Inhibition of the alternative pathway of complement by gold sodium thiomalate in vitro.
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Arthritis, Rheumatoid↗
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Serum bactericidal activity against Haemophilus influenzae.
The requirement for an intact thiolester bond in C3 for assembly of the membrane attack complex and bactericidal activity was demonstrated in a system permitting only alternative pathway activation. Serum depleted of C3 and C4 by treatment with potassium bromide was reconstituted with forms of C3 with an intact (native C3) or disrupted (NH3.C3) thiolester bond, and bactericidal activity against Haemophilus influenzae b was determined. For strain 885 in high-antibody-containing serum, reconstitution with native C3 was associated with marked bactericidal activity (log10 kill in 60 min 1.01 +/- 0.08) compared with reconstitution with NH3.C3 (log10 kill -0.04 +/- 0.19, p less than 0.001). Similar results were obtained with other strains of H. influenzae b. In serum lacking type-specific antibody no alternative pathway-mediated bactericidal activity was detected against any of the strains examined, even when native C3 was added to KBr serum. These experiments indicate how the biochemical structure of C3 directs its functions; only forms of C3 with an intact thiolester bond, which can covalently bind to bacterial surfaces, can serve as the C5 convertase and generate bacterial activity. In addition these experiments demonstrate an absolute antibody dependence for alternative pathway-mediated bactericidal activity against H. influenzae.
Antibodies, Bacterial↗
Alternative pathway of complement: nonenzymatic, reversible transition of precursor to active properdin.
A method for the purification of properdin in precursor state (pre-P) has been elaborated. Precursor properdin, in contrast to activated properdin (P), does not initiate the formation of a C3 convertase when added to properdin-depleted serum, rather it requires the presence of an activating substance such as zymosan for expression of its activity. Comparing the activities of pre-P and P it was found that some P preparations contained significant amounts of pre-P because they were fully active only in the presence of zymosan. This observation indicated that P can partly revert to pre-P. Comparison by immunoelectrophoresis and sodium dodecyl sulfate polyacrylamide gel electrophoresis revealed no charge or size differences between pre-P and P. Radiolabeled pre-P, when analyzed after its participation in the reactions of the pathway, displayed an unchanged subunit m.w. of 50,000. Taken together, these results strongly suggest that the transition of pre-P to P is due to a partly reversible change in the conformation of the protein rather than the result of proteolytic cleavage.
Complement System Proteins↗
A serum factor in chronic hypocomplementemic hephritis distinct from immunoglobulins and activating the alternate pathway of complement.
Nephritic factor (C3NeF) has been isolated from plasma of patients with hypocomplementemic chronic glomerulonephritis (HCG) by ion exchange and molecular sieve chromatography. This material was further treated with solidified anti-Ig antiserum. The purified material failed to react with antiserum to human IgG, IgG3, Fab, Fc, and kappa and lambda chains, but retained full C3NeF activity. The nonidentity of C3NeF with IgG was further demonstrated by Ouchterlony analysis using anti-IgG and anti-C3NeF. Isolated C3NeF was found to be a protein with a sedimentation coefficient of 7S and a mol wt of 150,000 daltons, which on microzone electrophoresis and gel electrophoresis at pH 8.6 behaved as a gamma-globulin. C3NeF is not a C1q precipitin and does not activate the classical complement pathway. Unlike cobra venom factor, it failed to enter into a complex with C3 proactivator (C3PA) when incubated with normal human serum (NHS) and then subjected to sucrose density gradient ultracentrifugation. The action of isolated C3NeF on C3 requires C3PA, C3PA convertase (C3PAse), and properdin (P). Similarly, C3PA conversion by C3NeF requires P, C3PAse, and C3. Total hemolytic activity was lost by incubation of 64 microg of C3NeF/1 ml NHS at 37 degrees C for 30 min. Both C3a and C5a anaphylatoxin could be generated by C3NeF in serum previously depleted of anaphylatoxin inactivator. Anti-C3NeF was found to detect an antigen in all NHS tested. Treatment of NHS with solidified anti-C3NeF caused impairment of the alternate complement pathway. It failed to sustain lysis of glutathione-treated human erythrocytes initiated by inulin. It is conceivable that the normal serum constituent which is removed by anti-C3NeF constitutes the inactive precursor of C3NeF, and a heretofore unrecognized component of the alternate pathway.
Adsorption↗
Eosinophil granule cationic proteins regulate complement. I. Activity on the alternative pathway.
Eosinophil granules contain several cationic proteins that mediate tissue damage in allergic disease. The present study examined the capacity and mechanisms by which these cationic proteins regulate activity of the alternative pathway of C. Eosinophil peroxidase and eosinophil cationic protein inhibited formation of cell-bound alternative pathway C3 convertase, causing 50% inhibition of lysis at about 0.19 and 0.75 microgram/10(7) cellular intermediates, respectively. Major basic protein inhibited alternative pathway C3 activity by only 19% at 1.5 micrograms/10(7) cellular intermediates. Eosinophil-derived neurotoxin had no activity on the alternative pathway. The eosinophil granule proteins were examined for the mechanism by which they inhibited alternative pathway activity. Eosinophil peroxidase and major basic protein inhibited fluid phase factor B consumption in a reaction mixture that also contained factors D and C3b, eosinophil-derived neurotoxin had no activity on factor B consumption, and eosinophil cationic protein consumed factor B in the absence of C3b and factor D. Both eosinophil cationic protein and eosinophil peroxidase enhanced the decay of preformed alternative pathway convertase. Lysis of EAC4b,3b cellular intermediates formed to contain a low surface amount of C3b was more inhibited than was lysis of cells formed with a standard amount of C3b on the surface. This suggests that these eosinophil proteins acted predominantly on C3b to regulate alternative pathway activity. We also found that none of the eosinophil granule cationic proteins had any effect on later events after the formation of the C3 convertase. We conclude that although eosinophil-derived neurotoxin (isoelectric pH value (pI) = 8.9) does not regulate alternative pathway activity, the more highly charged eosinophil granule cationic proteins--major basic protein (pI = 10.9), eosinophil cationic protein (pI = 10.8), and eosinophil peroxidase (pI = 10.8)--do share the capacity to regulate C activity and may exert this activity in vivo.
Blood Proteins↗
Identification of the C3b binding site in a recombinant vWF-A domain of complement factor B by surface-enhanced laser desorption-ionisation affinity mass spectrometry and homology modelling: implications for the activity of factor B.
Factor B is a key component of the alternative pathway of the complement system. During complement activation, factor B complexed with activated C3 is cleaved into the Ba and Bb fragments by the protease factor D to form the C3 convertase from the complex between C3b and Bb. The Ba fragment contains three short consensus/complement repeat (SCR) domains, and the Bb fragment contains a von Willebrand factor type A (vWF-A) domain and a serine protease (SP) domain. Surface-enhanced laser desorption-ionization affinity mass spectrometry (SELDIAMS) was used to investigate the reaction of factor B with immobilised activated C3(NH3) in the presence of Mg(2+). A recombinant vWF-A domain (residues G229-Q448), the native Ba and Bb fragments and native factor B all demonstrated specific interactions with C3(NH3), while no interactions were detected using bovine serum albumin as a control. A mass analysis of the proteolysis of the vWF-A domain when this was bound to immobilised C3(NH3) identified two peptides (residues G229-K265 and T355-R381) that were involved with vWF-A binding to C3(NH3). A homology model for the vWF-A domain was constructed using the vWF-A crystal structure in complement receptor type 3. Comparisons with five different vWF-A crystal structures showed that large surface insertions were present close to the carboxyl and amino edges of the central beta-sheet of the factor B vWF-A structure. The peptides G229-K265 and T355-R381 corresponded to the two sides of the active site cleft at the carboxyl edge of the vWF-A structure. The vWF-A connections with the SCR and SP domains were close to the amino edge of this vWF-A beta-sheet, and shows that the vWF-A domain can be involved in both C3b binding and the regulation of factor B activity. These results show that (i) a major function of the vWF-A domain is to bind to activated C3 during the formation of the C3 convertase, which it does at its active site cleft; and that (ii) SELDIAMS provides an efficient means of identifying residues involved in protein-protein interactions.
Amino Acid Sequence↗
[Selective binding in vitro of a modified form of the C3 component of complement to human erythrocytes].
C3 was bound to human erythrocytes from autologous plasma or from serum brought to low ionic strength (mu less than or equal to 0.03) and pH between 4.0 and 5.0, then subsequently incubated with erythrocytes (50/1, v/v) for 20 min at 0 degree C. This capacity was preserved up to 72 h by prolonged incubation at 20, 25 or 37 degrees C, whereas it was quickly lost by incubation at 0 degree C. C3 binding did not require complement activation and was not observed with neuraminidase-treated erythrocytes. Crossed immunoelectrophoretic analysis of the pretreated serum or plasma revealed that a fraction having more cathodal migration than that of native C3 was generated upon incubation in the above-mentioned conditions. This fraction appeared able to selectively bind to the erythrocytes. Cell-bound C3 reacted positively to antisera against C3a, C3c, C3d or native C3; they rosetted positively with EAC3b, clearly showing that this C3 binding was not dependent on the proteolysis of C3 and that it concerned the acceptor sites on the cells, since C3b receptors were free. The functional significance of this C3 binding was also investigated: EC3 were not able to lyse through the alternative pathway, whereas lysis clearly increased when C3 was found to AET-treated erythrocytes. This finding, together with the modulation in the capacity of EC3 or E(AET)C3 to form an alternative pathway convertase by antibodies to C3c or C3d, strongly suggests a contribution of bound C3 to such a convertase. In contrast to "C3b-like" C3, this modified C3 was able to bind to acceptor sites on erythrocytes but, like the former, it retained the capacity to form an alternative pathway convertase. In this light, it may represent an intermediate between C3 and "C3b-like" C3.
Complement Activation↗
Increased serum C3 levels in Crry transgenic mice partially abrogates its complement inhibitory effects.
Complement receptor 1-related gene/protein y (Crry) is a potent murine complement regulator that inhibits C3 convertases. Transgenic mice that overexpress soluble Crry (sCrry), directed systemically by the metallothionein-I promoter, have been used as an animal model for chronic blockade of complement activation. Recently we have found that alternative pathway (AP) activity in Crry transgenic mice was not inhibited as much as expected. To elucidate the mechanism of this effect, we evaluated the AP activities and levels of sCrry and AP complement components in transgenic and non-transgenic mice. In transgenic mice, expression of sCrry was induced by feeding zinc sulphate solution to 70.1 +/- 42.7 micro g/ml mean serum level. Its corresponding level of purified sCrry inhibited 49% of AP activity of normal mice serum; however, the actual AP activities in transgenic mice were not decreased when compared to non-transgenic mice (130.2 +/- 9.0%versus 113.0 +/- 35.4%). Expressed sCrry was functional, as immunoprecipitation and removal of sCrry from transgenic sera with rabbit anti-Crry polyclonal antibody resulted in enhanced AP activity, consistent with initial levels of sCrry. We then compared the changes to C3, factor B, factor H and factor D serum levels in transgenic and non-transgenic mice after induction of sCrry expression. Of these only C3 was increased after zinc feeding in transgenic mice compared to non-transgenic mice (142.8 +/- 14.1%versus 121.4 +/- 15.1%, P = 0.023). These results suggest that the inhibitory effect of chronic exposure to sCrry is compensated by concomitant alteration in C3 levels. This result also suggests the presence of a complement regulatory protein controls the level of serum C3, which has potential importance in the design and interpretation of studies involving chronic use of complement inhibitors.
Animals↗
Alternative complement pathway activation by C4b deposited during classical pathway activation.
Sheep erythrocytes (E) sensitized with anti-E antibody (A) were reacted with guinea pig C1 (C1gp) and human C4 (C4hu) or guinea pig C4 (C4gp) to prepare EAC1, 4b. Treatment of the EAC1, 4b with a buffer containing EDTA removes C1rgp and C1sgp, resulting in the formation of EAC4b. EAC4b prepared in this way were found to be lysed by human or guinea pig serum in a gelatin Veronal-buffered saline containing 2 mM MgCl2 and 8 mM EGTA (Mg-EGTA-GVB). In the hemolytic sensitivity of EAC4bhu, essentially no difference was noted whether IgG or IgM antibodies were used for preparation of EAC4bhu. The extent of the hemolysis of EAC4bhu was dependent on the dose of C4bhu. Because EAC4bhu were lysed even by C2-deficient human serum, C3 convertase of the classical complement pathway would not be involved in the hemolysis of EAC4bhu. Furthermore, the reactivity of EAC4bhu with serum in Mg-EGTA-GVB remained even after treatment of the intermediate cells with 1 mM PMSF, indicating that any remaining C1gp was not responsible for the hemolysis. Therefore, the hemolysis of EAC4b by sera in Mg-EGTA-GVB was considered to be mediated via activation of the alternative complement pathway (ACP). Pretreatment of EAC4bhu with anti-C4hu antibody or C4-binding protein suppressed the hemolysis of EAC4bhu via the ACP activation. Furthermore, EAC4bhu were more sensitive to hemolysis by the reaction with a mixture of C3, B, D, and H followed by rat serum in EDTA-GVB than EAC1qgp were. These results indicate that C4b molecules on the cell membrane participate in the activation of ACP.
Animals↗
Methionine modification impairs the C5-cleavage function of cobra venom factor-dependent C3/C5 convertase.
The complement-mediated lysis of guinea pig erythrocytes by cobra venom factor (CVF) decreased by 50-60% within 2 min of treatment with 5 mM sodium periodate at 0 degree C. This loss of activity paralleled modification of 3-4 Met; other amino acids and sugar residues of the oligosaccharide chains were not affected. Treatment with N-chlorosuccinimide or chloramine-T under conditions that specifically modified 3-4 readily-oxidizable Met also caused 50-60% loss of CVF activity. The secondary structure of CVF was not altered by these modifications. Methionine-modified CVF (MetCVF) supported the cleavage of factor B by factor D with equal efficiency as that of untreated CVF to form C3/C5 convertase (MetCVF,Bb) of the alternative pathway. MetCVF,Bb and CVF,Bb were indistinguishable with respect to C3 cleavage. However, the C5-cleavage ability of MetCVF,Bb was significantly lower than that of CVF,Bb. These results suggest the involvement of Met in CVF binding of C5.
Animals↗
Purification and characterization of decay-accelerating factor (DAF) from Raji cells.
Decay-accelerating factor (DAF), a membrane protein that regulates the complement system, was purified to homogeneity from lymphoblastoid (Raji) cells (DAF-R). It exhibited almost the same molecular weight as DAF from stroma of erythrocytes (DAF-S). Purified DAF-R, which could be reincorporated into cell membranes, accelerated the decay of the C3 convertases, in both the classical (C4b2a) and the alternative (C3bBb) pathways. This activity was completely inhibited by a monoclonal anti-DAF antibody, 1C6. From these results, DAF-R and DAF-S can not be distinguished; however, the decay-accelerating activity of DAF-R was much higher than that of DAF-S. 1C6 enhanced the binding of C3 to Raji cells by incubating with six purified components of the alternative pathway, whereas it did not induce the killing of Raji cells after a short incubation period. When antibodies against Raji cells were added to the above system, the blocking of DAF activity by 1C6 resulted in efficient killing of Raji cells by autologous complement. From these results, it is clear that DAF on nucleated cells plays an important role in protecting these cells from the damage caused by autologous complement.
Burkitt Lymphoma↗
Role of L-ficolin/mannose-binding lectin-associated serine protease complexes in the opsonophagocytosis of type III group B streptococci.
Serotype III group B streptococci (GBS) are a common cause of neonatal sepsis and meningitis. Although deficiency in maternal capsular polysaccharide (CPS)-specific IgG correlates with susceptibility of neonates to the GBS infection, serum deficient in CPS-specific IgG mediates significant opsonophagocytosis. This IgG-independent opsonophagocytosis requires activation of the complement pathway, a process requiring the presence of both Ca(2+) and Mg(2+), and is significantly reduced by chelating Ca(2+) with EGTA. In these studies, we defined a role of L-ficolin/mannose-binding lectin-associated serine protease (MASP) complexes in Ca(2+)-dependent, Ab-independent opsonophagocytosis of serotype III GBS. Incubation of GBS with affinity-purified L-ficolin/MASP complexes and C1q-depleted serum deficient in CPS-specific Ab supported opsonophagocytic killing, and this killing was inhibited by fluid-phase N-acetylglucosamine, the ligand for L-ficolin. Binding of L-ficolin was proportional to the CPS content of individual strains, and opsonophagocytic killing and C4 activation were inhibited by fluid-phase CPS, suggesting that L-ficolin binds to CPS. Sialic acid is known to inhibit alternative complement pathway activation, and, as expected, the bactericidal index (percentage of bacteria killed) for individual strains was inversely proportional to the sialic acid content of the CPS, and L-ficolin-initiated opsonophagocytic killing was significantly increased by addition of CPS-specific IgG2, which increased activation of the alternative pathway. We conclude that binding of L-ficolin/MASP complexes to the CPS generates C3 convertase C4b2a, which deposits C3b on GBS. C3b deposited by this lectin pathway forms alternative pathway C3 convertase C3bBb whose activity is enhanced by CPS-specific IgG2, leading to increased opsonophagocytic killing by further deposition of C3b on the GBS.
Animals↗
Structure/function studies of human decay-accelerating factor.
The decay-accelerating factor (DAF) contains four complement control protein repeats (CCPs) with a single N-linked glycan positioned between CCPs 1 and 2. In previous studies we found that the classical pathway regulatory activity of DAF resides in CCPs 2 and 3 while its alternative pathway regulatory activity resides in CCPs 2, 3 and 4. Molecular modelling of the protein predicted that a positively charged surface area on CCPs 2 and 3 (including KKK125-127) and nearby exposed hydrophobic residues (L147F148) on CCP3 may function as ligand-binding sites. To assess the roles of the N-linked glycan and the above two sets of amino acids in the function of DAF, we mutated N61 to Q, KKK125-127 to TTT and L147F148 to SS. Following expression of the mutated cDNAs in Chinese hamster ovary cells, the glycosylphosphatidylinositol (GPI)-anchored mutant proteins were affinity purified and their functions were assessed. In initial assays, the proteins were incorporated into sheep and rabbit erythrocytes and the effects of the mutations on regulation of classical and alternative C3 convertase activity were quantified by measuring C3b deposition. Since DAF also functions on C5 convertases, comparative haemolytic assays of cells bearing each mutant protein were performed. Finally, to establish if spatial orientation between DAF and the convertases on the cell surface played any role in the observed effects, fluid-phase C3a generation assays were performed. All three assays gave equivalent results and showed that the N-linked glycan of DAF is not involved in its regulatory function; that L147F148 in a hydrophobic area of CCP3 is essential in both classical and alternative pathway C3 convertase regulation; and that KKK125-127 in the positively charged pocket between CCPs 2 and 3 is necessary for the regulatory activity of DAF on the alternative pathway C3 convertase but plays a lesser role in its activity on the classical pathway enzyme.
Animals↗
Biochemical analysis of the membrane and soluble forms of the complement regulatory protein of Trypanosoma cruzi.
A developmentally regulated, 160-kDa trypomastigote surface glycoprotein was previously shown to bind the third component of complement and to inhibit activation of the alternative complement pathway, thus providing the parasites a means of avoiding the lytic effects of complement. We now show that this complement regulatory protein (CRP) binds human C4b, a component of the classical pathway C3 convertase, and may therefore also act to restrict classical complement activation. Characterization of the extent of carbohydrate modification of the protein revealed extensive N-linked glycosylation and no apparent O-linked sugars. The CRP purified from parasites treated with an inhibitor of N-linked glycosylation exhibited a decreased binding affinity for C3b compared with that of the fully glycosylated protein. We have previously shown that the protein was anchored to the membrane via a glycosyl phosphatidylinositol linkage and was spontaneously shed from the parasite surface. The spontaneous release of CRP from the parasite surface may augment the protection of the parasites from complement-mediated lysis by the removal of complement-CRP complexes. The majority of the shed CRP had an apparent molecular mass of 160 kDa and lacked the glycolipid anchor, whereas the membrane form was recovered with the glycolipid anchor attached and had an apparent molecular mass of 185 kDa. Both the membrane form (185 kDa) and the soluble form (160 kDa) retained binding affinity for C3b. Evidence is presented to indicate that the conversion of the 185-kDa membrane form to the 160-kDa form is the result of cleavage by an endogenous phospholipase C.
Animals↗
The requirement of localized, CR2-mediated, alternative pathway activation of complement for covalent deposition of C3 fragments on normal B cells.
We have shown previously that normal B cells share, with Epstein-Barr virus-transformed and malignant B cells, the ability to activate the alternative pathway (AP) of complement in vitro, resulting in the deposition of C3 fragments on the cell surface. Complement receptor type 2 (CR2, CD21) has been implicated directly as the site for formation of an AP convertase, which provides nascent C3b for deposition at secondary sites on the B-cell surface. In the present study, we have examined C3 fragment deposition in vitro in more detail by (1) assessing the importance of locally generated C3b for the deposition process, (2) investigating whether CR2 is the sole requirement for conferring AP activation capacity on a cell, and (3) determining whether CR2's function, as an AP activator, has different structural requirements from ligand binding. Increasing the availability of native C3, by increasing the serum (NHS) concentration, resulted in enhanced C3 fragment deposition on the B cells, whereas use of factor 1-depleted NHS, which showed massive fluid phase C3 conversion during the incubation, diminished the deposition. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting of untreated and hydroxylamine-treated lysates from B cells, after in vitro activation, revealed that the majority of C3 fragments (primarily iC3b and C3dg) had been covalently bound to the cell surface. Transfection of COS cells with wild-type CR2 or a deletion mutant lacking 11 of the molecule's 15 homologous domains, but retaining the ligand-binding site, revealed that expression of intact CR2 conferred a 12-fold increase in AP-activating capacity on these cells, while no increase in AP activity was apparent on cells transfected with the mutant CR2.
B-Lymphocytes↗
Complement alterations in inflammatory bowel disease.
A prospective evaluation of the activity of the complement system was undertaken in 32 patients at the time of diagnosis of inflammatory bowel disease, before the onset of therapy. Serum classical pathway components and function were normal, while significant abnormalities of the alternative pathway were found. Depressions of serum properdin and properdin convertase were noted in association with diminished consumption of C3--C9 after reaction with cobra venom. These abnormalities of alternative pathway integrity were most significant in regional enteritis and in ulcerative colitis with extraintestinal complications. Sequential studies extending into clinical remission revealed resolution of all significant abnormalities.
Adolescent↗
MPGN II--genetically determined by defective complement regulation?
MPGN II is a rare disease which is characterized by complement containing deposits within the GBM. The disease is characterized by functional impairment of the GBM causing progressive loss of renal function eventually resulting in end stage renal disease. It now becomes evident that in addition to C3NeF, which inhibits the inactivation of the alternative C3 convertase C3bBb, different genetically determined factors are also involved in the pathogenesis of MPGN II. These factors though different from C3NeF also result in defective complement regulation acting either through separate pathways or synergistically with C3NeF. Following the finding of MPGN II in Factor H deficient animals, patients with MPGN II were identified presenting with an activated complement system caused by Factor H deficiency. Factor H gene mutations result in a lack of plasma Factor H or in a functional defect of Factor H protein. Loss of Factor H function can also be caused by inactivating Factor H autoantibodies, C3 mutations preventing interaction between C3 and Factor H, or autoantibodies against C3. Identification of patients with MPGN II caused by defective complement control may allow treatment by replacement of the missing factor via plasma infusion, thus possibly preventing or at least delaying disease progress.
Animals↗
Complement activity and pharmacological inhibition in cardiovascular disease.
While complement is the most important component of humoral autoimmunity, and inflammation plays a key role in atherosclerosis, relatively few studies have looked at complement implications in atherosclerosis and its complications. C-reactive protein is a marker of inflammation and is also involved in atherosclerosis; it activates complement and colocalizes with activated complement proteins within the infarcting myocardium and the active atherosclerotic plaques. As new agents capable of modulating complement activity are being developed, new targets for the management of atherosclerosis are emerging that are related to autoimmunity and inflammation. The present paper reviews the putative roles of the various complement activation pathways in the development of atherosclerosis, in ST segment elevation and non-ST segment elevation acute coronary syndromes, and in coronary artery bypass graft surgery. It also provides a perspective on new therapeutic interventions being developed to modulate complement activity. These interventions include the C1 esterase inhibitor, which may be consumed in some inflammatory states resulting in the loss of one of the mechanisms inhibiting activation of the classical and lectin pathways; TP10, a recombinant protein of the soluble complement receptor type 1 (sCR1) which inhibits the C3 and C5 convertases of the common pathway by binding C3b and C4b; a truncated version of the soluble complement receptor type 1 CRI lacking the C4b binding site which selectively inhibits the alternative pathway; and pexelizumab, a monoclonal antibody selectively blocking C5 to prevent the activation of the terminal pathway that is involved in excessive inflammation and autoimmune responses.
Angina, Unstable↗