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| COMPLEMENT SYSTEM OVERVIEW |
THE COMPLEMENT SYSTEM
The Complement system consists of about 50 proteins that work in the extracellular matrix and ward off or clear the pathogen present in the extracellular matrix. Proteins of the complement system are synthesized in the liver. These proteins are soluble proteins that circulate through the blood to all parts of the body. The complement system is part of the second line of defense, it is called the complement system because it complements our immune system.
The complement system is part of innate immunity as well as adaptive immunity. In innate immunity, it works as a nonspecific system to clear the pathogen from the extracellular matrix. In adaptive immunity, it is activated by antigen-antibody interaction and further, work through recruitment of T cell or B cell to clear of the pathogen.
The molecules of the complement system are mainly globular proteins that are soluble in water these globular proteins are named C1 to C 9 B and D.
The complement system has other molecules that are part of its activity, these molecules come under the category of
Receptors,
Activators,
and Regulators.
MECHANISM OF ACTION OF COMPLEMENT SYSTEM
The complement system works only when it is triggered. Mechanism of the action of the complement system is broadly classified into three different Pathways. All three pathways have three different triggers.
The classical pathway triggered by antigen-antibody interaction,
The Lectin pathway is triggered by glucose- mannose of pathogen cell membrane and
the alternative pathway is triggered by hydrolysis of C3 molecule.
the culmination of all three pathways can be opsonization, cell lysis, or inflammation.
In opsonization, components of the complement system cover the pathogenic cell so that the phagocytes can recognize this neutralized pathogen and engulf it.
Inflammation, the secondary products of the complement system such as C3a, C4a, C5a initiate chemotaxis as these molecules are inflammatory in action. They act through the receptors present on the cell and recruit mast cells that act through the synthesis of histamine and serotonin, these molecules are pro-inflammatory molecules and cause inflammation in the affected area.
The complement system produces a membrane attack complex( MAC) which is a complex protein mainly composed of C5b, 6, 7, and 8 and multiple-unit of C9. The C5b recruit C6 and C7 and then attract C8 to the pathogen membrane where they attach themselves to the pathogenic membrane. C8 is the molecule that inserts itself into the pathogenic membrane and forms the base for the assembly of the C 9 complex, where 13 to 15 C9 molecules assemble to form the membrane attack complex MAC, which is 10nm in diameter and it creates a pore in the pathogenic membrane through which the cytoplasm of pathogenic cell escapes to extracellular space and this result in cell lysis.
The complement system act through a different mechanism as listed earlier that they are activated through the classical pathway, the lectin pathway, alternative pathway
In the classical pathway, the complement system is triggered by antigen-antibody interaction where the binding of antibody IgM or IgG (5-6) on the surface of the pathogen activates the complement system. The antigen-antibody binding attracts C1 protein that has three domains C1q, C1r, C1s. The binding of this molecule then initiates a cascade of events in which different convertases participate. In this process, C3 convertase is synthesized which breakdown the C3 molecule into C3a and C3b, the C3b joins with C2b and forms the C5 convertase. C5 convertase then breakdown the C5 molecule into C5a and C5b.
C5b recruits C6 and C7 and then C8 on the pathogen cell membrane and result in the formation of membrane attack complex.
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| CLASSICAL PATHWAY: COMPLEMENT SYSTEM |
The lectin pathway has general and coded pattern recognition receptors such as MBL the mannose-binding lectin, that conduct nonself recognition. These receptors focus on the highly conserved structure of a large group of microorganisms referred to as associated molecular patterns PAMS(pattern associated molecules) include endotoxins, lipopolysaccharides of Gram-Negative bacteria, lipoteichoic acid of Gram-positive bacteria, and beta-glucan of the fungal cell membrane.
In this pathway, MBL can bind with some common carbohydrates of bacteria, yeast, and some viruses, MBL is complexed with MBL associated serine proteases MASPs 1,2,3, which are functionally similar to the C1 complex, and this association result in the formation of C3 convertase similar to the classical pathway and then the formation of C5 convertase, which dissociates C5 in C5a and C5b. C5b recruited C6, C7, C8, and ultimately C9 for the formation of membrane attack complex(MAC).
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| LECTIN PATHWAY: COMPLEMENT SYSTEM |
The alternative pathway is initiated by hydrolysis of C3 that bind to the factor B, which is dissociated to Factor Bb and Ba in presence of Factor D and result information of C3 convertase which is
C3 (H2O )Bb. The C3 convertase dissociates C3 in C3a and C3b. C3b joins the complex and forms C5 convertase, C5 convertase dissociates C5 in C5a and C5b. C5b recruits C6, C7, C8, and ultimately C9, this results in the formation of MAC the membrane attack complex.
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| ALTERNATIVE PATHWAY COMPLEMENT SYSTEM |
Cell lysis
Cell lysis or the breakdown of the pathogenic cell is one of the effector mechanisms of action of the complement system. The C5b molecule formed by dissociation of C5 in presence of C5 convertase initiates the formation of membrane attack complex. Where C5b associates with C6, C7, and C8 to form the C5bC6C7C8 complex. This complex attaches itself to the pathogen membrane, C8 even penetrates the membrane. This assembly is joined by the C9 molecule. 12 to 15 molecules of C9 form membrane attack complex MAC. The MAC has a height of 15nm and a diameter of 10nm. It creates a pore in the pathogen membrane due to which the pathogen cell undergoes lysis.
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| MAC (MEMBRANE ATTACK COMPLEX) |
Inflammatory response
THE secondary molecules formed during the complement system i.e. C3a, C4a, C5a are proinflammatory chemotaxis molecules. These molecules have a receptor on cells of the extracellular matrix. These receptors are called C3aR, C4aR, C5aR. These receptor molecules are transmembrane protein that is associated with G protein, and through a cascade of events, they help in the secretion of serotonin and histamine and are associated with recruitment of mast cells and which results in inflammation in that area.
Opsonisation and phagocytosis
The C3b/C4b can bind with the bacterial cell membrane and MBL bind with bacterial cell membrane or antibodies that are bound to bacterial cell membrane resulting in opsonization of pathogen i.e. the covering of the pathogenic cell. This attracts phagocytes to the site of infection. The phagocytes have receptors as CR1, CR2, CR3, CR4, CR1g, and Fc receptors against all these molecules and thus it can bind with the receptors on the pathogen and engulf the opsonized cell this will reduce the population of pathogens in the extracellular matrix.
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| PHAGOCYTOSIS |
Regulation of complement system
The complement system has some side effects also. If it remains triggered it may damage the body tissue. Thus to prevent its damage to body tissues it is required that the complement system must be regulated. Its regulation includes degradation of C3b and C4b in presence of Factor 1. If these molecules are degraded then they will be unable to initiate the membrane attack complex formation.
Further, the decay-accelerating activity for C3 convertase where decay activating factor disassemble
C 3 convertase this disassembly will stop the pathway in between.
For inhibition of cell lysis, C5b 6 7 8 complexes are decayed by vitronectin,
S protein, or CD 58, which inhibits assembly of membrane attack complex.
C3a, C4a, C5a the pro-inflammatory complexes, are degraded by carboxypeptidases, these are named carboxypeptidase N, carboxypeptidase B, carboxypeptidase R.
Reference
https://www.nature.com/articles/cr2009139
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