scholarly journals Complement receptor is an inhibitor of the complement cascade.

1981 ◽  
Vol 153 (5) ◽  
pp. 1138-1150 ◽  
Author(s):  
K Iida ◽  
V Nussenzweig
Keyword(s):  
Alternative Pathway ◽  
Protein A ◽  
Fluid Phase ◽  
Local Concentration ◽  
Classical Pathway ◽  
Strong Inhibitor ◽  
Complement Components ◽  
Serum Inhibitor ◽  
Irreversible Effects ◽  
High Concentrations

A glycoprotein from the membrane of human erythrocytes has been identified as a receptor for C3b (CR1). It promotes the dissociation of the alternative pathway C3 convertase C3b,Bb and the cleavage of C3b by C3b/C4b inactivator. We find that CR1 also inactivates the C3 and C5 convertases of the classical pathway. CR1 inhibits the consumption of C3 by C3 convertase EAC142 and enhances the decay of C4b,2a sites. On a weight basis, CR1 is approximately 5-10 times more active than C4 binding protein, a serum inhibitor of C4b,2a. The binding of 125I-CR1 to EAC14 cells is inhibited by C2. Therefore, it is likely that CR1 and C2 compete for a site on C4b. CR1 inhibited C5 convertase even more effectively, but had no effect on the assembly of the late complement components. At high concentrations, CR1 alone has no irreversible effects on cell-bound C4b. In the fluid phase, CR1 can function as a cofactor for the cleavage of the alpha' chain of C4b by C3b/C4b inactivator. A well-known function of CR1 is to promote adherence of microbes or immune complexes bearing C3b and C4b to cells. This interaction could result in a microenvironment damaging to the plasma membrane of the responding cell because the extrinsic C3b and C4b fragments can serve as additional sites of assembly of enzymes of the cascade. We therefore wish to propose that CR1 on the surface of cells supplies an increased local concentration of a strong inhibitor of the amplifying enzymes of the complement system and provides cells with a mechanism for circumventing damage when they bind C3b- and C4b-bearing substrates.

scholarly journals Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

2010 ◽  
Vol 23 (4) ◽  
pp. 740-780 ◽  
Author(s):  
Sanjay Ram ◽  
Lisa A. Lewis ◽  
Peter A. Rice
Keyword(s):  
Complement Activation ◽  
Antigen Processing ◽  
Respiratory Infections ◽  
Alternative Pathway ◽  
Fluid Phase ◽  
Host Cells ◽  
Medical Attention ◽  
Classical Pathway ◽  
Complement Components ◽  
Complement Pathways

SUMMARY The complement system comprises several fluid-phase and membrane-associated proteins. Under physiological conditions, activation of the fluid-phase components of complement is maintained under tight control and complement activation occurs primarily on surfaces recognized as “nonself” in an attempt to minimize damage to bystander host cells. Membrane complement components act to limit complement activation on host cells or to facilitate uptake of antigens or microbes “tagged” with complement fragments. While this review focuses on the role of complement in infectious diseases, work over the past couple of decades has defined several important functions of complement distinct from that of combating infections. Activation of complement in the fluid phase can occur through the classical, lectin, or alternative pathway. Deficiencies of components of the classical pathway lead to the development of autoimmune disorders and predispose individuals to recurrent respiratory infections and infections caused by encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. While no individual with complete mannan-binding lectin (MBL) deficiency has been identified, low MBL levels have been linked to predisposition to, or severity of, several diseases. It appears that MBL may play an important role in children, who have a relatively immature adaptive immune response. C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci. Deficiencies of the alternative and terminal complement pathways result in an almost exclusive predisposition to invasive meningococcal disease. The spleen plays an important role in antigen processing and the production of antibodies. Splenic macrophages are critical in clearing opsonized encapsulated bacteria (such as pneumococci, meningococci, and Escherichia coli) and intraerythrocytic parasites such as those causing malaria and babesiosis, which explains the fulminant nature of these infections in persons with anatomic or functional asplenia. Paramount to the management of patients with complement deficiencies and asplenia is educating patients about their predisposition to infection and the importance of preventive immunizations and seeking prompt medical attention.

Complement in the Newborn Infant

PEDIATRICS ◽  
1979 ◽  
Vol 64 (5) ◽  
pp. 781-786
Author(s):  
Richard B. Johnston ◽  
Karl M. Altenburger ◽  
Alva W. Atkinson ◽  
Robert H. Curry
Keyword(s):  
Newborn Infant ◽  
Gestational Age ◽  
Hemolytic Activity ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Term Infants ◽  
Complement Components ◽  
Factor B ◽  
Serious Infection ◽  
Dual Pathway

Classical pathway activities and component concentrations in sera from newborns can be compared more realistically to normal adult values than to maternal values since activities and components are increased in maternal sera. Whole complement hemolytic activity appears to be subnormal in approximately half of term infants, with mean activity being about 70% to 90% of normal. Concentrations of Clq, C4, C2, C3, and C7 have been 60% to 100% of adult concentrations in term infants and somewhat less in preterm infants. Younger gestational age has been correlated with lower levels of total hemolytic activity, Clq, C4, and C3. Activity of the alternative pathway appears to be more frequently subnormal in newborn sera than does activity of the classical pathway. Factor B and properdin concentrations have varied from about 35% to 60% and 35% to 70% of adult values, respectively. Opsonization and hemolysis mediated by the alternative pathway have been subnormal in 15% to 75% of term infants, depending upon the assay. Gestational age appears to correlate with alternative pathway hernobytic activity and properdin concentration but not with concentration of factor B. Reductions such as these in single complement components and functions probably would not predispose an otherwise normal individual to infection. However, it seems likely that the multicomponent and dual pathway deficiencies found in neonates, especially in conjunction with the decreased phagocyte function known to exist in that population, could increase the likelihood of serious infection. Predicted infections with this configuration of abnormalities would be extracellular bacterial. Whether the newborn infant is actually predisposed to infection because of the complement deficiencies summarized here remains to be proved. This and other unanswered questions lead us to conclude that understanding of the complement system in the newborn is, pardon the expression, still in its infancy.

scholarly journals Structural homology and expression tendency of the natural immune response of the terminal complement components to inoculations in pigs: a review

2013 ◽  
Vol 58 (No. 1) ◽  
pp. 1-9
Author(s):  
D.V.A. Khoa
Keyword(s):  
Health Status ◽  
Candidate Genes ◽  
Production Systems ◽  
Animal Health ◽  
Mammalian Species ◽  
Protein A ◽  
Retinol Binding Protein ◽  
Classical Pathway ◽  
Complement Components ◽  
Terminal Complement

The transmission of infectious agents from domestic animals to humans is a matter of particular concern at present. Inoculation can enhance the defences of each individual animal but only in the short term. Certainly, it will be of immense benefit if biotechnology and genetic techniques are applied to farm animal breeding and selection programs to improve productivity, performance and health status as well as for the construction of sustainable animal production systems and promotion of animal welfare. In recent years, efforts to drive candidate genes like cytokines, haptoglobin, complement system, C-reactive protein, a 2-macroglobulin, retinol binding protein, transcortin, and etc. associated with immune traits have successfully been studied in human and different animal species. Here, we compared the molecular structure and evaluated the expression tendency of the haemolytic complement activity (HCA) of porcine candidate genes encoding the terminal complement components (TCC) C6–9. The results suggested that (1) high homology of complement genes among mammalian species may open new ways in cure/ treatment of disease; (2) Muong Khuong animals (Vietnamese potbelly pig) have a great genetic potential to improve the health status of pigs; and (3) HCA in the classical pathway can be developed further by different activation modes, with the potential improvement of animal health.

scholarly journals Development of a Novel Cytomedical Treatment that can Protect Entrapped Cells from Host Humoral Immunity

2002 ◽  
Vol 11 (8) ◽  
pp. 787-797 ◽  
Author(s):  
Ryo Suzuki ◽  
Yasuo Yoshioka ◽  
Etsuko Kitano ◽  
Tatsunobu Yoshioka ◽  
Hiroaki Oka ◽  
...  
Keyword(s):  
Humoral Immunity ◽  
Complement System ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Dependent Manner ◽  
Complement Components ◽  
Alternative Pathways ◽  
Low Cytotoxicity ◽  
The Complement System

Cell therapy is expected to relieve the shortage of donors needed for organ transplantation. When patients are treated with allogeneic or xenogeneic cells, it is necessary to develop a means by which to isolate administered cells from an immune attack by the host. We have developed “cytomedicine, ” which consists of functional cells entrapped in semipermeable polymer, and previously reported that alginate-poly-l-lysine-alginate microcapsules and agarose microbeads could protect the entrapped cells from injury by cellular immunity. However, their ability to isolate from humoral immunity was insufficient. It is well known that the complement system plays an essential role in rejection of transplanted cells by host humoral immunity. Therefore, the goal of the present study was to develop a novel cytomedical device containing a polymer capable of inactivating complement. In the screening of various polymers, polyvinyl sulfate (PVS) exhibited high anticomplement activity and low cytotoxicity. Murine pancreatic β-cell line (MIN6 cell) entrapped in agarose microbeads containing PVS maintained viability and physiological insulin secretion, replying in response to glucose concentration, and resisted rabbit antisera in vitro. PVS inhibited hemolysis of sensitized sheep erythrocytes (EAs) and rabbit erythrocytes by the complement system. This result suggests that PVS inhibits both the classical and alternative complement pathways of the complement system. Next, the manner in which PVS exerts its effects on complement components was examined. PVS was found to inhibit generation of C4a and Ba generation in activation of the classical and alternative pathways, respectively. Moreover, when the EAC1 cells, which were carrying C1 on the EAs, treated with PVS were exposed to C1-deficient serum, hemolysis decreased in a PVS dose-dependent manner. These results suggest that PVS inhibits C1 in the classical pathway and C3 convertase formation in the alternative pathway. Therefore, PVS may be a useful polymer for developing an anticomplement device for cytomedical therapy.

Complement-mediated host defense in the lung

2000 ◽  
Vol 279 (5) ◽  
pp. L790-L798 ◽  
Author(s):  
Wendy T. Watford ◽  
Andrew J. Ghio ◽  
Jo Rae Wright
Keyword(s):  
Alternative Pathway ◽  
Protein A ◽  
Lavage Fluid ◽  
Surfactant Protein ◽  
The Body ◽  
Surfactant Protein D ◽  
Classical Pathway ◽  
Pathway Activity ◽  
Protein Factor ◽  
Pathway Activation

Complement is a system of plasma proteins that aids in the elimination of pathogens from the body. We hypothesized that there is a functional complement system present in the lung that aids in the removal of pathogens. Western blot analysis revealed complement proteins of the alternative and classical pathways of complement in bronchoalveolar lavage fluids (BALF) from healthy volunteers. Functional classical pathway activity was detected in human BALF, but there was no significant alternative pathway activity in lavage fluid, a finding that correlates with the low level of the alternative pathway protein, factor B, in these samples. Although the classical pathway of complement was functional in lavage fluid, the level of the classical pathway activator C1q was very low. We tested the ability of the lung- specific surfactant proteins, surfactant protein A (SP-A) and surfactant protein D (SP-D), to substitute for C1q in classical pathway activation, since they have structural homology to C1q. However, neither SP-A nor SP-D restored classical pathway activity to C1q-depleted serum. These data suggest that the classical pathway of complement is functionally active in the lung where it may play a role in the recognition and clearance of bacteria.

scholarly journals The human complement system: assembly of the classical pathway C3 convertase

1980 ◽  
Vol 189 (1) ◽  
pp. 173-181 ◽  
Author(s):  
M A Kerr
Keyword(s):  
Direct Evidence ◽  
Gel Filtration ◽  
Fluid Phase ◽  
Classical Pathway ◽  
Human Complement ◽  
Stabilizing Effect ◽  
Excess Substrate ◽  
High Concentrations ◽  
Low Ionic Strength

The assembly of the classical pathway C3 convertase in the fluid phase has been studied. The enzyme is assembled from C2 and C4 on cleavage of these proteins by C1s. Once assembled, the enzyme activity decays rapidly. Kinetic evidence has been obtained that this decay is even more rapid than previously suggested (kdecay is 2.0 min-1 at 37 degrees C). As a result, optimal C3 convertase activity is only observed with high C1s levels, which result in rapid rates of cleavage of C2 and increased rates of formation of the C3 convertase. Using high concentrations of C1s at lower temperatures (22 degrees C) in the presence of excess substrate we have demonstrated kinetically that the enzyme comprises an equimolar complex of C4b and cleaved C2. We have obtained direct evidence from gel-filtration experiments for the role of C2a as the catalytic subunit of the enzyme. C2b appears to mediate the interaction between C4 (or C4b) and C2 at pH 8.5 and at low ionic strength where the interactions can easily be detected. It may therefore be important in the assembly of the enzyme, though it is not involved in the catalytic activity. The decay of the C3 convertase reflects the release of C2a from the C4b x (C2b) x C2a complex, and the stabilizing effect of iodine on the C3 convertase is therefore apparently one of stabilizing the C4b-C2z interaction, which is otherwise weak. C1s is not a part of the C3 convertase enzyme.

scholarly journals The Human Complement Regulator Factor H Binds Pneumococcal Surface Protein PspC via Short Consensus Repeats 13 to 15

2002 ◽  
Vol 70 (10) ◽  
pp. 5604-5611 ◽  
Author(s):  
Thomas G. Duthy ◽  
Rebecca J. Ormsby ◽  
Eleni Giannakis ◽  
A. David Ogunniyi ◽  
Uwe H. Stroeher ◽  
...  
Keyword(s):  
Alternative Pathway ◽  
Regulatory System ◽  
Surface Protein ◽  
Fluid Phase ◽  
Direct Consequence ◽  
Factor H ◽  
Negative Regulator ◽  
Short Consensus Repeats ◽  
High Concentrations ◽  
Complement Regulator

ABSTRACT The innate ability of Streptococcus pneumoniae to resist complement activation and complement-mediated phagocytosis may be a direct consequence of the ability of the bacteria to bind components of the complement regulatory system. One such component, factor H (fH), is a crucial fluid-phase negative regulator of the alternative pathway of complement and is utilized by a number of pathogenic organisms to resist complement attack. The pneumococcal surface protein C (PspC [also known as CbpA] and SpsA) has been shown to bind fH, although the exact binding site within one or more of the 20 short consensus repeats (SCRs) of the molecule is not known. The purpose of the current study was to map specific SCRs on fH responsible for this binding. Initial experiments utilizing type 2 pneumococcal strain D39 and its isogenic PspC-negative derivative (D39/pspC mutant) showed that fH binding was PspC dependent. A purified recombinant protein derivative of PspC that lacked the proline-rich region (PspCΔPro) had a reduced binding efficiency for fH, thereby directly showing the importance of this region for the fH interaction. We have specifically shown by inhibition experiments that SCRs responsible for heparin and C3b binding of fH are not involved in binding PspC and the interaction between fH and PspC is largely hydrophobic, since no inhibition was observed in the presence of high concentrations of NaCl. Construction of SCR proteins encompassing the whole fH molecule showed that SCRs 8 to 15 (SCR 8-15) mediated binding to PspC. Further localization experiments revealed that SCR 13 and SCR 15 were required for full binding, although partial binding was retained when either SCR was removed.

scholarly journals PspA and PspC Minimize Immune Adherence and Transfer of Pneumococci from Erythrocytes to Macrophages through Their Effects on Complement Activation

2007 ◽  
Vol 75 (12) ◽  
pp. 5877-5885 ◽  
Author(s):  
Jie Li ◽  
David T. Glover ◽  
Alexander J. Szalai ◽  
Susan K. Hollingshead ◽  
David E. Briles
Keyword(s):  
Alternative Pathway ◽  
Protein A ◽  
Surface Protein ◽  
Major Effect ◽  
Complement C3 ◽  
Invasive Infection ◽  
Classical Pathway ◽  
Immune Adherence ◽  
Major Increase ◽  
Isogenic Mutants

ABSTRACT Pneumococcal surface protein A (PspA) and PspC are important virulence factors. Their absence has been shown to allow improved clearance of pneumococci from the blood of mice and to decrease pneumococcal virulence. In the presence of antibody and complement, pneumococci attach to erythrocytes in a process called immune adherence (IA), which facilitates their delivery to, and eventual phagocytosis by, macrophages. It is not known, however, if PspA and PspC affect IA. Using PspA and/or PspC isogenic mutants and complement-deficient mouse sera, we demonstrated that absence of PspA allows greater deposition of C1q and thus increased classical-pathway-mediated C3 deposition. In the absence of both PspA and PspC, there is also a major increase in C1q-independent C3 deposition through the alternative pathway. The latter was observed even though absence of PspC alone did not have a major effect on alternative-pathway-dependent complement deposition. The enhanced complement C3 deposition realized in the absence of PspA alone and in the absence of PspA and PspC resulted in both greatly increased IA to human erythrocytes and improved transfer of pneumococci from erythrocytes to phagocytes. These data provide new insight into how PspA and PspC act in synergy to protect pneumococci from complement-dependent clearance during invasive infection.

scholarly journals Multi-organ complement deposition in COVID-19 patients

2021 ◽  
Author(s):  
Paolo Macor ◽  
Paolo Durigutto ◽  
Alessandro Mangogna ◽  
Rossana Bussani ◽  
Stefano D'Errico ◽  
...  
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Tissue Level ◽  
Spike Protein ◽  
Classical Pathway ◽  
Limited Information ◽  
Alveolar Cells ◽  
Complement Components ◽  
Alternative Pathways ◽  
Activation Products

Background: Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at tissue level. The mechanisms and pathways of local complement activation remain unclear. Methods: We performed immunofluorescence analyses of autopsy specimens of lungs, kidney and liver from nine COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG and spike protein of SARS-CoV-2. Findings: Lung deposits of C1q, C4, C3 and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. Factor B deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on hepatic artery and portal vein of the liver. Interpretation. Complement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease.

scholarly journals Complement-dependent Clearance of Apoptotic Cells by Human Macrophages

1998 ◽  
Vol 188 (12) ◽  
pp. 2313-2320 ◽  
Author(s):  
Dror Mevorach ◽  
John O. Mascarenhas ◽  
Debra Gershov ◽  
Keith B. Elkon
Keyword(s):  
Cell Surface ◽  
Complement Activation ◽  
Apoptotic Cell ◽  
Alternative Pathway ◽  
Systemic Circulation ◽  
Classical Pathway ◽  
Apoptotic Cells ◽  
Complement Components ◽  
Serum Factors ◽  
Systemic Autoimmunity

Apoptotic cells are rapidly engulfed by phagocytes, but the receptors and ligands responsible for this phenomenon are incompletely characterized. Previously described receptors on blood- derived macrophages have been characterized in the absence of serum and show a relatively low uptake of apoptotic cells. Addition of serum to the phagocytosis assays increased the uptake of apoptotic cells by more than threefold. The serum factors responsible for enhanced uptake were identified as complement components that required activation of both the classical pathway and alternative pathway amplification loop. Exposure of phosphatidylserine on the apoptotic cell surface was partially responsible for complement activation and resulted in coating the apoptotic cell surface with C3bi. In the presence of serum, the macrophage receptors for C3bi, CR3 (CD11b/CD18) and CR4 (CD11c/CD18), were significantly more efficient in the uptake of apoptotic cells compared with previously described receptors implicated in clearance. Complement activation is likely to be required for efficient uptake of apoptotic cells within the systemic circulation, and early component deficiencies could predispose to systemic autoimmunity by enhanced exposure to and/or aberrant deposition of apoptotic cells.

Sign in / Sign up

Export Citation Format

Share Document