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Article:Classical complement pathway
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Classical Complement Pathway Draft

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Lead

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Figure 1 Classical and alternative pathways shown with their corresponding proteins.

The classical complement pathway is one of three complement pathways which can activate the complement system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM.[1][2] Following activation, a series of proteins are recruited to generate C3 convertase (C4bC2a), which cleaves the C3 protein. The C3b component of the cleaved C3 binds to C3 convertase (C4bC2a) to generate C5 convertase (C4bC2aC3b). The C5 convertase initiates the terminal phase of the complement system, leading to the assembly of the membrane attack complex (MAC). The membrane attack complex creates a pore on the target cell's membrane, inducing cell lysis and death.[2][3]

The classical complement pathway can also be activated by apoptotic cells, necrotic cells, and acute phase proteins.[1][3][4]

Complement Cascade

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The classical pathway is distinct from the other complement pathways in its unique activation triggers and cascade sequence. Activation of the complement pathway through the classical, lectin or alternative complement pathway is followed by a cascade of reactions eventually leading to the membrane attack complex.

Initiation

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The classical complement pathway can be initiated by the binding of antigen-antibody complexes to the C1q protein. The globular regions of C1q recognize and bind to the Fc region of antibody isotypes IgG or IgM.[2] These globular regions of C1q can also bind to bacterial and viral surface proteins, apoptotic cells, and acute phase proteins.[5] In the absence of these activation factors, C1q is part of the inactive C1 complex which consists of six molecules of C1q, two molecules of C1r, and two molecules of C1s .[1][4]

 
Figure 2 The classical complement pathway leading into a complement cascade that is shared with the alternative pathway.

Formation of C3 convertase

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The binding of C1q leads to conformational changes and the activation of the serine protease C1r. The activated C1r then cleaves and activates the serine protease C1s.[3][4] The activated C1s cleaves C4 into C4a and C4b, and C2 into C2a and C2b.[6] The larger and active fragments, C4b and C2a form C4bC2a, a C3 convertase.[2] C3 convertase then cleaves C3 into C3a and C3b. While the anaphylatoxin C3a interacts with its C3a receptor (C3aR) to recruit leukocytes, C3a contributes to further downstream complement activation.[1][3]

Formation of C5 convertase and MAC

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C3b binds to to the C3 convertase (C4bC2a), to form C5 convertase (C4bC2aC3b). C5 convertase then cleaves C5 into C5a and C5b.[3] Like C3a, C5a is also an anaphylatoxin with interacts with its cognate C5a receptor (C5aR) to attract leukocytes.[1] Subsequent interactions between C5b and other terminal components C6, C7, C8, and C9 form the membrane attack complex or the C5b-9 complex which forms pores on the target cell membranes to lysing. [7]

Clinical Significance

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Lack of regulation of the classical complement pathway through the deficiency in C1-inhibitor results in episodic angioedema.[1] C1-inhibitor defiency can be hereditary or acquired, resulting in hereditary or acquired angioedema.[8] C1-inhibitor plays the role of inactivating C1r and C1s to prevent further downstream classical complement activity.[9][10] C1-inhibitor controls the processes involved in maintaining vascular. As a result, C1-inhibitor levels of less than 50% of the standard lead to increased vascular permeability, characteristic of angioedema.[10] Cinryze, a human plasma derived C1-esterase inhibitor, has been approved for use in 2008 for the prevention of hereditary angioedema attacks.[11][12]

Deficiency in the C1q protein of the classical complement pathway can lead to development of systemic lupus erythematosus.[2][13] Among the many functions of C1q, C1q triggers clearance of immune complexes and apoptotic cells by activating the classical pathway and binding directly onto phagocytes.[1][14] Consequently, systemic lupus erythematosus from insufficient amounts of C1q is characterized by the accumulation of autoantibodies and apoptotic cells.[4] Studies are being done to look into antibodies against C1q as a diagnostic marker for systemic lupus erythematosus.[15][16]

References

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  1. ^ a b c d e f g Noris, Marina; Remuzzi, Giuseppe (November 2013). "Overview of Complement Activation and Regulation". Seminars in Nephrology. 33 (6): 479–492. doi:10.1016/j.semnephrol.2013.08.001. PMC 3820029.{{cite journal}}: CS1 maint: PMC format (link)
  2. ^ a b c d e Vignesh, Pandiarajan; Rawat, Amit; Sharma, Madhubala; Singh, Surjit (February 2017). "Complement in autoimmune diseases". Clinica Chimica Acta. 465: 123–130. doi:10.1016/j.cca.2016.12.017.
  3. ^ a b c d e Nesargikar, Prabhu; Spiller, B.; Chavez, R. (June 2012). "The complement system: History, pathways, cascade and inhibitors". European Journal of Microbiology and Immunology. 2 (2): 103–111. doi:10.1556/EuJMI.2.2012.2.2. PMC 3956958.{{cite journal}}: CS1 maint: PMC format (link)
  4. ^ a b c d Thielens, Nicole M.; Tedesco, Francesco; Bohlson, Suzanne S.; Gaboriaud, Christine; Tenner, Andrea J. (June 2017). "C1q: A fresh look upon an old molecule". Molecular Immunology. doi:10.1016/j.molimm.2017.05.025.
  5. ^ Ahearn, Joseph M.; Fearon, Douglas T. (1989-01-01). Dixon, Frank J. (ed.). Structure and Function of the Complement Receptors, CR1 (CD35) and CR2 (CD21). Vol. 46. Academic Press. pp. 183–219. doi:10.1016/s0065-2776(08)60654-9.
  6. ^ Krych-Goldberg, M.; Atkinson, J. P. (2001-04-01). "Structure-function relationships of complement receptor type 1". Immunological Reviews. 180: 112–122. doi:10.1034/j.1600-065x.2001.1800110.x. ISSN 0105-2896. PMID 11414353.
  7. ^ Rus, Horea; Cudrici, Cornelia; Niculescu, Florin (2005-11-01). "The role of the complement system in innate immunity". Immunologic Research. 33 (2): 103–112. doi:10.1385/IR:33:2:103. ISSN 0257-277X. PMID 16234578.
  8. ^ Cugno, Massimo; Zanichelli, Andrea; Foieni, Fabrizio; Caccia, Sonia; Cicardi, Marco. "C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress". Trends in Molecular Medicine. 15 (2): 69–78. doi:10.1016/j.molmed.2008.12.001.
  9. ^ Levy, Michael; Mealy, Maureen A. (2014-06-01). "Purified human C1-esterase inhibitor is safe in acute relapses of neuromyelitis optica". Neurology - Neuroimmunology Neuroinflammation. 1 (1): e5. doi:10.1212/nxi.0000000000000005. ISSN 2332-7812. PMID 25340061.
  10. ^ a b Cugno, Massimo; Zanichelli, Andrea; Foieni, Fabrizio; Caccia, Sonia; Cicardi, Marco. "C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress". Trends in Molecular Medicine. 15 (2): 69–78. doi:10.1016/j.molmed.2008.12.001.
  11. ^ Lunn, Michael (2010-08-24). "Cinryze™ as the first approved C1 inhibitor in the USA for the treatment of hereditary angioedema: approval, efficacy and safety". Journal of Blood Medicine. 1. doi:10.2147/jbm.s9576.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ "Approval History, Letters, Reviews and Related Documents - CINRYZE". Retrieved 2015-01-21.
  13. ^ Stegert, Mihaela; Bock, Merete; Trendelenburg, Marten. "Clinical presentation of human C1q deficiency: How much of a lupus?". Molecular Immunology. 67 (1): 3–11. doi:10.1016/j.molimm.2015.03.007.
  14. ^ Taylor, Philip R.; Carugati, Anna; Fadok, Valerie A.; Cook, H. Terence; Andrews, Mark; Carroll, Michael C.; Savill, John S.; Henson, Peter M.; Botto, Marina (2000-08-07). "A Hierarchical Role for Classical Pathway Complement Proteins in the Clearance of Apoptotic Cells in Vivo". The Journal of Experimental Medicine. 192 (3): 359–366. ISSN 0022-1007. PMC 2193213. PMID 10934224.{{cite journal}}: CS1 maint: PMC format (link)
  15. ^ Chi, Shuhong; Yu, Yunxia; Shi, Juan; Zhang, Yurong; Yang, Jijuan; Yang, Lijuan; Liu, Xiaoming (2015). "Antibodies against C1q Are a Valuable Serological Marker for Identification of Systemic Lupus Erythematosus Patients with Active Lupus Nephritis". Disease Markers. 2015: 1–11. doi:10.1155/2015/450351. ISSN 0278-0240.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ^ Mahler, Michael; van Schaarenburg, Rosanne; Trouw, Leendert (2013). "Anti-C1q Autoantibodies, Novel Tests, and Clinical Consequences". Frontiers in Immunology. 4. doi:10.3389/fimmu.2013.00117. ISSN 1664-3224.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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