classical complement pathway


Summary: Complement activation initiated by the binding of COMPLEMENT C1 to ANTIGEN-ANTIBODY COMPLEXES at the COMPLEMENT C1Q subunit. This leads to the sequential activation of COMPLEMENT C1R and COMPLEMENT C1S subunits. Activated C1s cleaves COMPLEMENT C4 and COMPLEMENT C2 forming the membrane-bound classical C3 CONVERTASE (C4B2A) and the subsequent C5 CONVERTASE (C4B2A3B) leading to cleavage of COMPLEMENT C5 and the assembly of COMPLEMENT MEMBRANE ATTACK COMPLEX.

Top Publications

  1. Fischer M, Ma M, Goerg S, Zhou X, Xia J, Finco O, et al. Regulation of the B cell response to T-dependent antigens by classical pathway complement. J Immunol. 1996;157:549-56 pubmed
    ..e., C3b and C3d to the Ag-Ab complex, increases its immunogenicity. ..
  2. Mevorach D, Mascarenhas J, Gershov D, Elkon K. Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med. 1998;188:2313-20 pubmed
  3. Csencsits K, Burrell B, Lu G, Eichwald E, Stahl G, Bishop D. The classical complement pathway in transplantation: unanticipated protective effects of C1q and role in inductive antibody therapy. Am J Transplant. 2008;8:1622-30 pubmed publisher
    ..In contrast, the protective effects of anti-CD40L mAb were less compromised in C1q-/- recipients. Hence, this study reveals unanticipated roles for C1q in the rejection process. ..
  4. Abdullah M, Nepluev I, Afonina G, Ram S, Rice P, Cade W, et al. Killing of dsrA mutants of Haemophilus ducreyi by normal human serum occurs via the classical complement pathway and is initiated by immunoglobulin M binding. Infect Immun. 2005;73:3431-9 pubmed
    ..We speculate that an undefined neo-epitope, possibly carbohydrate, is exposed in the dsrA mutant that is recognized by naturally occurring bactericidal IgM antibodies present in human sera. ..
  5. Krych Goldberg M, Hauhart R, Porzukowiak T, Atkinson J. Synergy between two active sites of human complement receptor type 1 (CD35) in complement regulation: implications for the structure of the classical pathway C3 convertase and generation of more potent inhibitors. J Immunol. 2005;175:4528-35 pubmed
    ..These observations increase our understanding of the mechanism of DAA. In addition, a more potent decay-accelerating form of CR1 was generated. ..
  6. Brown J, Hussell T, Gilliland S, Holden D, Paton J, Ehrenstein M, et al. The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice. Proc Natl Acad Sci U S A. 2002;99:16969-74 pubmed
    ..The classical complement pathway is activated by antibody-antigen complexes on the bacterial surface and has been considered ..
  7. Roos A, Nauta A, Broers D, Faber Krol M, Trouw L, Drijfhout J, et al. Specific inhibition of the classical complement pathway by C1q-binding peptides. J Immunol. 2001;167:7052-9 pubmed
    ..We aim for prevention of complement-mediated damage by specific inhibition of the classical complement pathway, thus not affecting the antimicrobial functions of the complement system via the alternative pathway ..
  8. Celik I, Stover C, Botto M, Thiel S, Tzima S, Kunkel D, et al. Role of the classical pathway of complement activation in experimentally induced polymicrobial peritonitis. Infect Immun. 2001;69:7304-9 pubmed
  9. Christadoss P, Tuzun E, Li J, Saini S, Yang H. Classical complement pathway in experimental autoimmune myasthenia gravis pathogenesis. Ann N Y Acad Sci. 2008;1132:210-9 pubmed publisher
    ..Therefore, EAMG/MG could be treated by blocking the activation of classical complement pathway (CCP) and/or IL-6...

More Information


  1. Garcia Hernandez P, Rodero M, Cuellar C. Study of the effect of Anisakis simplex larval products on the early and late components in the classical complement pathway. J Parasitol. 2009;95:240-1 pubmed publisher
    ..Therefore, CE and ES products from A. simplex interact with C3 and C2 complement proteins, which are early components of the complement system, but not with the late complement components. ..
  2. Shaio M, Hou S, Chen J, Wu C, Yang K, Chang F. Immunoglobulin G-dependent classical complement pathway activation in neutrophil-mediated cytotoxicity to infective larvae of Angiostrongylus cantonensis. Ann Trop Med Parasitol. 1990;84:185-91 pubmed
    ..The results of this study indicate that the neutrophil-mediated adherence and cytotoxicity to L3 of A. cantonensis are mediated through IgG-dependent classical complement pathway activation.
  3. Morris J, Francois C, OLSON P, Cotton B, Summar M, Jenkins J, et al. Genetic variation in complement component 2 of the classical complement pathway is associated with increased mortality and infection: a study of 627 patients with trauma. J Trauma. 2009;66:1265-70; discussion 1270-2 pubmed publisher
  4. Spiller O, Morgan B. Antibody-independent activation of the classical complement pathway by cytomegalovirus-infected fibroblasts. J Infect Dis. 1998;178:1597-603 pubmed
    ..CMV-infected fibroblasts activated via the classical complement pathway independent of specific anti-CMV antibody and incubation of CMV-infected fibroblasts with serum ..
  5. Barilla LaBarca M, Liszewski M, Lambris J, Hourcade D, Atkinson J. Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells. J Immunol. 2002;168:6298-304 pubmed
    ..However, if the alternative pathway mediates C3b deposition, then MCP's cofactor activity is sufficient to restrict complement activation. ..
  6. Wouters D, Voskuyl A, Molenaar E, Dijkmans B, Hack C. Evaluation of classical complement pathway activation in rheumatoid arthritis: measurement of C1q-C4 complexes as novel activation products. Arthritis Rheum. 2006;54:1143-50 pubmed
    ..that are stable and minimally susceptible to in vitro artefacts have recently been described in the classical complement pathway. The present study assessed circulating levels of these products, i.e...
  7. Li K, Sacks S, Sheerin N. The classical complement pathway plays a critical role in the opsonisation of uropathogenic Escherichia coli. Mol Immunol. 2008;45:954-62 pubmed
    ..In conclusion, uropathogenic E. coli are readily opsonised by complement in a classical pathway dependent manner. This can occur within the urinary tract during the development of clinical infection. ..
  8. Bastian F, Stelzmüller M, Kratochwill K, Kasimir M, Simon P, Weigel G. IgG deposition and activation of the classical complement pathway involvement in the activation of human granulocytes by decellularized porcine heart valve tissue. Biomaterials. 2008;29:1824-32 pubmed publisher
    ..of decellularized porcine tissue with human plasma led to adsorption of IgG, activation of the classical complement pathway and adhesion of activated polymorphonuclear leukocytes (PMN)...
  9. Hwang H, Duvall M, Tomlinson S, Boackle R. Highly specific inhibition of C1q globular-head binding to human IgG: a novel approach to control and regulate the classical complement pathway using an engineered single chain antibody variable fragment. Mol Immunol. 2008;45:2570-80 pubmed publisher selectively elucidating, differentiating, inducing or inhibiting specific roles of human C1q and the classical complement pathway in complement-mediated physiological processes...
  10. 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
  11. Hoshino A, Nagao T, Nagi Miura N, Ohno N, Yasuhara M, Yamamoto K, et al. MPO-ANCA induces IL-17 production by activated neutrophils in vitro via classical complement pathway-dependent manner. J Autoimmun. 2008;31:79-89 pubmed publisher
    ..that the activated neutrophils produce IL-17A and IL-23 in response to MPO-ANCA via their Fc-region and classical complement pathway, which initiate the first steps of chronic autoimmune inflammation by allowing the local environment to ..
  12. Courtois A, Simon Colin C, Boisset C, Berthou C, Deslandes E, Guezennec J, et al. Floridoside extracted from the red alga Mastocarpus stellatus is a potent activator of the classical complement pathway. Mar Drugs. 2008;6:407-17 pubmed publisher
    ..immune response in human xenografts and is mediated by natural anti-gal antibodies that activate the classical complement pathway. Based on this property, we analyzed the potential activities of floridoside on the immune system...
  13. Ying S, Gewurz A, Jiang H, Gewurz H. Human serum amyloid P component oligomers bind and activate the classical complement pathway via residues 14-26 and 76-92 of the A chain collagen-like region of C1q. J Immunol. 1993;150:169-76 pubmed
    ..Thus, SAP oligomers bind C1q and activate the classical C pathway via the collagen-like region of C1q, at sites located within residues 14-26 and/or 76-92 of the C1q A chain. ..
  14. Prohaszka Z, Nemet K, Csermely P, Hudecz F, Mezo G, Fust G. Defensins purified from human granulocytes bind C1q and activate the classical complement pathway like the transmembrane glycoprotein gp41 of HIV-1. Mol Immunol. 1997;34:809-16 pubmed
  15. Cutler A, Cornall R, Ferry H, Manderson A, Botto M, Walport M. Intact B cell tolerance in the absence of the first component of the classical complement pathway. Eur J Immunol. 2001;31:2087-93 pubmed
  16. Mitchell D, Taylor P, Cook H, Moss J, Bygrave A, Walport M, et al. Cutting edge: C1q protects against the development of glomerulonephritis independently of C3 activation. J Immunol. 1999;162:5676-9 pubmed
  17. Yuste J, Sen A, Truedsson L, Jonsson G, Tay L, Hyams C, et al. Impaired opsonization with C3b and phagocytosis of Streptococcus pneumoniae in sera from subjects with defects in the classical complement pathway. Infect Immun. 2008;76:3761-70 pubmed publisher specific complement factors and clinical data on patients with an inherited deficiency of the classical complement pathway component C2 suggest that the classical pathway is vital for immunity to Streptococcus pneumoniae...
  18. 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
    ..We studied the presence and localization of C4b-binding protein (C4bp), the major inhibitor of the classical complement pathway, in human atherosclerotic lesions in relation to complement activation products and protein S, which ..
  19. Nayak A, Ferluga J, Tsolaki A, Kishore U. The non-classical functions of the classical complement pathway recognition subcomponent C1q. Immunol Lett. 2010;131:139-50 pubmed publisher
    C1q, the ligand recognition subcomponent of the classical complement pathway has steadily been gaining recognition as a bridge between innate and adaptive immunity...
  20. Zhang J, Li G, Liu X, Wang Z, Liu W, Ye X. Influenza A virus M1 blocks the classical complement pathway through interacting with C1qA. J Gen Virol. 2009;90:2751-8 pubmed publisher
    ..that M1 is able to interact with complement C1qA and plays an important inhibitory function in the classical complement pathway. The N-terminal domain of M1 protein was required for its binding to the globular region of C1qA...
  21. Navratil J, Korb L, Ahearn J. Systemic lupus erythematosus and complement deficiency: clues to a novel role for the classical complement pathway in the maintenance of immune tolerance. Immunopharmacology. 1999;42:47-52 pubmed
  22. Blom A, Villoutreix B, Dahlback B. Complement inhibitor C4b-binding protein-friend or foe in the innate immune system?. Mol Immunol. 2004;40:1333-46 pubmed
    ..This contributes to the serum resistance and the pathogenicity of these bacteria. In this review, the structural requirements and functional importance of the interactions between C4BP and its various ligands are discussed. ..
  23. Bruins P, te Velthuis H, Eerenberg Belmer A, Yazdanbakhsh A, de Beaumont E, Eijsman L, et al. Heparin-protamine complexes and C-reactive protein induce activation of the classical complement pathway: studies in patients undergoing cardiac surgery and in vitro. Thromb Haemost. 2000;84:237-43 pubmed
    ..bypass (CPB) to neutralize heparin and to reduce the risk of bleeding, induces activation of the classical complement pathway mainly by heparin-protamine complexes...
  24. Matheswaran K, Dhinakar Raj G, Nachimuthu K. Demonstration of alternative and classical complement pathway activity in colostrum from buffalo (Bubalus bubalis). Vet Res Commun. 2003;27:445-52 pubmed
    ..06 to 8.48 CH50 units/ml. Using a standard system for titrating the classical complement pathway and rabbit red blood cells sensitized with goat haemolysin, the range of complement activity in buffalo ..
  25. Matsushita M, Matsushita A, Endo Y, Nakata M, Kojima N, Mizuochi T, et al. Origin of the classical complement pathway: Lamprey orthologue of mammalian C1q acts as a lectin. Proc Natl Acad Sci U S A. 2004;101:10127-31 pubmed
    The lectin complement pathway in innate immunity is closely related to the classical complement pathway in adaptive immunity, with respect to the structures and functions of their components...
  26. Kaneko Y, Takashima Y, Xuaun X, Igarashi I, Nagasawa H, Mikami T, et al. Natural IgM antibodies in sera from various animals but not the cat kill Toxoplasma gondii by activating the classical complement pathway. Parasitology. 2004;128:123-9 pubmed
    ..Swine and rabbit sera contained natural IgM antibody against the tachyzoites, and the classical complement pathway was activated by the binding of natural IgM antibody to the tachyzoites, leading to lysis. Anti-T...
  27. Tuzun E, Scott B, Goluszko E, Higgs S, Christadoss P. Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis. J Immunol. 2003;171:3847-54 pubmed
    ..The data provide the first direct genetic evidence for the classical complement pathway in the induction of EAMG induced by AChR immunization...
  28. Engelkens H, Kant M, Onvlee P, Stolz E, van der Sluis J. Rapid in vitro immobilisation of purified Treponema pallidum (Nichols strain), and protection by extraction fluids from rabbit testes. Genitourin Med. 1990;66:367-73 pubmed
    ..the protection offered to the purified treponemes by the testicular extracts is based on their deteriorating effect on the classical complement pathway or is due to a re-establishment of the protective cover around the treponemes.
  29. Banda N, Levitt B, Wood A, Takahashi K, Stahl G, Holers V, et al. Complement activation pathways in murine immune complex-induced arthritis and in C3a and C5a generation in vitro. Clin Exp Immunol. 2010;159:100-8 pubmed publisher
    ..We conclude that neither the CP nor LP alone is capable of mediating CAIA in vivo and that mouse sera exhibits a high level of IgG-induced C5a generation in vitro through either the CP or AP. ..
  30. Fiane A, Videm V, Johansen H, Mellbye O, Nielsen E, Mollnes T. C1-inhibitor attenuates hyperacute rejection and inhibits complement, leukocyte and platelet activation in an ex vivo pig-to-human perfusion model. Immunopharmacology. 1999;42:231-43 pubmed
    ..C1-INH may be useful to attenuate hyperacute rejection, probably through inhibition of complement. The reduced activation of neutrophils and platelets may mainly be secondary to inhibition of complement. ..
  31. Petri W, Haque R, Mann B. The bittersweet interface of parasite and host: lectin-carbohydrate interactions during human invasion by the parasite Entamoeba histolytica. Annu Rev Microbiol. 2002;56:39-64 pubmed
    ..The structure and function of the lectin that controls these divergent cell biologic processes are the subject of this review. ..
  32. Walpen A, Laumonier T, Aebi C, Mohacsi P, Rieben R. Immunoglobulin M-enriched intravenous immunoglobulin inhibits classical pathway complement activation, but not bactericidal activity of human serum. Xenotransplantation. 2004;11:141-8 pubmed
    ..coli by human serum. In conclusion, IgM-enriched IVIg is a specific inhibitor of the classical complement pathway, leaving the alternative pathway intact, which is an important natural anti-bacterial defense, ..
  33. Bloch E, Morrison K, McDonald Pinkett S, Baskin S, Campbell S, Peters S, et al. The deposition of C5b-9 complexes and its precursors on E. coli J5 during complement activation enhances uptake and toxicities of gentamicin. Immunol Invest. 2008;37:245-61 pubmed publisher
    ..Since C5b and C5b6 do not form pores, we suggest that disturbances and or cracks in the outer membrane by the deposited complexes accelerates uptake of the antibiotics and enhanced killing of E. coli J5 employed in these studies. ..
  34. Kang Y, Tan L, Carroll M, Gentle M, Sim R. Target pattern recognition by complement proteins of the classical and alternative pathways. Adv Exp Med Biol. 2009;653:117-28 pubmed
    ..The recognition protein of the complement classical pathway, C1q is described in detail here, with comparisons to the alternative pathway. ..
  35. Nielsen C, Pedersen M, Marquart H, Prodinger W, Leslie R. The role of complement receptors type 1 (CR1, CD35) and 2 (CR2, CD21) in promoting C3 fragment deposition and membrane attack complex formation on normal peripheral human B cells. Eur J Immunol. 2002;32:1359-67 pubmed
    ..On the other hand, the presence of extrinsic CR1, on E, may serve to limit spontaneous MAC formation and thereby ensure cell survival in the circulation. ..
  36. Shelton G, Hoffman E, Ghimbovschi S, Peters I, Day M, Mullins M, et al. Immunopathogenic pathways in canine inflammatory myopathies resemble human myositis. Vet Immunol Immunopathol. 2006;113:200-14 pubmed
    ..This study strengthens the argument that forms of canine myositis may be important animal models of human myositis and suggests useful biomarkers for therapeutic response using the dog in pre-clinical trials. ..
  37. Malbran A, Parra L, Casas J, Malbrán E, Yeyati E, Magariños G, et al. Case report: diffuse plane xanthoma with low C4 and systemic inflammatory symptoms. Dermatol Online J. 2009;15:5 pubmed
    ..A normolipemic patient with diffuse plane xanthomas, IgG monoclonal gammopathy of unknown significance, low levels of C4, and systemic inflammatory symptoms is presented. Delay from disease onset to diagnosis is discussed. ..
  38. Davies C, Harris C, Morgan B. Glycation of CD59 impairs complement regulation on erythrocytes from diabetic subjects. Immunology. 2005;114:280-6 pubmed
    ..These data implicate glycation-induced inactivation of CD59 as a factor contributing to anaemia in type 1 diabetes. ..
  39. Richards A, Kavanagh D, Atkinson J. Inherited complement regulatory protein deficiency predisposes to human disease in acute injury and chronic inflammatory statesthe examples of vascular damage in atypical hemolytic uremic syndrome and debris accumulation in age-related macular degene. Adv Immunol. 2007;96:141-77 pubmed
    ..A response to acute injury or chronic debris accumulation must be appropriately balanced. In either case, too much activation or too little regulation promotes undesirable tissue damage and human disease. ..
  40. Avirutnan P, Fuchs A, Hauhart R, Somnuke P, Youn S, Diamond M, et al. Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. J Exp Med. 2010;207:793-806 pubmed publisher
    ..Through this mechanism, NS1 protects DENV from complement-dependent neutralization in solution. These studies define a novel immune evasion mechanism for restricting complement control of microbial infection...
  41. Ikeda K, Sannoh T, Kawasaki N, Kawasaki T, Yamashina I. Serum lectin with known structure activates complement through the classical pathway. J Biol Chem. 1987;262:7451-4 pubmed
  42. Bergamaschini L, Canziani S, Bottasso B, Cugno M, Braidotti P, Agostoni A. Alzheimer's beta-amyloid peptides can activate the early components of complement classical pathway in a C1q-independent manner. Clin Exp Immunol. 1999;115:526-33 pubmed
  43. Parmentier H, Baelmans R, Savelkoul H, Dorny P, Demey F, Berkvens D. Serum haemolytic complement activities in 11 different MHC (B) typed chicken lines. Vet Immunol Immunopathol. 2004;100:25-32 pubmed
    ..Our results suggest that levels of haemolytic complement activity, either from the classical or from the alternative pathways, may underlie part of the immunocompetence ascribed to the MHC (B) complex in chickens. ..
  44. Lin T, Zhou W, Farrar C, Hargreaves R, Sheerin N, Sacks S. Deficiency of C4 from donor or recipient mouse fails to prevent renal allograft rejection. Am J Pathol. 2006;168:1241-8 pubmed
  45. Popadiak K, Potempa J, Riesbeck K, Blom A. Biphasic effect of gingipains from Porphyromonas gingivalis on the human complement system. J Immunol. 2007;178:7242-50 pubmed
    ..At later stages of infection the concentration of proteases is high enough to destroy complement factors and thus render the bacteria resistant to the bactericidal activity of complement. ..
  46. Dutta R, Mondal A, Arora V, Nag T, Das N. Immunomodulatory effect of DDT (bis[4-chlorophenyl]-1,1,1-trichloroethane) on complement system and macrophages. Toxicology. 2008;252:78-85 pubmed publisher
  47. Jacobson A, Weis J. Comparative functional evolution of human and mouse CR1 and CR2. J Immunol. 2008;181:2953-9 pubmed
  48. Libert N, Scherier S, Dubost C, Franck L, Rouquette I, Tortosa J, et al. [Anaesthesic management of vaginal delivery in a parturient with C1 esterase deficiency]. Ann Fr Anesth Reanim. 2009;28:375-80 pubmed publisher
    ..The management included administration of C1 INH during labor and early epidural analgesia for pain relief. A short review of the pathophysiology and therapeutic options follows. ..
  49. Zhang M, Cutler J, Han Y, Kozel T. Contrasting roles of mannan-specific monoclonal immunoglobulin M antibodies in the activation of classical and alternative pathways by Candida albicans. Infect Immun. 1998;66:6027-9 pubmed
    Polyclonal antimannan immunoglobulin G (IgG) activates the classical complement pathway and accelerates initiation of the alternative pathway by Canidida albicans...
  50. Wu P, Lin G, Kang X, Yuan H, Shen Y. Complement activation by carotenoid derived aldehydes in cultured human vein epithelial cells. Phytother Res. 2009;23:1696-700 pubmed publisher
    ..The results revealed that CDA could activate the complement by way of the classical pathway. The study suggests that high carotenoid supplementation for the treatment of coronary heart disease should be used cautiously. ..
  51. Szebeni J. Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity. Toxicology. 2005;216:106-21 pubmed
    ..Overall, the CARPA concept may help in the prediction, prevention and treatment of the acute immune toxicity of numerous state-of-the-art drugs. ..
  52. Zhang T, Chen D. Anticomplementary principles of a Chinese multiherb remedy for the treatment and prevention of SARS. J Ethnopharmacol. 2008;117:351-61 pubmed publisher
    ..Luteolin could be a potential anticomplementary agent. ..
  53. Watanabe T, Sato Y. Renal involvement and hypocomplementemia in a patient with acute hemorrhagic edema of infancy. Pediatr Nephrol. 2007;22:1979-81 pubmed
    ..We suggest that activation of the classical pathway of complement might be one of the pathogenic mechanisms underlying the development of AHEI. ..