Complement system

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Complement protein
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Scheme of the complement system

The complement system, also known as complement cascade, is a part of the

microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane. It is part of the innate immune system,[1] which is not adaptable and does not change during an individual's lifetime. The complement system can, however, be recruited and brought into action by antibodies generated by the adaptive immune system
.

The complement system consists of a number of small, inactive, liver synthesized

serum proteins, and cell membrane receptors. They account for about 10% of the globulin fraction of blood serum.[2]

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,

bacterium that causes anthrax.[5] The killing activity disappeared when he heated the blood.[6] In 1891, Hans Ernst August Buchner, noting the same property of blood in his experiments, named the killing property "alexin", which means "to ward off" in Greek.[7][8] By 1894, several laboratories had demonstrated that serum from guinea pigs that had recovered from cholera killed the cholera bacterium in vitro. Heating the serum destroyed its killing activity. Nevertheless, the heat-inactivated serum, when injected into guinea pigs exposed to the cholera bacteria, maintained its ability to protect the animals from illness. Jules Bordet, a young Belgian scientist in Paris at the Pasteur Institute, concluded that this principle has two components, one that maintained a "sensitizing" effect after being heated and one (alexin) whose toxic effect was lost after being heated.[9] The heat-stable component was responsible for immunity against specific microorganisms, whereas the heat-sensitive component was responsible for the non-specific antimicrobial activity conferred by all normal sera. In 1899, Paul Ehrlich renamed the heat-sensitive component "complement".[10][6]

Ehrlich introduced the term "complement" as part of his larger theory of the immune system.

antigens. Upon immunization with an antigen, more of these receptors are formed, and they are then shed from the cells to circulate in the blood. Those receptors, which we now call "antibodies", were called by Ehrlich "amboceptors" to emphasise their bifunctional binding capacity: They recognise and bind to a specific antigen, but they also recognise and bind to the heat-labile antimicrobial component of fresh serum. Ehrlich, therefore, named this heat-labile component "complement", because it is something in the blood that "complements" the cells of the immune system. Ehrlich believed that each antigen-specific amboceptor has its own specific complement, whereas Bordet believed that there is only one type of complement. In the early 20th century, this controversy was resolved when it became understood that complement can act in combination with specific antibodies, or on its own in a non-specific way.[citation needed
]

Functions

Membrane Attack Complex (Terminal Complement Complex C5b-9)

Complement triggers the following immune functions:[12]

  1. Classical Complement Pathway
    )
  2. Phagocytosis – by opsonizing antigens. C3b has most important opsonizing activity. (Alternative Complement Pathway)
  3. Inflammation – by attracting macrophages and neutrophils. (Lectin pathway)

Overview

Most of the

opsonization.[citation needed
]

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.

Kupffer cells and other macrophage cell types help clear complement-coated pathogens. As part of the innate immune system, elements of the complement cascade can be found in species earlier than vertebrates; most recently in the protostome horseshoe crab species, putting the origins of the system back further than was previously thought.[citation needed
]

Reaction Cascade of the Complement System: Classical, Alternative and Lectin Pathway, Amplification Loop, Terminal Pathway, and Membrane Attack Complex.

Classical pathway

The classical and alternative complement pathways

The

IgM or IgG complexed with antigens. A single pentameric IgM can initiate the pathway, while several, ideally six, IgGs are needed. This also occurs when C1q binds directly to the surface of the pathogen. Such binding leads to conformational changes in the C1q molecule, which leads to the activation of two C1r molecules. C1r is a serine protease. They then cleave C1s (another serine protease). The C1r2s2 component now splits C4 and then C2, producing C4a, C4b, C2a, and C2b (historically, the larger fragment of C2 was called C2a but is now referred to as C2b). C4b and C2b bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage of C3 into C3a and C3b. C3b later joins with C4b2b to make C5 convertase (C4b2b3b complex).[15]

Alternative pathway

The

alternative pathway is continuously activated at a low level, analogous to a car engine at idle, as a result of spontaneous C3 hydrolysis due to the breakdown of the internal thioester bond (C3 is mildly unstable in aqueous environment). The alternative pathway does not rely on pathogen-binding antibodies like the other pathways.[3] C3b that is generated from C3 by a C3 convertase enzyme complex in the fluid phase is rapidly inactivated by factor H and factor I, as is the C3b-like C3 that is the product of spontaneous cleavage of the internal thioester. In contrast, when the internal thioester of C3 reacts with a hydroxyl or amino group of a molecule on the surface of a cell or pathogen, the C3b that is now covalently bound to the surface is protected from factor H-mediated inactivation. The surface-bound C3b may now bind factor B to form C3bB. This complex in the presence of factor D will be cleaved into Ba and Bb. Bb will remain associated with C3b to form C3bBb, which is the alternative pathway C3 convertase.[16]

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

membrane attack complex. This creates a hole or pore in the membrane that can kill or damage the pathogen or cell.[1]

Lectin pathway

The

mannose-binding lectin (MBL), and ficolins, instead of C1q. This pathway is activated by binding of MBL to mannose residues on the pathogen surface, which activates the MBL-associated serine proteases, MASP-1, and MASP-2 (very similar to C1r and C1s, respectively), which can then split C4 into C4a and C4b and C2 into C2a and C2b. C4b and C2b then bind together to form the classical C3-convertase, as in the classical pathway. Ficolins are homologous to MBL and function via MASP in a similar way. Several single-nucleotide polymorphisms have been described in M-ficolin in humans, with effect on ligand-binding ability and serum levels. Historically, the larger fragment of C2 was named C2a, but it is now referred to as C2b.[17] In invertebrates without an adaptive immune system, ficolins are expanded and their binding specificities diversified to compensate for the lack of pathogen-specific recognition molecules.[citation needed
]

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

pathogen-associated molecular patterns (PAMPs),[28] however, utilizing specificity of the antibody, complements can detect non-self targets much more specifically.[citation needed
]

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

GPI anchor.[35]

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

Gram-negative bacteria).[43]

Infections with N. meningitidis and

N. gonorrhoeae are the only conditions known to be associated with deficiencies in the MAC components of complement.[44] 40–50% of those with MAC deficiencies experience recurrent infections with N. meningitidis.[45]

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.

AIDS, in a way that further damages the body.[52]

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

  1. ^ 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.
  2. ^ Glovsky MM (9 November 2019). Talavera F, Dreskin SC, Kaliner MA (eds.). "Complement-Related Disorders: Background, Pathophysiology, Activation". Medscape.
  3. ^ .
  4. ^ .
  5. ^ 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
  6. ^
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  7. ^ 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).)
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  9. ^ 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.
  10. ^ 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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  15. ^ "Classical Pathway (CP)". www.complementsystem.se. Euro Diagnostica. Archived from the original on 2 June 2016. Retrieved 6 June 2022.
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  18. ^ ]
  19. ^ ]
  20. ^ . Note that, in older texts, the smaller fragment is often called C2b, and the larger one is called C2a for historical reasons.
  21. ]
  22. ]
  23. .
  24. .
  25. ^ ]
  26. ]
  27. ]
  28. ^ ]
  29. .
  30. .
  31. ^ Doan T, Melvold R, Viselli S, Waltenbaugh C (2007). Lippincott's Illustrated Reviews: Immunology, 320p. Lippincott Williams & Wilkins[page needed]
  32. ]
  33. .
  34. .
  35. ^ .
  36. .
  37. .
  38. .
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  40. .
  41. .
  42. .
  43. .
  44. .
  45. .
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  47. .
  48. .
  49. .
  50. ^ "Complement Deficiencies Workup: Laboratory Studies, Imaging Studies, Other Tests". emedicine.medscape.com. Retrieved 2018-04-26.
  51. PMID 34912108
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External links