b and VCP-C4b complex formation; (v) VCP does not bind simultaneously to C3b and C4b; and (vi) the binding site of VCP on C3b and C4b is located in the C3dg and C4c regions, respectively.

Binding Sites↗
PubMed2006

Immunophysical properties and prediction of activities for vaccinia virus complement control protein and smallpox inhibitor of complement enzymes using molecular dynamics and electrostatics.

We present immunophysical modeling for VCP, SPICE, and three mutants using MD simulations and Poisson-Boltzmann-type electrostatic calculations. VCP and SPICE are homologous viral proteins that control the complement system by imitating, structurally and functionally, natural regulators of complement activation. VCP and SPICE consist of four CCP modules connected with short flexible loops. MD simulations demonstrate that the rather complex modules of VCP/SPICE and their mutants exhibit a high degree of intermodular spatial mobility, which is affected by surface mutations. Electrostatic calculations using snapshots from the MD trajectories demonstrate variable spatial distribution of the electrostatic potentials, which suggests dynamic binding properties. We use covariance analysis to identify correlated modular oscillations. We also use electrostatic similarity indices to cluster proteins with common electrostatic properties. Our results are compared with experimental data to form correlations between the overall positive electrostatic potential of VCP/SPICE with binding and activity. We show how these correlations can be used to predict binding and activity properties. This work is expected to be useful for understanding the function of native CCP-containing regulators of complement activation and receptors and for the design of antiviral therapeutics and complement inhibitors.

Amino Acid Sequence↗
PubMed1995

Role of complement in the pathogenesis of postpartum thyroiditis: relationship between complement activation and disease presentation and progression.

The aim of this study was to assess whether the presentation and progression of autoimmune postpartum thyroiditis (PPT) was related to the degree of thyroid peroxidase autoantibody (TPO-ab)-mediated activation of the complement cascade. One hundred and forty-eight thyroid autoantibody-positive women have been followed during their postpartum year. Seventy-five women remained euthyroid during this time whilst the remaining 73 showed one or more episodes of thyroid dysfunction. Fourteen women showed hyperthyroid PPT, 23 showed a biphasic PPT and the remaining 36 showed hypothyroid PPT. Hyperthyroid PPT was always transient but 29 of the 59 women with hypothyroidism remained hypothyroid or still required thyroxine replacement therapy at the conclusion of the study. Thyroid autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA), free triiodothyronine and free thyroxine by the Amerlex M methods and thyrotrophin by the Amerlite TSH (monoclonal) assay. Complement component C3b, immobilized as a result of classical complement pathway activation in the presence of TPO/TPO-ab complexes in vitro, was measured by ELISA. Bioactive TPO-ab were calculated as the product of the C3 index and TPO-ab level. Basal levels of complement C3 activation were seen in the euthyroid TPO-ab-positive women (C3 index 0.06 at delivery rising to 0.36 at 12 months postpartum; bioactive TPO-ab activity 0.4 kIU/l at delivery rising to 10.4 kIU/l at 12 months' postpartum (N = 75). These parameters were elevated progressively as the severity of the clinical syndrome increased. In 14 hyperthyroid PPT women the C3 index was 0.47 at 8 months' postpartum (bioactive TPO-ab activity = 20 kIU/I; p vs euthyroid group, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Autoantibodies↗
PubMed1992

Synthesis and regulation of the fourth component of complement (C4) in the human monocytic cell line U937: comparison with that of the third component of complement (C3).

Production of the fourth component of complement (C4) by the human monocytic cell line U937 and its regulation were investigated in comparison with the production of the third component of complement (C3) in a cell culture system. Although no detectable C4 was produced by U937 without stimulation, U937 was induced by recombinant interferon-gamma (IFN-gamma) to synthesize C4 in a dose- and time-dependent fashion. The production of C4 was reversibly inhibited by cycloheximide, indicating that it resulted from de novo synthesis. The C4 synthesized by U937 cells was functionally active as assessed by haemolytic assay. SDS-PAGE following biosynthetic labelling showed that subunit structure of C4 synthesized by U937 cells was identical with that of plasma C4 but that molecular weight of alpha-chain was greater than that of plasma C4. We compared the regulation of C4 synthesis with that of C3 synthesis. Although C3 synthesis by U937 cells was enhanced by IFN-gamma, lipopolysaccharide (LPS) and phorbol myristate acetate (PMA), C4 synthesis was induced only by IFN-gamma. LPS and IFN-gamma induced a synergistic increase in C3 synthesis by U937 cells. U937 cells incubated with LPS and IFN-gamma synthesized a greater amount of C4 than those incubated with IFN-gamma alone. Thus it was demonstrated that the synthesis of C3 and C4 was independently regulated. This study shows that the U937 cell line provides a useful model for studies on the synthesis of complement proteins and on the regulation of complement production.

Cell Line↗
PubMed1981

Induction of complement receptor expression in cell lines derived from human undifferentiated lymphomas. II. Characterization of the induced complement receptors and demonstration of the simultaneous induction of EBV receptor.

We have studied the specificity of complement receptors induced by theophylline in 2 cell lines derived from undifferentiated lymphomas, one of Burkitt's type, and compared it to that of complement receptors in other cell types. Both C3b and C3d receptors were induced. The induced C3b receptor differed from the C3b receptor of mature normal lymphocytes, polymorphonuclear leukocytes and the cells of a nodular lymphoma in 2 respects. Firstly, it bound C3b much less avidly (by a factor of several hundred-fold) and secondly, we were unable to demonstrate C4b binding. EBV receptors were induced at the same time as complement receptors, and permitted the conversion of a greater fraction of cells to EBNA positivity after experimental infection with EBV. The induction of receptors was not associated with a change in the fluidity of the plasma membranes and our data do not favor a different orientation of induced receptors within the membrane as compared to receptors of other cell types--a potential explanation for the different specificities. Our findings are consistent with the possibility that the complement receptors of lymphocyte precursors differ from these of mature lymphocytes.

Binding, Competitive↗
PubMed1986

Inhibition of complement by a series of substituted 2-aryl-1,3-indandiones: interaction with the fifth component of complement.

A series of substituted 2-aryl-1,3-indandiones were investigated for their ability to inhibit the complement system. Some of them were found to be considerably strong inhibitors. The inhibitory activity was mainly dependent on substitutions at positions 3 and 5 of the phenyl ring. 3,5-dichloro-(8), 3,5-bis(trifluoromethyl)- (7), 3,5-diisopropyl- (3) and 3,5-di-t-butyl- (5) phenylindandiones were the strongest inhibitors of the series. The generation of EAC1-5 cells from EAC1-3 cells and C5 was most strongly inhibited by these compounds although some inhibition of the interaction of EAC1-5 with C6-C9 and EAC1-6 with C7-C9 was also observed. Slight inhibition at other steps of complement activation was also seen but this was not considered to be appreciable. Dialysis of normal serum or purified C5 pre-incubated with compounds 3, 5, 7 and 8 did not cause recovery of the hemolytic activity of normal serum or purified C5. Thus, the main site of inhibition in the complement cascade appeared to be at C5. The total alternative pathway was also inhibited to some extent by these compounds, probably due to their interaction with C5.

Animals↗
PubMed1984

Local opsonization by secreted macrophage complement components. Role of receptors for complement in uptake of zymosan.

We have examined the role of macrophage (M phi plasma membrane receptors for the cleaved third complement component (iC3b; CR3) and mannosyl, fucosyl terminated glycoproteins (MFR) in uptake of unopsonized zymosan. Monoclonal antibodies against CR3, M1/70 (Mac-1) and MO1, each inhibited approximately 50% of uptake of 125I-zymosan by murine and human M phi, respectively. Yeast mannan inhibited 0-50% of zymosan uptake in various M phi, in parallel with their expression of MFR. We demonstrated that M phi were the source of C3 in our assay and that the activity of other components of the complement system, namely a C3 convertase, factor I, and a factor I cofactor were also present in serum-free cultures of human monocytes. Macrophage C3 was deposited rapidly, within 10 min, on the zymosan particles and mediated binding, ingestion, and stimulation of superoxide release in BCG-activated and thioglycollate-elicited peritoneal M phi via CR3. Local secretion of complement proteins by M phi themselves can therefore opsonize pathogens and cells able to activate the alternative pathway and effect their destruction.

Animals↗