Complement system
The complement system, also known as complement cascade, is a part of the
The complement system consists of a number of small, inactive, liver synthesized
Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the lectin pathway.[3] The alternative pathway accounts for the majority of terminal pathway activation and so therapeutic efforts in disease have revolved around its inhibition.[4]
History
In 1888,
Ehrlich introduced the term "complement" as part of his larger theory of the immune system.
Functions
Complement triggers the following immune functions:[12]
- Classical Complement Pathway)
- Phagocytosis – by opsonizing antigens. C3b has most important opsonizing activity. (Alternative Complement Pathway)
- Inflammation – by attracting macrophages and neutrophils. (Lectin pathway)
Overview
Most of the
In the alternative pathway, C3b binds to Factor B. Factor D releases Factor Ba from Factor B bound to C3b. The complex of C3b(2)Bb is a protease which cleaves C5 into C5b and C5a.
Classical pathway
The
Alternative pathway
The
The C3bBb complex is stabilized by binding oligomers of
Once the alternative C3 convertase enzyme is formed on a pathogen or cell surface, it may bind covalently another C3b, to form C3bBbC3bP, the C5 convertase. This enzyme then cleaves C5 to C5a, a potent
Lectin pathway
The
Complement protein fragment nomenclature
Immunology textbooks have used different naming assignments for the smaller and larger fragments of C2 as C2a and C2b. The preferred assignment appears to be that the smaller fragment be designated as C2a: as early as 1994, a well known textbook recommended that the larger fragment of C2 should be designated C2b.[18] However, this was amplified in their 1999 4th edition, to say that:[19] "It is also useful to be aware that the larger active fragment of C2 was originally designated C2a, and is still called that in some texts and research papers. Here, for consistency, we shall call all large fragments of complement b, so the larger fragment of C2 will be designated C2b. In the classical and lectin pathways the C3 convertase enzyme is formed from membrane-bound C4b with C2b."[19]
This nomenclature is used in another literature:[20] The assignment is mixed in the latter literature, though. Some sources designate the larger and smaller fragments as C2a and C2b respectively[21][22][23][24][25][26][27][28][29] while other sources apply the converse.[18][19][30][31][32] However, due to the widely established convention, C2b here is the larger fragment, which, in the classical pathway, forms C4b2b (classically C4b2a). It may be noteworthy that, in a series of editions of Janeway's book, 1st to 7th, in the latest edition[28] they withdraw the stance to indicate the larger fragment of C2 as C2b.
Viral inhibition
Fixation of the MBL protein on viral surfaces has also been shown to enhance neutralization of viral pathogens.[33]
Review
Activation pathway | Classic | Alternative | Lectin |
---|---|---|---|
Activator | Ag–Ab Complex | spontaneous hydrolysis of C3 | MBL-Mannose Complex |
C3-convertase | C4b2b | C3bBb | C4b2b |
C5-convertase | C4b2b3b | C3bBbC3b | C4b2b3b |
MAC development | C5b+C6+C7+C8+C9 |
Activation of complements by antigen-associated antibody
In the classical pathway, C1 binds with its C1q subunits to Fc fragments (made of CH2 region) of IgG or IgM, which has formed a complex with antigens. C4b and C3b are also able to bind to antigen-associated IgG or IgM, to its Fc portion.[20][25][28]
Such immunoglobulin-mediated binding of the complement may be interpreted as that the complement uses the ability of the immunoglobulin to detect and bind to non-self antigens as its guiding stick. The complement itself can bind non-self pathogens after detecting their
Some components have a variety of binding sites. In the classical pathway, C4 binds to Ig-associated C1q and C1r2s2 enzyme cleaves C4 to C4b and 4a. C4b binds to C1q, antigen-associated Ig (specifically to its Fc portion), and even to the microbe surface. C3b binds to antigen-associated Ig and to the microbe surface. Ability of C3b to bind to antigen-associated Ig would work effectively against antigen-antibody complexes to make them soluble.[citation needed]
Regulation
The complement system has the potential to be extremely damaging to host tissues, meaning its activation must be tightly regulated. The complement system is regulated by
Role in disease
Complement deficiency
It is thought that the complement system might play a role in many diseases with an immune component, such as Barraquer–Simons syndrome, asthma, lupus erythematosus, glomerulonephritis, various forms of arthritis, autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome and ischemia-reperfusion injuries,[37][38] and rejection of transplanted organs.[39]
The complement system is also becoming increasingly implicated in diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions such as spinal cord injuries.[40][41][42]
Deficiencies of the terminal pathway predispose to both
Infections with N. meningitidis and
Deficiencies in complement regulators
Mutations in the genes of complement regulators, especially
Mutations in the C1 inhibitor gene can cause hereditary angioedema, a genetic condition resulting from reduced regulation of bradykinin by C1-INH.[citation needed]
Paroxysmal nocturnal hemoglobinuria is caused by complement breakdown of RBCs due to an inability to make GPI. Thus the RBCs are not protected by GPI anchored proteins such as DAF.[49]
Diagnostic tools
Diagnostic tools to measure complement activity include the total complement activity test.[50]
The presence or absence of complement fixation upon a challenge can indicate whether particular antigens or antibodies are present in the blood. This is the principle of the complement fixation test.
Modulation of the body by complement with infection
Excessive complement activity contributes to severe Covid-19 symptoms and disease.
Role in the brain
Research from over the last decade has shown that complement proteins of the classical complement pathway have an important role in synaptic pruning in the brain during early development.[53][54]
References
- ^ a b Janeway Jr CA, Travers P, Walport M, Shlomchik MJ (2001). "The complement system and innate immunity". Immunobiology: The Immune System in Health and Disease. New York: Garland Science. Retrieved 25 February 2013.
- ^ Glovsky MM (9 November 2019). Talavera F, Dreskin SC, Kaliner MA (eds.). "Complement-Related Disorders: Background, Pathophysiology, Activation". Medscape.
- ^ ISBN 978-1-4160-3123-9.
- ^ S2CID 226274874.
- ^ Nuttall G (1888). "Experimente über die bakterien feindlichen Einflüsse des tierischen Körpers" [Experiments on the antibacterial influences of animal substances]. Zeitschrift für Hygiene (in German). 4: 353–394.English translation here
- ^ PMID 16178664.
- ^ Buchner named "alexin" during an address to a meeting of the Medical Society (Aerztlichen Verein) in Munich, Germany on 3 June 1891. Buchner's address was published in: Buchner H (23 June 1891). "Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe" [Brief overview of the development of bacteriology since Naegeli's involvement in it]. Münchener Medizinische Wochenschrift (in German). 38 (25): 435–437, (26): 454–456. From p. 437: "Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die mit irgend welchen bisher bekannten sich nicht identificieren lassen, und die man am besten deshalb mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet." (So it's a matter of protein of a new type, which cannot be identified with any [protein] which [has been] known until now, and which one therefore designates best with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)
- Buchner's address was reprinted in condensed form in: Buchner H (1891). "Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe". Centralblatt für Bakteriologie und Parasitenkunde (in German). 10: 349–352. From p. 350: "Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die besonders durch grosse Labilität ausgezeichnet sind (bei 50-55°C erlischt rasch die Wirksamkeit), und die am besten mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet werden könnten." (So it's a matter of protein of a new type, which is especially distinguished by great lability (at 50-55°C its efficacy suddenly ceases to exist), and which can best be designated with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)
- PMID 24672678.
- ^ Bordet J (1895). "Les leucocytes et les propriétés actives du sérum chez les vaccinés" [Leucocytes and the active properties of serum in vaccinated [animals]]. Annales de l'Institut Pasteur (in French). 9: 462–506.
- ^ Ehrlich P, Morgenroth J (29 May 1899). "Ueber Haemolysine" [On hemolysin]. Berliner klinische Wochenschrift (in German). 36 (22): 481–486. From p. 483: "Es sprechen diese Versuche nach unseren früheren Erfahrungen dafür, dass auch hier in dem Serum ein Analogon des Immunkörpers, ein mit zwei haptophoren Gruppen versehener Complex, der als Zwischenkörper bezeichnet werde, und ein Addiment, das wir im Folgenden mit dem allgemeineren Ausdruck Complement bezeichnen wollen, besteht, und dass von den Blutkörperchen vorweigend der Zwischenkörper gebunden worden ist." (According to our earlier experiences, these experiments indicate (1) that here too there exists in the serum an analog of the immune bodies — a complex [that's] provided with two haptophoric groups, [one of] which may be designated as an "intermediate body" and [the other, as] an addiment [i.e., a component of a hemolysin that's induced by an antigen (see p. 481)], which we will designate in the following with the more general term "complement" — and (2) that the intermediate body has been bound mainly by the blood cells.)
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- ^ "Classical Pathway (CP)". www.complementsystem.se. Euro Diagnostica. Archived from the original on 2 June 2016. Retrieved 6 June 2022.
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- ^ ISBN 0-8153-1691-7.[page needed]
- ^ ISBN 0-8153-3217-3.[page needed]
- ^ ISBN 978-0-7216-0008-6.
Note that, in older texts, the smaller fragment is often called C2b, and the larger one is called C2a for historical reasons.
- ISBN 0-443-04672-7.[page needed]
- ISBN 0-7817-1412-5.[page needed]
- ISBN 0-443-07954-4.
- ISBN 0-7817-2120-2.
- ^ ISBN 0-7234-3189-2.[page needed]
- ISBN 0-7216-0146-4.[page needed]
- ISBN 0-8153-4093-1.[page needed]
- ^ ISBN 978-0-8153-4123-9.[page needed]
- ISBN 978-1-4160-3285-4.
- ISBN 978-0-8153-3642-6.
- ^ Doan T, Melvold R, Viselli S, Waltenbaugh C (2007). Lippincott's Illustrated Reviews: Immunology, 320p. Lippincott Williams & Wilkins[page needed]
- ISBN 978-0-9539181-0-2.[page needed]
- PMID 21292294.
- PMID 27031863.
- ^ PMID 26489954.
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- PMID 24104403.
- S2CID 6330326.
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- ^ "Complement Deficiencies Workup: Laboratory Studies, Imaging Studies, Other Tests". emedicine.medscape.com. Retrieved 2018-04-26.
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External links
- Media related to Complement system at Wikimedia Commons