Classical complement pathway

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Classical and alternative pathways shown with their corresponding proteins Complement pathways.png
Classical and alternative pathways shown with their corresponding proteins

The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM. [1] [2]

Contents

Following activation, a series of proteins are recruited to generate C3 convertase (C4b2b, historically referred C4b2a), which cleaves the C3 protein. The C3b component of the cleaved C3 binds to C3 convertase (C4b2b) to generate C5 convertase (C4b2b3b), which cleaves the C5 protein. The cleaved products attract phagocytes to the site of infection and tags target cells for elimination by phagocytosis. In addition, 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

The classical complement pathway leading into a complement cascade that is shared with the alternative pathway. Complement pathway.svg
The classical complement pathway leading into a complement cascade that is shared with the alternative pathway.

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

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]

Formation of C4b convertase

The binding of C1q with pathogen surface or antigen-antibody immune complex 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] Activated C1s cleaves C4 into C4a and C4b.

Regulation of C4b

The newly formed C4b cannot stay activated as a highly reactive thioester bond is revealed once C4 has been cleaved. The thioester bond is cleaved by water resulting in its cleavage permanently deactivating the C4b molecule. As a result of this C4b is restricted to only bind to pathogen surfaces. They would undergo rapid deactivation in the time it took to travel from the origin of activation where C1q is complexed with an antigen-antibody immune complex(IC) or where C1q is directly attached to the pathogens surface. [6]

Formation of C3-convertase.

Surface-bound C4b acts as a receptor for the binding of C2. [6] The binding of C2 and C4b results in C2 being cleaved by C1s into C2a and C2b. C2b diffuses into the plasma as a protein inflammatory mediator while C2a remains attached with C4b, forming the C3-convertase (C4b2a). The function of the membrane-bound C3-convertase is the cleavage of many many molecules of C3 into C3a and C3b. C3a is a smaller fragment of C3 is a potent inflammatory mediator.

C3b function and structure.

C3b can act as an opsonin. C3b is very similar to C4 in both structure and function also has a thioester bond that forces it to attach to surface nucleophile of the activator(namely the pathogen or IC). Phagocytes have receptors for C3b and as a result of receptor-ligand binding are able to more easily recognize and engulf pathogen molecules. While the anaphylatoxin C3a interacts with its C3a receptor (C3aR) to recruit leukocytes, C3b contributes to further downstream complement activation. [1] [3]

Formation of C5 convertase and MAC

C3b binds to the C3 convertase (C4b2a), to form C5 convertase (C4b2b3b). C5 convertase then cleaves C5 into C5a and C5b. [3] Like C3a, C5a is also an anaphylatoxin that 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

Because of its role in the innate immune system classical complement has been implicated in a number of pathogen related disorders. Complement is responsible for immune inflammatory response in adipose tissues which has been implicated in the development of obesity. [8] Obesity in turn results in an abnormally high level of complement activation via production of the C1 component of the classical pathway, which can lead to tissue inflammation and eventually insulin resistance, however the exact mechanisms that causes this is yet unknown. [8]

Immunotherapies have been developed to detect and destroy cells infected by the HIV virus via classical complement activation. [9] This process involves creating synthetic peptides that target conserved regions in HIV specific proteins and induce an antibody specific immune response through IgG antibodies. This is important for targeting the virus in its intracellular phase because the antibodies specific to the synthetic peptides can trigger the classical complement pathway and induce the death of HIV infected cells.

Classical complement activation has also been shown to combat Methicillin-resistant Staphylococcus aureus. [10] Certain variants of the IgM antibody were found to bind the Methicillin-resistant Staphylococcus aureus these IgM were found to be critical in complement activation through the classical pathway and subsequent destruction of the bacteria. Therapies that utilize classical complement activation have been shown to be effective in targeting and killing cancer cells and destroying tumors. [11] Tachyplesin, a small peptide, has been shown to exhibit these effects. When injected into target tissue encourages recruitment of C1q and activates downstream events, eventually leading to the formation of the C5b-9 complex which damages tumor cells, killing them.

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. [12] C1-inhibitor plays the role of inactivating C1r and C1s to prevent further downstream classical complement activity. [13] [12] C1-inhibitor controls the processes involved in maintaining vascular permeability. As a result, C1-inhibitor levels of less than 50% of the standard lead to increased vascular permeability, characteristic of angioedema. [12] Cinryze, a human plasma derived C1-esterase inhibitor, has been approved for use in 2008 for the prevention of hereditary angioedema attacks. [14] [15]

Deficiency in the C1q protein of the classical complement pathway can lead to development of systemic lupus erythematosus. [2] [16] 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] [17] 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. [18] [19]

See also

Related Research Articles

<span class="mw-page-title-main">Complement system</span> Part of the immune system that enhances the ability of antibodies and phagocytic cells

The complement system, also known as complement cascade, is a part of the humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane. Despite being part of the innate immune system, the complement system can be recruited and brought into action by antibodies generated by the adaptive immune system.

<span class="mw-page-title-main">Alternative complement pathway</span> Type of cascade reaction of the complement system

The alternative pathway is a type of cascade reaction of the complement system and is a component of the innate immune system, a natural defense against infections.

<span class="mw-page-title-main">C3-convertase</span>

C3 convertase belongs to family of serine proteases and is necessary in innate immunity as a part of the complement system which eventuate in opsonisation of particles, release of inflammatory peptides, C5 convertase formation and cell lysis.

Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed by phagocytes. Different types of things ("targets") can be tagged by opsonins for phagocytosis, including: pathogens, cancer cells, aged cells, dead or dying cells, excess synapses, or protein aggregates. Opsonins help clear pathogens, as well as dead, dying and diseased cells.

<span class="mw-page-title-main">Complement membrane attack complex</span> Protein complex

The membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, and as such is an effector of the immune system. Antibody-mediated complement activation leads to MAC deposition on the surface of infected cells. Assembly of the MAC leads to pores that disrupt the cell membrane of target cells, leading to cell lysis and death.

<span class="mw-page-title-main">Complement component 3</span> Protein found in humans

Complement component 3, often simply called C3, is a protein of the immune system that is found primarily in the blood. It plays a central role in the complement system of vertebrate animals and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called C3.

<span class="mw-page-title-main">C5-convertase</span> Serine protease that plays key role in innate immunity.

C5 convertase is an enzyme belonging to a family of serine proteases that play key role in the innate immunity. It participates in the complement system ending with cell death.

<span class="mw-page-title-main">Properdin</span> Protein-coding gene in the species Homo sapiens

Properdin is a protein that in humans is encoded by the CFP gene.

<span class="mw-page-title-main">Lectin pathway</span> Type of cascade reaction in the compliment system

The lectin pathway or MBL pathway is a type of cascade reaction in the complement system, similar in structure to the classical complement pathway, in that, after activation, it proceeds through the action of C4 and C2 to produce activated complement proteins further down the cascade. In contrast to the classical complement pathway, the lectin pathway does not recognize an antibody bound to its target. The lectin pathway starts with mannose-binding lectin (MBL) or ficolin binding to certain sugars.

<span class="mw-page-title-main">Complement component 2</span> Protein found in humans

Complement C2 is a protein that in humans is encoded by the C2 gene. The protein encoded by this gene is part of the classical pathway of the complement system, acting as a multi-domain serine protease. Deficiency of C2 has been associated with certain autoimmune diseases.

<span class="mw-page-title-main">C4b-binding protein</span> Protein complex involved in the complement system

C4b-binding protein (C4BP) is a protein complex involved in the complement system where it acts as inhibitor. C4BP has an octopus-like structure with a central stalk and seven branching alpha-chains. The main form of C4BP in human blood is composed of 7 identical alpha-chains and one unique beta-chain, which in turn binds anticoagulant, vitamin K-dependent protein S.

<span class="mw-page-title-main">Complement component 1q</span> Protein complex

The complement component 1q is a protein complex involved in the complement system, which is part of the innate immune system. C1q together with C1r and C1s form the C1 complex.

Complement component 4 (C4), in humans, is a protein involved in the intricate complement system, originating from the human leukocyte antigen (HLA) system. It serves a number of critical functions in immunity, tolerance, and autoimmunity with the other numerous components. Furthermore, it is a crucial factor in connecting the recognition pathways of the overall system instigated by antibody-antigen (Ab-Ag) complexes to the other effector proteins of the innate immune response. For example, the severity of a dysfunctional complement system can lead to fatal diseases and infections. Complex variations of it can also lead to schizophrenia. The C4 protein was thought to derive from a simple two-locus allelic model, which however has been replaced by a much more sophisticated multimodular RCCX gene complex model which contain long and short forms of the C4A or C4B genes usually in tandem RCCX cassettes with copy number variation, that somewhat parallels variation in the levels of their respective proteins within a population along with CYP21 in some cases depending on the number of cassettes and whether it contains the functional gene instead of pseudogenes or fragments. Originally defined in the context of the Chido/Rodgers blood group system, the C4A-C4B genetic model is under investigation for its possible role in schizophrenia risk and development.

<span class="mw-page-title-main">C3b</span>

C3b is the larger of two elements formed by the cleavage of complement component 3, and is considered an important part of the innate immune system. C3b is potent in opsonization: tagging pathogens, immune complexes (antigen-antibody), and apoptotic cells for phagocytosis. Additionally, C3b plays a role in forming a C3 convertase when bound to Factor B, or a C5 convertase when bound to C4b and C2b or when an additional C3b molecule binds to the C3bBb complex.

The following outline is provided as an overview of and topical guide to immunology:

<span class="mw-page-title-main">C3a (complement)</span>

C3a is one of the proteins formed by the cleavage of complement component 3; the other is C3b. C3a is a 77 residue anaphylatoxin that binds to the C3a receptor (C3aR), a class A G protein-coupled receptor. It plays a large role in the immune response.

<span class="mw-page-title-main">Acquired C1 esterase inhibitor deficiency</span> Medical condition

Acquired C1 esterase inhibitor deficiency, also referred to as acquired angioedema (AAE), is a rare medical condition that presents as body swelling that can be life-threatening and manifests due to another underlying medical condition. The acquired form of this disease can occur from a deficiency or abnormal function of the enzyme C1 esterase inhibitor (C1-INH). This disease is also abbreviated in medical literature as C1INH-AAE. This form of angioedema is considered acquired due to its association with lymphatic malignancies, immune system disorders, or infections. Typically, acquired angioedema presents later in adulthood, in contrast to hereditary angioedema which usually presents from early childhood and with similar symptoms.

Urticarial vasculitis is a skin condition characterized by fixed urticarial lesions that appear histologically as a vasculitis.

<span class="mw-page-title-main">Complement 3 deficiency</span> Medical condition

Complement 3 deficiency is a genetic condition affecting complement component 3 (C3). People can suffer from either primary or secondary C3 deficiency. Primary C3 deficiency refers to an inherited autosomal-recessive disorder that involves mutations in the gene for C3. Secondary C3 deficiency results from a lack of factor I or factor H, two proteins that are key for the regulation of C3. Both primary and secondary C3 deficiency are characterized by low levels or absence of C3.

The C1 complex is a protein complex involved in the complement system. It is the first component of the classical complement pathway and is composed of the subcomponents C1q, C1r and C1s.

References

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  2. 1 2 3 4 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. PMID   28040558.
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  5. ↑ Ahearn, Joseph M.; Fearon, Douglas T. (1989-01-01). "Structure and Function of the Complement Receptors, CR1 (CD35) and CR2 (CD21)". In Dixon, Frank J. (ed.). Advances in Immunology Volume 46. Vol. 46. pp. 183–219. doi:10.1016/s0065-2776(08)60654-9. ISBN   9780120224463. PMID   2551147.
  6. 1 2 Janeway, Ca Jr (2001). "The complement system and innate immunity". Immunobiology: The Immune System in Health and Disease (5th ed.). New York: Garland Science.
  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. S2CID   46096567.
  8. 1 2 Zhang, Jinhui; Wright, Wendy; Bernlohr, David A.; Cushman, Samuel W.; Chen, Xiaoli (2007-05-01). "Alterations of the classic pathway of complement in adipose tissue of obesity and insulin resistance". American Journal of Physiology. Endocrinology and Metabolism. 292 (5): E1433–E1440. doi:10.1152/ajpendo.00664.2006. ISSN   0193-1849. PMID   17244723.
  9. ↑ Pleguezuelos, Olga; Stoloff, Gregory A; Caparrós-Wanderley, Wilson (2013-04-04). "Synthetic immunotherapy induces HIV virus specific Th1 cytotoxic response and death of an HIV-1 infected human cell line through classic complement activation". Virology Journal. 10 (1): 107. doi: 10.1186/1743-422x-10-107 . PMC   3626621 . PMID   23557359.
  10. ↑ An, Jingang; Li, Zhengxiao; Dong, Yingying; Wu, Jiawen; Ren, Jianwen (2015-05-22). "Complement activation contributes to the anti-methicillin-resistant Staphylococcus aureus effect of natural anti-keratin antibody". Biochemical and Biophysical Research Communications. 461 (1): 142–147. doi:10.1016/j.bbrc.2015.03.182. PMID   25862372.
  11. ↑ Chen, Jinguo; Xu, Xue-Ming; Underhill, Charles B.; Yang, Shanmin; Wang, Luping; Chen, Yixin; Hong, Shuigen; Creswell, Karen; Zhang, Lurong (2005-06-01). "Tachyplesin Activates the Classic Complement Pathway to Kill Tumor Cells". Cancer Research. 65 (11): 4614–4622. doi: 10.1158/0008-5472.CAN-04-2253 . ISSN   0008-5472. PMID   15930279.
  12. 1 2 3 Cugno, Massimo; Zanichelli, Andrea; Foieni, Fabrizio; Caccia, Sonia; Cicardi, Marco (2009). "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. PMID   19162547.
  13. ↑ 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. PMC   4202676 . PMID   25340061.
  14. ↑ 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: 163–70. doi: 10.2147/jbm.s9576 . PMC   3262319 . PMID   22282695.
  15. ↑ "Approval History, Letters, Reviews and Related Documents - CINRYZE". Food and Drug Administration . Retrieved 2015-01-21.
  16. ↑ Stegert, Mihaela; Bock, Merete; Trendelenburg, Marten (2015). "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. PMID   25846716.
  17. ↑ 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. doi:10.1084/jem.192.3.359. ISSN   0022-1007. PMC   2193213 . PMID   10934224.
  18. ↑ 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: 450351. doi: 10.1155/2015/450351 . ISSN   0278-0240. PMC   4621353 . PMID   26549923.
  19. ↑ Mahler, Michael; van Schaarenburg, Rosanne; Trouw, Leendert (2013). "Anti-C1q Autoantibodies, Novel Tests, and Clinical Consequences". Frontiers in Immunology. 4: 117. doi: 10.3389/fimmu.2013.00117 . ISSN   1664-3224. PMC   3653116 . PMID   23717311.
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