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.

scholarly journals Infectious diseases associated with complement deficiencies.

1991 ◽  
Vol 4 (3) ◽  
pp. 359-395 ◽  
Author(s):  
J E Figueroa ◽  
P Densen
Keyword(s):  
Infectious Diseases ◽  
Host Defense ◽  
Complement Activation ◽  
Immune Modulation ◽  
Alternative Pathway ◽  
Membrane Attack Complex ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Classical Pathway ◽  
Cellular Effects

The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular effects of complement activation, and regulatory proteins, which protect host cells from complement-mediated injury. Complement activation occurs via either the classical or the alternative pathway, which converge at the level of C3 and share a sequence of terminal components. Four aspects of the complement cascade are critical to its function and regulation: (i) activation of the classical pathway, (ii) activation of the alternative pathway, (iii) C3 convertase formation and C3 deposition, and (iv) membrane attack complex assembly and insertion. In general, mechanisms evolved by pathogenic microbes to resist the effects of complement are targeted to these four steps. Because individual complement proteins subserve unique functional activities and are activated in a sequential manner, complement deficiency states are associated with predictable defects in complement-dependent functions. These deficiency states can be grouped by which of the above four mechanisms they disrupt. They are distinguished by unique epidemiologic, clinical, and microbiologic features and are most prevalent in patients with certain rheumatologic and infectious diseases. Ethnic background and the incidence of infection are important cofactors determining this prevalence. Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. The availability of effective polysaccharide vaccines and antibiotics provides an immunologic and chemotherapeutic rationale for preventing and treating infection in patients with these deficiencies.

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 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.

scholarly journals Continual Low-Level Activation of the Classical Complement Pathway

2001 ◽  
Vol 194 (6) ◽  
pp. 747-756 ◽  
Author(s):  
Anthony P. Manderson ◽  
Matthew C. Pickering ◽  
Marina Botto ◽  
Mark J. Walport ◽  
Christopher R. Parish
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Blood Stasis ◽  
Classical Pathway ◽  
Complement Pathway ◽  
Complement Components ◽  
Classical Complement Pathway ◽  
Alternative Complement ◽  
Classical Complement

There is evidence that the classical complement pathway may be activated via a “C1-tickover” mechanism, analogous to the C3-tickover of the alternative pathway. We have quantitated and characterized this pathway of complement activation. Analysis of freshly collected mouse and human plasma revealed that spontaneous C3 activation rapidly occurred with the generation of C3 fragments in the plasma. By the use of complement- and Ig-deficient mice it was found that C1q, C4, C2, and plasma Ig were all required for this spontaneous C3 activation, with the alternative complement pathway further amplifying C3 fragment generation. Study of plasma from a human with C1q deficiency before and after therapeutic C1q infusion confirmed the existence of a similar pathway for complement activation in humans. Elevated levels of plasma C3 were detected in mice deficient in complement components required for activation of either the classical or alternative complement pathways, supporting the hypothesis that there is continuous complement activation and C3 consumption through both these pathways in vivo. Blood stasis was found to stimulate C3 activation by classical pathway tick-over. This antigen-independent mechanism for classical pathway activation may augment activation of the complement system at sites of inflammation and infarction.

scholarly journals Multiple-Organ Complement Deposition on Vascular Endothelium in COVID-19 Patients

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1003
Author(s):  
Paolo Macor ◽  
Paolo Durigutto ◽  
Alessandro Mangogna ◽  
Rossana Bussani ◽  
Luca De Maso ◽  
...  
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Tissue Level ◽  
Multiple Organ ◽  
Spike Protein ◽  
Classical Pathway ◽  
Limited Information ◽  
Alveolar Cells ◽  
Complement Components ◽  
Activation Products

Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at the tissue level. The mechanisms and pathways of local complement activation remain unclear. The aim of this study was to investigate the deposition of complement components in the lungs, kidneys, and liver in patients with COVID-19 patients and to determine the pathway/s of complement activation. We performed immunofluorescence analyses of autopsy specimens of lungs, kidney, and liver from 12 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. 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. FB 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 the hepatic artery and portal vein of the liver. 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 and the contribution of the complement system to inflammation and tissue damage.

scholarly journals Complement Activation and Formation of the Membrane Attack Complex on Serogroup B Neisseria meningitidis in the Presence or Absence of Serum Bactericidal Activity

2002 ◽  
Vol 70 (7) ◽  
pp. 3752-3758 ◽  
Author(s):  
M. Drogari-Apiranthitou ◽  
E. J. Kuijper ◽  
N. Dekker ◽  
J. Dankert
Keyword(s):  
Bactericidal Activity ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Membrane Attack Complex ◽  
Fluid Phase ◽  
Normal Serum ◽  
Chimeric Antibody ◽  
Classical Pathway ◽  
Bacterial Surface ◽  
Serum Bactericidal Activity

ABSTRACT Encapsulated meningococci are complement sensitive only in the presence of bactericidal antibodies by yet-unexplored mechanisms. The objective of this study was to investigate the involvement of major bacterial surface constituents on complement activation and membrane attack complex (MAC) formation on serogroup B meningococci in the presence or absence of antibody-dependent serum bactericidal activity (SBA). The strains used were the encapsulated H44/76, five of its variants differing in capsulation and expression of the class 1 porin (PorA), and its lipopolysaccharide (LPS)-deficient isogenic mutant (LPS−) pLAK33. Two normal sera, one with high SBA (SBA+) and one with no bactericidal activity (SBA−) against H44/76 as well as an a-γ-globulinemic serum were used for sensibilization of the bacteria. C3b and iC3b deposition on H44/76, its unencapsulated variant v24, and pLAK33 was similar in SBA+ and SBA− serum, and no difference was present between the strains. MAC deposition on H44/76 was higher in SBA+ serum than in SBA− serum and the a-γ-globulinemic serum. The amounts of C3b on H44/76, v24, and pLAK33 in the a-γ-globulinemic serum were also not different, indicating immunoglobulin G (IgG)- and LPS-independent complement activation. H44/76 PorA(+) and its PorA(−) variant and the v24 PorA(+) and its PorA(−) variant incubated in SBA− serum induced comparable amounts of MAC, despite their different serum sensitivities. Complement formation on the surface of the bacteria occurred almost exclusively via the classical pathway, but the considerable amounts of Bb measured in the serum indicated alternative pathway activation in the fluid phase. We conclude that complement deposition on meningococci is, for the most part, independent of classical pathway IgG and is not influenced by the presence of PorA or LPS on the meningococcal surface. Addition of an anti-PorA chimeric antibody to the nonbactericidal normal serum, while promoting a dose-related bacterial lysis, did not influence the amounts of C3b, iC3b, and MAC formed on the bacterial surface. These findings support the hypothesis that proper MAC insertion rather than the quantity of MAC formed on the bacterial surface is of importance for efficient lysis of meningococci.

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 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.

Effect of Complement Inhibition By Anti-C5 (Eculizumab) or a Small Molecule Inhibitor of Factor D (ACH-4471) on Survival of Meningococci in Blood from Vaccinated Adults

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2429-2429 ◽  
Author(s):  
Monica Konar ◽  
Eduardo Lujan ◽  
Dan Granoff
Keyword(s):  
Small Molecule ◽  
Meningococcal Disease ◽  
Whole Blood ◽  
Alternative Pathway ◽  
Geometric Mean ◽  
Classical Pathway ◽  
Bacterial Killing ◽  
C5a Receptor ◽  
Increased Risk ◽  
Complement Pathways

Abstract Background. Complement pathways are important targets for treatment of paroxysmal nocturnalhemoglobinuria (PNH) and autoimmune diseases. Because complement is essential in host defense against Neisseria, patients treated with complement inhibitors are at increased risk of life-threatening meningococcal disease. Meningococcal vaccination is recommended. However, the ability of vaccine-induced antibodies to confer protection when different complement pathways are blocked is poorly understood. Inhibiting formation of the membrane attack complex, C5b-C9, blocks serum bactericidal activity (SBA). In the absence of SBA, antibodies can prevent meningococcal disease byopsonophagocytosis (OPA) by binding of antibody to bacteria and activation of C4b and C3b via the classical pathway (CP). When antibody is limited, or the antigenic target is sparse, amplification of C3b deposition via the alternative pathway (AP) is required. OPA killing also depends on activation of phagocytic cells and up-regulation of Fc- and CR3 receptors, which is stimulated by C5a. In this study, we used a whole blood meningococcal killing assay to investigate blocking terminal pathway components C5 or C7 on bacterial survival. We also investigated the effect of blocking the AP using a small molecule factor D inhibitor. Methods. Bloodanticoagulated withlepirudin was obtained from five adults previously immunized with a meningococcal polysaccharide or conjugate vaccine. Four subjects also had completed serogroup B vaccination within 10 months. At time 0, ~5000cfu/ml of serogroup B or C bacteria were added to blood. Meningococcal killing was measured after incubation for 1 and 3hrs in the presence or absence of 50 µg/ml of anti-C5 (eculizumab) or a mouse anti-C7 mAb, both of which blocked SBA, or by 1 to 8 µM of a factor D inhibitor (ACH-4471,Achillion) that inhibited Factor D. By ELISA, 1 µM of the factor D inhibitor completely blocked the AP at 1 µM (the lowest concentration tested) and at 8 µM (the highest concentration tested) had no effect on CP. Results. In the absence of inhibitor, blood from all five subjects incubated with bacteria showed no growth after 1 hr (<50 colony forming units (cfu)/mL). For the serogroup C strain, addition of the C5 inhibitor abolished bacterial killing, as evidenced by lack of decrease in cfu/mL at 1 hr relative to time 0, and an increase of >1 log10 cfu/mL at 3 hr (geometric mean, 74,200, Figure, left Panel). With the C7 inhibitor, cfu/mL decreased at 1 hr (p=0.04) and 3 hr (p=0.07) relative to time 0, and at both time points cfu/mL was significantly lower than with the anti-C5 inhibitor (p<0.007). In blood from four subjects tested, addition of the Factor D inhibitor had less effect on inhibiting serogroup C bacterial killing than anti-C5 or anti-C7 as evidence by an average of 1 log10 decreased cfu/mL at 1 hr with the Factor D inhibitor relative to time 0, and <50 cfu/mL at 3 hr. Similar results were obtained with the serogroup B strain by the addition of the C5 or C7 inhibitor to the blood from the three vaccinated subjects tested, and the addition of the Factor D inhibitor did not interfere with bacterial killing (<50 cfu/mL at 1 hr and 3 hr, Figure, right Panel). When tests were done with blood from a serogroup B unvaccinated subject, the Factor D inhibitor blocked killing (42,000 cfu/mL at 3 hr). In experiments with blood from two vaccinated subjects and serogroup B and C strains, the addition of a C5a receptor antagonist to blood containing anti-C7 increased cfu/mL by >1 log10 at 3 hr, compared to anti-C7 alone. Conclusions. Blocking C5 cleavage and release of C5a by a C5 inhibitor impairs both SBA and OPA killing of meningococci in whole blood, which provides a biologic basis for reports of failure of vaccination in preventing meningococcal disease in some patients treated witheculizumab. Blocking C7 impairs SBA but has less effect on impairing whole blood OPA killing than with anti-C5, since release of C5a, which stimulates phagocytic cell activity, is not inhibited by anti-C7. Effective killing of meningococci by blood from vaccinated subjects was seen at 3 hr (< 50cfu/mL) in the presence of ACH-4471. However, ACH-4471 impaired killing of serogroup B strain by blood from an unvaccinated adult, in which bacterial killing depended on the AP. These data suggest that vaccination may be more effective in decreasing the risk of meningococcal disease in the presence of an AP inhibitor as compared to a C5 inhibitor. Figure Figure. Disclosures Granoff: Achillion Pharmaceuticals: Other: Consultant, ended May 1, 2016, Research Funding.

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