Compliment System

8/10/2019 Compliment System

1/4

1

Complement system

The complement systemhelps or complements the ability of antibodies and phagocytic cellsto clearpathogens from an organism. It is part of the immune system called theinnate immune

system that is not adaptable and does not change over the course of an individual's lifetime.

However, it can be recruited and brought into action by theadaptive immune system.

The complement system consists of a number of small proteins found in the blood, generally

synthesized by the liver, and normally circulating as inactive precursors (pro-proteins). When

stimulated by one of several triggers,proteases in the system cleave specific proteins to releasecytokines and initiate an amplifying cascade of further cleavages. The end-result of this

activation cascade is massive amplification of the response and activation of the cell-killing

membrane attack complex. Over 25 proteins and protein fragments make up the complementsystem, includingserumproteins, serosalproteins, and cell membrane receptors. They accountfor about 5% of theglobulin fraction of blood serum.

Threebiochemical pathways activate the complement system:

classical complement pathway,

alternative complement pathway,

mannose-binding lectin pathway.

In the late 19th century,Hans Ernst August Buchner found that blood serum contained a "factor"or "principle" capable of killing bacteria. In 1896, Jules Bordet, a young Belgian scientist in

Paris at the Pasteur Institute, demonstrated that this principle had two components: one that

maintained this effect after being heated, and one that lost this effect after being heated. The

heat-stable component was responsible for the immunity against specific microorganisms,whereas the heat-sensitive (heat-labile) component was responsible for the non-specific

antimicrobial activity conferred by all normal serum. This heat-labile component is what we nowcall "complement."

The term "complement" was introduced by Paul Ehrlich in the late 1890s, as part of his larger

theory of the immune system. According to this theory, the immune system consists of cells thathave specific receptors on their surface to recognize 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. These receptors, which we now call "antibodies," were called by Ehrlich
http://en.wikipedia.org/wiki/Pathogenshttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Innate_immune_systemhttp://en.wikipedia.org/wiki/Innate_immune_systemhttp://en.wikipedia.org/wiki/Adaptive_immune_systemhttp://en.wikipedia.org/wiki/Liverhttp://en.wikipedia.org/wiki/Pro-proteinshttp://en.wikipedia.org/wiki/Proteaseshttp://en.wikipedia.org/wiki/Cytokineshttp://en.wikipedia.org/wiki/Membrane_attack_complexhttp://en.wikipedia.org/wiki/Blood_plasmahttp://en.wikipedia.org/wiki/Serous_membranehttp://en.wikipedia.org/wiki/Serum_globulinshttp://en.wikipedia.org/wiki/Metabolic_pathwayhttp://en.wikipedia.org/wiki/Classical_complement_pathwayhttp://en.wikipedia.org/wiki/Alternative_complement_pathwayhttp://en.wikipedia.org/wiki/Mannose-binding_lectin_pathwayhttp://en.wikipedia.org/wiki/Hans_Ernst_August_Buchnerhttp://en.wikipedia.org/wiki/Jules_Bordethttp://en.wikipedia.org/wiki/Paul_Ehrlichhttp://en.wikipedia.org/wiki/Paul_Ehrlichhttp://en.wikipedia.org/wiki/Jules_Bordethttp://en.wikipedia.org/wiki/Hans_Ernst_August_Buchnerhttp://en.wikipedia.org/wiki/Mannose-binding_lectin_pathwayhttp://en.wikipedia.org/wiki/Alternative_complement_pathwayhttp://en.wikipedia.org/wiki/Classical_complement_pathwayhttp://en.wikipedia.org/wiki/Metabolic_pathwayhttp://en.wikipedia.org/wiki/Serum_globulinshttp://en.wikipedia.org/wiki/Serous_membranehttp://en.wikipedia.org/wiki/Blood_plasmahttp://en.wikipedia.org/wiki/Membrane_attack_complexhttp://en.wikipedia.org/wiki/Cytokineshttp://en.wikipedia.org/wiki/Proteaseshttp://en.wikipedia.org/wiki/Pro-proteinshttp://en.wikipedia.org/wiki/Liverhttp://en.wikipedia.org/wiki/Adaptive_immune_systemhttp://en.wikipedia.org/wiki/Innate_immune_systemhttp://en.wikipedia.org/wiki/Innate_immune_systemhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Pathogenshttps://donate.wikimedia.org/wiki/Special:FundraiserLandingPage?uselang=en&country=IN&template=Lp-layout-default&appeal-template=Appeal-template-default&appeal=Appeal-default&form-template=Form-template-default&form-countryspecific=Form-countryspecific-control&utm_medium=sitenotice&utm_source=B11_Donate_Jimmy_Accept_IN&utm_campaign=C11_1114_AvsB_IN


2/4

2

"amboceptors" to emphasize their bifunctional binding capacity: They recognize and bind to a

specific antigen, but they also recognize and bind to the heat-labile antimicrobial component of

fresh serum. Ehrlich, therefore, named this heat-labile component "complement," because it issomething in the blood that "complements" the cells of the immune system. In the early half of

the 1930s, a team led by the renowned Irish researcher, Jackie Stanley, stumbled upon the all-

important opsonization-mediated effect of C3b. Building off Ehrlich's work, Stanley's teamproved the role of complement in both the innate as well as the cell-mediated immune response.

Functions of the Complement

The following are the basic functions of the complement

1. Opsonization - enhancing phagocytosis of antigens2. Chemotaxis - attracting macrophages and neutrophils

3. Lysis - rupturing membranes of foreign cells

4. Clumping of antigen-bearing agents

Overview

The proteins and glycoproteins that constitute the complement system are synthesized by theliver hepatocytes. But significant amounts are also produced by tissue macrophages, blood

monocytes, and epithelial cells of the genitourinal tract and gastrointestinal tract.

The three pathways of activation all generate homologous variants of the protease C3-

convertase.The classical complement pathway typically requires antigen:antibody complexes for

activation (specific immune response), whereas the alternative and mannose-binding lectin

pathways can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, a C3-convertase cleaves and activates

componentC3,creating C3a and C3b, and causing a cascade of further cleavage and activationevents. C3b binds to the surface of pathogens, leading to greater internalization by phagocytic

cells by opsonization. C5a is an important chemotactic protein, helping recruit inflammatory

cells. C3a is the precursor of an important cytokine (adipokine). Both C3a and C5a have

anaphylatoxin activity, directly triggering degranulation of mast cells as well as increasingvascular permeability and smooth muscle contraction. C5b initiates the membrane attack

pathway,which results in themembrane attack complex (MAC), consisting of C5b,C6,C7,C8,

and polymeric C9. MAC is the cytolytic endproduct of the complement cascade; it forms a

transmembrane channel, which causes osmotic lysis of the target cell. Kupffer cells and othermacrophage cell types help clear complement-coated pathogens.
http://en.wikipedia.org/wiki/Proteasehttp://en.wikipedia.org/wiki/C3-convertasehttp://en.wikipedia.org/wiki/C3-convertasehttp://en.wikipedia.org/wiki/C3_%28complement%29http://en.wikipedia.org/wiki/Phagocytehttp://en.wikipedia.org/wiki/Phagocytehttp://en.wikipedia.org/wiki/Opsonizationhttp://en.wikipedia.org/wiki/C5ahttp://en.wikipedia.org/wiki/Chemokinehttp://en.wikipedia.org/wiki/Cytokinehttp://en.wikipedia.org/wiki/Anaphylatoxinhttp://en.wikipedia.org/wiki/Degranulationhttp://en.wikipedia.org/wiki/Mast_cellhttp://en.wikipedia.org/wiki/Smooth_musclehttp://en.wikipedia.org/wiki/Complement_membrane_attack_complexhttp://en.wikipedia.org/wiki/Complement_membrane_attack_complexhttp://en.wikipedia.org/wiki/Complement_membrane_attack_complexhttp://en.wikipedia.org/wiki/Complement_component_6http://en.wikipedia.org/wiki/Complement_component_7http://en.wikipedia.org/wiki/C8_complexhttp://en.wikipedia.org/wiki/Complement_component_9http://en.wikipedia.org/wiki/Osmosishttp://en.wikipedia.org/wiki/Kupffer_cellshttp://en.wikipedia.org/wiki/Kupffer_cellshttp://en.wikipedia.org/wiki/Osmosishttp://en.wikipedia.org/wiki/Complement_component_9http://en.wikipedia.org/wiki/C8_complexhttp://en.wikipedia.org/wiki/Complement_component_7http://en.wikipedia.org/wiki/Complement_component_6http://en.wikipedia.org/wiki/Complement_membrane_attack_complexhttp://en.wikipedia.org/wiki/Complement_membrane_attack_complexhttp://en.wikipedia.org/wiki/Complement_membrane_attack_complexhttp://en.wikipedia.org/wiki/Smooth_musclehttp://en.wikipedia.org/wiki/Mast_cellhttp://en.wikipedia.org/wiki/Degranulationhttp://en.wikipedia.org/wiki/Anaphylatoxinhttp://en.wikipedia.org/wiki/Cytokinehttp://en.wikipedia.org/wiki/Chemokinehttp://en.wikipedia.org/wiki/C5ahttp://en.wikipedia.org/wiki/Opsonizationhttp://en.wikipedia.org/wiki/Phagocytehttp://en.wikipedia.org/wiki/Phagocytehttp://en.wikipedia.org/wiki/C3_%28complement%29http://en.wikipedia.org/wiki/C3-convertasehttp://en.wikipedia.org/wiki/C3-convertasehttp://en.wikipedia.org/wiki/Protease


3/4

3

Classical pathway

Figure The classical and alternative complement pathways.

Theclassical pathway is triggered by activation of the C1-complex (composed of 1 molecule of

C1q, 2 molecules of C1r and 2 molecules of C1s, thus forming C1qr2s2), which occurs when C1q

binds to IgM or IgG complexed with antigens (a single IgM can initiate the pathway, while

multiple IgGs are needed), or 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 (a serine protease) molecules. They then cleave C1s (another serine protease). TheC1r

2s

2component now splitsC4 and then C2,producing C4a,C4b,C2a,and C2b. C4b and C2b

bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage ofC3 into C3a and C3b; C3b later joins with C4b2b (the C3 convertase) to make C5 convertase

(C4b2b3b complex). The inhibition of C1r and C1s is controlled byC1-inhibitor.
http://en.wikipedia.org/wiki/Classical_complement_pathwayhttp://en.wikipedia.org/wiki/IgMhttp://en.wikipedia.org/wiki/IgGhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/C1Q_complexhttp://en.wikipedia.org/wiki/Complement_component_1Shttp://en.wikipedia.org/wiki/Complement_component_4http://en.wikipedia.org/wiki/Complement_component_2http://en.wikipedia.org/wiki/C1-inhibitorhttp://en.wikipedia.org/wiki/File:Complement-pathways.pnghttp://en.wikipedia.org/wiki/File:Complement-pathways.pnghttp://en.wikipedia.org/wiki/File:Complement-pathways.pnghttp://en.wikipedia.org/wiki/File:Complement-pathways.pnghttp://en.wikipedia.org/wiki/C1-inhibitorhttp://en.wikipedia.org/wiki/Complement_component_2http://en.wikipedia.org/wiki/Complement_component_4http://en.wikipedia.org/wiki/Complement_component_1Shttp://en.wikipedia.org/wiki/C1Q_complexhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/IgGhttp://en.wikipedia.org/wiki/IgMhttp://en.wikipedia.org/wiki/Classical_complement_pathway


4/4

4

Alternative pathway

Thealternative pathway is continuously activated at a low level, as a result of spontaneous C3

hydrolysis due to the breakdown of the internal thioester bond(C3 is mildly unstable in aqueousenvironment). The alternative pathway does not rely on pathogen-binding antibodies like the

other pathways. C3b that is generated from C3 by a C3 convertase enzyme. The surface-boundC3b may now bind factor B to form C3bB. This complex in the presence of factor D will becleaved into Ba and Bb. Bb will remain associated with C3b to form C3bBb, which is the

alternative pathway C3 convertase.

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 potentanaphylatoxin,and C5b. The C5b then recruits and assembles C6, C7, C7, C8

and multiple C9 molecules to assemble the membrane attack complex. This creates a hole orpore in the membrane that can kill or damage the pathogen or cell.

Lectin pathway (MBL - MASP)

The lectin pathway is homologous to the classical pathway, but with the opsonin, mannose-

binding lectin (MBL), and ficolins, instead of C1q. This pathway is activated by bindingmannose-binding lectin 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 C2a then bind

together to form the C3-convertase, as in the classical pathway. Ficolins are homologous to MBLand function via MASP in a similar way.

Regulation of the complement system

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 bycomplement control

proteins,which are present at a higher concentration in the blood plasma than the complementproteins themselves. Some complement control proteins are present on the membranes of self-

cells preventing them from being targeted by complement. One example isCD59,also known as

protectin, which inhibits C9 polymerisation during the formation of the membrane attackcomplex.The classical pathway is inhibited by C1-inhibitor,which binds to C1 to prevent its

activation.
http://en.wikipedia.org/wiki/Alternate_complement_pathwayhttp://en.wikipedia.org/wiki/Complement_factor_Bhttp://en.wikipedia.org/wiki/Factor_Dhttp://en.wikipedia.org/wiki/Anaphylatoxinhttp://en.wikipedia.org/wiki/Membrane_attack_complexhttp://en.wikipedia.org/wiki/Lectinhttp://en.wikipedia.org/wiki/Complement_control_proteinhttp://en.wikipedia.org/wiki/Complement_control_proteinhttp://en.wikipedia.org/wiki/CD59http://en.wikipedia.org/wiki/Protectinhttp://en.wikipedia.org/wiki/Membrane_attack_complexhttp://en.wikipedia.org/wiki/Membrane_attack_complexhttp://en.wikipedia.org/wiki/C1-inhibitorhttp://en.wikipedia.org/wiki/C1-inhibitorhttp://en.wikipedia.org/wiki/Membrane_attack_complexhttp://en.wikipedia.org/wiki/Membrane_attack_complexhttp://en.wikipedia.org/wiki/Protectinhttp://en.wikipedia.org/wiki/CD59http://en.wikipedia.org/wiki/Complement_control_proteinhttp://en.wikipedia.org/wiki/Complement_control_proteinhttp://en.wikipedia.org/wiki/Lectinhttp://en.wikipedia.org/wiki/Membrane_attack_complexhttp://en.wikipedia.org/wiki/Anaphylatoxinhttp://en.wikipedia.org/wiki/Factor_Dhttp://en.wikipedia.org/wiki/Complement_factor_Bhttp://en.wikipedia.org/wiki/Alternate_complement_pathway

Documents

Compliment System