alternative complement pathway


Summary: Complement activation initiated by the interaction of microbial ANTIGENS with COMPLEMENT C3B. When COMPLEMENT FACTOR B binds to the membrane-bound C3b, COMPLEMENT FACTOR D cleaves it to form alternative C3 CONVERTASE (C3BBB) which, stabilized by COMPLEMENT FACTOR P, is able to cleave multiple COMPLEMENT C3 to form alternative C5 CONVERTASE (C3BBB3B) leading to cleavage of COMPLEMENT C5 and the assembly of COMPLEMENT MEMBRANE ATTACK COMPLEX.

Top Publications

  1. Ponnuraj K, Xu Y, Macon K, Moore D, Volanakis J, Narayana S. Structural analysis of engineered Bb fragment of complement factor B: insights into the activation mechanism of the alternative pathway C3-convertase. Mol Cell. 2004;14:17-28 pubmed
    The C-terminal fragment, Bb, of factor B combines with C3b to form the pivotal C3-convertase, C3bBb, of alternative complement pathway. Bb consists of a von Willebrand factor type A (vWFA) domain that is structurally similar to the I ..
  2. Kozel T, Wilson M, Pfrommer G, Schlageter A. Activation and binding of opsonic fragments of C3 on encapsulated Cryptococcus neoformans by using an alternative complement pathway reconstituted from six isolated proteins. Infect Immun. 1989;57:1922-7 pubmed
    ..We examined the interaction of the yeast cells with an alternative complement pathway reconstituted from isolated factor D, factor B, factor H, factor I, C3, and properdin...
  3. Lee L, Hook M, Haviland D, Wetsel R, Yonter E, Syribeys P, et al. Inhibition of complement activation by a secreted Staphylococcus aureus protein. J Infect Dis. 2004;190:571-9 pubmed
    ..These data suggest that Efb is a virulence factor involved in facilitating persistent S. aureus infections by interfering with complement activity in vivo. ..
  4. Kinoshita T, Takata Y, Kozono H, Takeda J, Hong K, Inoue K. C5 convertase of the alternative complement pathway: covalent linkage between two C3b molecules within the trimolecular complex enzyme. J Immunol. 1988;141:3895-901 pubmed
    ..Covalent association of two subunits and the bivalent binding of the substrate are then common properties of the alternative and classical pathway C5 convertases. ..
  5. Pangburn M, Schreiber R, Muller Eberhard H. Formation of the initial C3 convertase of the alternative complement pathway. Acquisition of C3b-like activities by spontaneous hydrolysis of the putative thioester in native C3. J Exp Med. 1981;154:856-67 pubmed
    ..Organomercurial agarose was employed for the rapid removal of sulfhydryl-bearing, hemolytically inactive forms of C3 and C3b from native hemolytically active C3. ..
  6. Tomlinson S, Nussenzweig V. Human alternative complement pathway-mediated lysis of rabbit erythrocytes is enhanced by natural anti-Galalpha1-3Gal antibodies. J Immunol. 1997;159:5606-9 pubmed
    Human serum is effective at lysing unsensitized rabbit erythrocytes due to activation of the alternative complement pathway. Hemolysis is known to be enhanced by the addition of human IgG...
  7. Stapelberg M, Williams R, Byrne S, Halliday G. The alternative complement pathway seems to be a UVA sensor that leads to systemic immunosuppression. J Invest Dermatol. 2009;129:2694-701 pubmed publisher
    ..We found upregulation of mRNA for the alternative complement pathway. The core-enriched genes complement component 3, properdin, and complement factor B were all activated ..
  8. Rooijakkers S, Wu J, Ruyken M, van Domselaar R, Planken K, Tzekou A, et al. Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Nat Immunol. 2009;10:721-7 pubmed publisher
    ..Understanding the mechanistic basis of the central complement-activation step and microbial immune evasion strategies targeting this step will aid in the development of complement therapeutics. ..
  9. Mold C, Bradt B, Nemerow G, Cooper N. Activation of the alternative complement pathway by EBV and the viral envelope glycoprotein, gp350. J Immunol. 1988;140:3867-74 pubmed
    ..These results indicate that gp350, an EBV envelope glycoprotein, is an efficient alternative pathway activator and its expression on cell membranes is associated with the ability to activate C. ..

Scientific Experts

More Information


  1. Fischer E, Ouaissi M, Velge P, Cornette J, Kazatchkine M. gp 58/68, a parasite component that contributes to the escape of the trypomastigote form of T. cruzi from damage by the human alternative complement pathway. Immunology. 1988;65:299-303 pubmed
    ..Gp 58/68 provides trypomastigotes with an additional potential mechanism for escaping complement lysis by the human alternative pathway. ..
  2. Fearon D, Austen K. Current concepts in immunology: the alternative pathway of complement--a system for host resistance to microbial infection. N Engl J Med. 1980;303:259-63 pubmed
  3. Hung S, Peng C, Kostavasili I, Friedman H, Lambris J, Eisenberg R, et al. The interaction of glycoprotein C of herpes simplex virus types 1 and 2 with the alternative complement pathway. Virology. 1994;203:299-312 pubmed
    ..Thus, gC-1 contains two structural domains, one for C3b binding, residues 124 to 366, and another, residues 33 to 133, which interferes with properdin binding to C3b. ..
  4. Stahl G, Xu Y, Hao L, Miller M, Buras J, Fung M, et al. Role for the alternative complement pathway in ischemia/reperfusion injury. Am J Pathol. 2003;162:449-55 pubmed
    ..These data suggest that the alternative complement pathway plays an important role in local and remote tissue injury after GI/R...
  5. Paglialunga S, Fisette A, Yan Y, Deshaies Y, Brouillette J, Pekna M, et al. Acylation-stimulating protein deficiency and altered adipose tissue in alternative complement pathway knockout mice. Am J Physiol Endocrinol Metab. 2008;294:E521-9 pubmed
    ..Overall, a reduction/deficiency in ASP is associated with an antiadipogenic state and ASP may provide a target for controlling fat storage. ..
  6. Zhang M, Kozel T. Mannan-specific immunoglobulin G antibodies in normal human serum accelerate binding of C3 to Candida albicans via the alternative complement pathway. Infect Immun. 1998;66:4845-50 pubmed
    ..Thus, antimannan IgG antibodies play an important regulatory role in interactions between the host complement system and C. albicans. ..
  7. Rawal N, Pangburn M. Formation of high-affinity C5 convertases of the alternative pathway of complement. J Immunol. 2001;166:2635-42 pubmed
    ..The catalytic rate of these convertases approaches maximum velocity, thereby switching the enzyme from cleavage of C3 to cleavage of C5, and production of the cytolytic C5b-9 complex. ..
  8. Xiao H, Schreiber A, Heeringa P, Falk R, Jennette J. Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol. 2007;170:52-64 pubmed
  9. Lutz H, Jelezarova E. Complement amplification revisited. Mol Immunol. 2006;43:2-12 pubmed
    ..Such antibodies are known to stimulate alternative complement pathway activation...
  10. Rohrer B, Long Q, Coughlin B, Wilson R, Huang Y, Qiao F, et al. A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2009;50:3056-64 pubmed publisher
    ..The most common AMD-associated variant of fH resides within a native cell-binding region of fH (Tyr402His). These data may open new avenues for AMD treatment strategies. ..
  11. Griffiss J, Jarvis G, O BRIEN J, Eads M, Schneider H. Lysis of Neisseria gonorrhoeae initiated by binding of normal human IgM to a hexosamine-containing lipooligosaccharide epitope(s) is augmented by strain-specific, properdin-binding-dependent alternative complement pathway activation. J Immunol. 1991;147:298-305 pubmed
  12. Lynch A, Murphy J, Byers T, Gibbs R, Neville M, Giclas P, et al. Alternative complement pathway activation fragment Bb in early pregnancy as a predictor of preeclampsia. Am J Obstet Gynecol. 2008;198:385.e1-9 pubmed publisher
    ..This observation suggests that events linked to activation of complement in early pregnancy are associated with the pathogenesis of preeclampsia. ..
  13. Hourcade D, Mitchell L, Medof M. Decay acceleration of the complement alternative pathway C3 convertase. Immunopharmacology. 1999;42:167-73 pubmed
    ..An understanding of the biochemical mechanisms providing for their activities would be helpful for the therapeutic control of the complement response. ..
  14. Jiang H, Wagner E, Zhang H, Frank M. Complement 1 inhibitor is a regulator of the alternative complement pathway. J Exp Med. 2001;194:1609-16 pubmed
    We studied complement 1 inhibitor (C1-INH) as an inhibitor of the alternative complement pathway. C1-INH prevented lysis, induced by the alternative complement pathway, of paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes in human ..
  15. Oksjoki R, Kovanen P, Mäyränpää M, Laine P, Blom A, Meri S, et al. Complement regulation in human atherosclerotic coronary lesions. Immunohistochemical evidence that C4b-binding protein negatively regulates the classical complement pathway, and that C5b-9 is formed via the alternative complement pathway. Atherosclerosis. 2007;192:40-8 pubmed
    ..but, instead, colocalized with properdin deeper in the intima, suggesting that C5b-9 is formed by the alternative complement pathway. A fraction of C4bp was associated with protein S and apoptotic cells...
  16. Yuste J, Ali S, Sriskandan S, Hyams C, Botto M, Brown J. Roles of the alternative complement pathway and C1q during innate immunity to Streptococcus pyogenes. J Immunol. 2006;176:6112-20 pubmed
    ..pyogenes and suggest that C1q-mediated innate immunity to at least some strains of S. pyogenes may involve mechanisms that are independent of C3b on the bacteria. ..
  17. Sahu A, Isaacs S, Soulika A, Lambris J. Interaction of vaccinia virus complement control protein with human complement proteins: factor I-mediated degradation of C3b to iC3b1 inactivates the alternative complement pathway. J Immunol. 1998;160:5596-604 pubmed
    ..These results suggest that the interaction of VCP with C3 is different from that of factor H and CR1 and that VCP-supported first cleavage of C3b by factor I is sufficient to render C3b nonfunctional. ..
  18. Devaux P, Christiansen D, Plumet S, Gerlier D. Cell surface activation of the alternative complement pathway by the fusion protein of measles virus. J Gen Virol. 2004;85:1665-73 pubmed
    ..The C3b/C3bi coating of MV-infected cells and virus should ensure enhanced targeting of MV antigens to the immune system, through binding to complement receptors. ..
  19. Boyajyan A, Khoyetsyan A, Chavushyan A. Alternative complement pathway in schizophrenia. Neurochem Res. 2010;35:894-8 pubmed publisher
    ..Based upon the results obtained we hypothesize that hyperactivation of the alternative complement pathway in schizophrenia is stimulated by apoptotic cells.
  20. Taube C, Thurman J, Takeda K, Joetham A, Miyahara N, Carroll M, et al. Factor B of the alternative complement pathway regulates development of airway hyperresponsiveness and inflammation. Proc Natl Acad Sci U S A. 2006;103:8084-9 pubmed
    ..a critical component of the classical pathway, or factor B (fB-/-), an essential protein in the alternative complement pathway. WT, C4-/-, and fB-/- mice were sensitized to ovalbumin and subsequently exposed to nebulized ..
  21. Licht C, Heinen S, Jozsi M, Löschmann I, Saunders R, Perkins S, et al. Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int. 2006;70:42-50 pubmed
    ..H protein is considered relevant for unrestricted activation of the disease-causing activation of the alternative complement pathway. Replacement of functional Factor H by fresh frozen plasma (10-15 ml/kg/14 days) was well tolerated, ..
  22. Katschke K, Stawicki S, Yin J, Steffek M, Xi H, Sturgeon L, et al. Structural and functional analysis of a C3b-specific antibody that selectively inhibits the alternative pathway of complement. J Biol Chem. 2009;284:10473-9 pubmed publisher
    ..This study for the first time demonstrates the structural basis for complement inhibition by a C3b-selective antibody and provides insights into the molecular mechanisms of alternative pathway complement activation. ..
  23. Peake P, Kriketos A, Campbell L, Charlesworth J. Response of the alternative complement pathway to an oral fat load in first-degree relatives of subjects with type II diabetes. Int J Obes (Lond). 2005;29:429-35 pubmed
    ..These data do not support an essential requirement of the hypothesis that ASP is produced in response to the intake of fat. ..
  24. Watanabe H, Garnier G, Circolo A, Wetsel R, Ruiz P, Holers V, et al. Modulation of renal disease in MRL/lpr mice genetically deficient in the alternative complement pathway factor B. J Immunol. 2000;164:786-94 pubmed
    ..Although the alternative complement pathway is activated in lupus nephritis, its role in disease pathogenesis is unknown...
  25. Chava A, Chatterjee M, Sharma V, Sundar S, Mandal C. Variable degree of alternative complement pathway-mediated hemolysis in Indian visceral leishmaniasis induced by differential expression of 9-O-acetylated sialoglycans. J Infect Dis. 2004;189:1257-64 pubmed
    ..We assessed the capacity of this glycotope to influence hemolysis via activation of the alternative complement pathway in patients with VL, compared with that in healthy control subjects...
  26. Yancey K, Overholser O, Domloge Hultsch N, Li L, Caughman S, Bisalbutra P. Human keratinocytes and A-431 cells synthesize and secrete factor B, the major zymogen protease of the alternative complement pathway. J Invest Dermatol. 1992;98:379-83 pubmed
  27. Goicoechea de Jorge E, Harris C, Esparza Gordillo J, Carreras L, Arranz E, Garrido C, et al. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci U S A. 2007;104:240-5 pubmed
    ..of the genetic factors conferring predisposition to aHUS, demonstrate the critical role of the alternative complement pathway in the pathogenesis of aHUS, and provide support for the use of complement-inhibition therapies to ..
  28. Banda N, Thurman J, Kraus D, Wood A, Carroll M, Arend W, et al. Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen-induced arthritis. J Immunol. 2006;177:1904-12 pubmed
    ..The mechanisms by which these target organ-specific mAbs bypass the requirements for engagement of the classical pathway remain to be defined but do not appear to involve a lack of alternative pathway regulatory proteins. ..
  29. Thurman J, Ljubanovic D, Edelstein C, Gilkeson G, Holers V. Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. J Immunol. 2003;170:1517-23 pubmed
    ..Our results demonstrate that complement activation in the kidney after I/R occurs exclusively via the alternative pathway, and that selective inhibition of this pathway provides protection to the kidneys from ischemic ARF. ..
  30. Sprong T, Roos D, Weemaes C, Neeleman C, Geesing C, Mollnes T, et al. Deficient alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the complement factor D gene in a family with meningococcal infections. Blood. 2006;107:4865-70 pubmed
    ..This deficiency abolishes alternative-pathway dependent complement activation by N meningitidis, and leads to an increased susceptibility to invasive meningococcal disease. ..
  31. Thurman J, Holers V. The central role of the alternative complement pathway in human disease. J Immunol. 2006;176:1305-10 pubmed
    ..Herein we examine recent evidence that the alternative complement pathway plays a key and, in most instances, obligate role in generating proinflammatory complement activation ..
  32. Seelen M, Roos A, Wieslander J, Mollnes T, Sjoholm A, Wurzner R, et al. Functional analysis of the classical, alternative, and MBL pathways of the complement system: standardization and validation of a simple ELISA. J Immunol Methods. 2005;296:187-98 pubmed
    ..The results demonstrate the value of these ELISA-based procedures for the functional assessment of complement deficiencies in clinical practice. The assay is now available commercially in kit form. ..
  33. Jiang H, Wang Z, Serra D, Frank M, Amalfitano A. Recombinant adenovirus vectors activate the alternative complement pathway, leading to the binding of human complement protein C3 independent of anti-ad antibodies. Mol Ther. 2004;10:1140-2 pubmed
    ..These reactions can progress rapidly and are factors important in serious complications, including the systemic inflammatory response syndrome and the adult respiratory distress syndrome. ..
  34. Recinos A, Carr B, Bartos D, Boldogh I, Carmical J, Belalcazar L, et al. Liver gene expression associated with diet and lesion development in atherosclerosis-prone mice: induction of components of alternative complement pathway. Physiol Genomics. 2004;19:131-42 pubmed
    ..0005] were involved in lipid metabolism. In addition, we identified components of the alternative complement pathway, including C3, properdin, and factor D, for which mRNA levels were independently confirmed by ..
  35. Rosen B, Cook K, Yaglom J, Groves D, Volanakis J, Damm D, et al. Adipsin and complement factor D activity: an immune-related defect in obesity. Science. 1989;244:1483-7 pubmed
    ..These results suggest that adipsin and the alternative pathway of complement may play an unexpected but important role in the regulation of systemic energy balance in vivo. ..
  36. Shimizu S, Kitada H, Yokota H, Yamakawa J, Murayama T, Sugiyama K, et al. Activation of the alternative complement pathway by Agaricus blazei Murill. Phytomedicine. 2002;9:536-45 pubmed
    ..Further, the resident human peripheral nucleated cells incubated in the presence of iC3b-ABP-F complexes inhibited the proliferation of human tumor cell line TPC-1 in vitro. ..
  37. Rosas A, MacGill R, Nosanchuk J, Kozel T, Casadevall A. Activation of the alternative complement pathway by fungal melanins. Clin Diagn Lab Immunol. 2002;9:144-8 pubmed
  38. Harboe M, Mollnes T. The alternative complement pathway revisited. J Cell Mol Med. 2008;12:1074-84 pubmed publisher
  39. Banda N, Takahashi K, Wood A, Holers V, Arend W. Pathogenic complement activation in collagen antibody-induced arthritis in mice requires amplification by the alternative pathway. J Immunol. 2007;179:4101-9 pubmed
    ..These results indicate that the alternative pathway amplification loop, with its ability to greatly enhance C3 activation, is necessary to mediate inflammatory arthritis induced by adherent immune complexes. ..
  40. Pyaram K, Kieslich C, Yadav V, Morikis D, Sahu A. Influence of electrostatics on the complement regulatory functions of Kaposica, the complement inhibitor of Kaposi's sarcoma-associated herpesvirus. J Immunol. 2010;184:1956-67 pubmed publisher
    ..Together, our data provide functional relevance to conservation of positive potential in CCPs 1 and 4 and the linkers of viral complement regulators. ..
  41. Kenney D, Davis A. Association of alternative complement pathway components with human blood platelets: secretion and localization of factor D and beta 1H Globulin. Clin Immunol Immunopathol. 1981;21:351-63 pubmed
  42. Soriano E, Fischman D, Cheriyath P. Membranoproliferative glomerulonephritis in patients with cystic fibrosis: coincidence or comorbidity? A case series. South Med J. 2008;101:641-5 pubmed publisher
    ..Diagnostic evaluation likewise confirmed the MPGN diagnosis. Immunologic associations linking CF and MPGN, including derangements in the complement system and the effects of superantigen production, are reviewed. ..
  43. Kumar K, Ponsuksili S, Schellander K, Wimmers K. Molecular cloning and sequencing of porcine C5 gene and its association with immunological traits. Immunogenetics. 2004;55:811-7 pubmed
    ..Association of C5 with complement activity traits and acute phase proteins promotes pC5 as a candidate gene for innate disease resistance. ..
  44. Brook E, Herbert A, Jenkins H, Soares D, Barlow P. Opportunities for new therapies based on the natural regulators of complement activation. Ann N Y Acad Sci. 2005;1056:176-88 pubmed
  45. Skelly P. Intravascular schistosomes and complement. Trends Parasitol. 2004;20:370-4 pubmed
    ..In addition, a surface Fc receptor might bind immunoglobulin and limit its ability to fix complement. However, the actual protective role of these proteins in vivo remains unresolved. ..
  46. Ritchie G, Moffatt B, Sim R, Morgan B, Dwek R, Rudd P. Glycosylation and the complement system. Chem Rev. 2002;102:305-20-19 pubmed
  47. Hui K, Magnadottir B, Schifferli J, Inal J. CRIT peptide interacts with factor B and interferes with alternative pathway activation. Biochem Biophys Res Commun. 2006;344:308-14 pubmed
    ..Binding of CRIT-H17 to FB did not interfere with the assembly of C3bB complex. In a haemolytic assay using C2-deficient serum, CRIT-H17 interfered with AP complement activation. ..
  48. Huemer H, Wechselberger C, Bennett A, Falke D, Harrington L. Cloning and expression of the complement receptor glycoprotein C from Herpesvirus simiae (herpes B virus): protection from complement-mediated cell lysis. J Gen Virol. 2003;84:1091-100 pubmed
    ..gC(SHBV) isolated from protein-free culture supernatants did not interfere with the binding of the alternative complement pathway activator properdin to C3b, which is similar to our findings with gC(HSV-2) and could be attributed to ..
  49. Jokiranta T, Solomon A, Pangburn M, Zipfel P, Meri S. Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H. J Immunol. 1999;163:4590-6 pubmed
    ..Thus, the lambda light chain dimer LOI represents the first described pathogenic miniautoantibody in human disease. ..
  50. Xu Y, Narayana S, Volanakis J. Structural biology of the alternative pathway convertase. Immunol Rev. 2001;180:123-35 pubmed
    ..Both mechanisms contribute to the regulation of the proteolytic activity of these enzymes. Additional studies are necessary for a complete description of the elegant mechanisms mediating these processes. ..
  51. Pangburn M. Analysis of the natural polymeric forms of human properdin and their functions in complement activation. J Immunol. 1989;142:202-7 pubmed
  52. Pascual M, Paccaud J, Macon K, Volanakis J, Schifferli J. Complement activation by the alternative pathway is modified in renal failure: the role of factor D. Clin Nephrol. 1989;32:185-93 pubmed
    ..g., C5a produced during hemodialysis), while others might be beneficial, e.g., solubilization of immune precipitates. ..
  53. Zipfel P, Heinen S, Jozsi M, Skerka C. Complement and diseases: defective alternative pathway control results in kidney and eye diseases. Mol Immunol. 2006;43:97-106 pubmed
    ..These scenarios explain how defects of a single regulator lead to local, organ specific damage. ..