Complement system
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.[1] 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.
This article is about an aspect of the immune system. For other uses, see Complement.
The complement system consists of a number of small, inactive, liver synthesized protein precursors circulating in the blood. When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. The end result of this complement activation or complement fixation cascade is stimulation of phagocytes to clear foreign and damaged material, inflammation to attract additional phagocytes, and activation of the cell-killing membrane attack complex. About 50 proteins and protein fragments make up the complement system, including plasma 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[edit]
In 1888, George Nuttall found that sheep blood serum had mild killing activity against the 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.[11] According to this theory, the immune system consists of cells that have 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. 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.
Activation of complements by antigen-associated antibody[edit]
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.
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.
Regulation[edit]
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 complement control proteins, which are present at blood plasma and host cell membrane.[34] Some complement control proteins are present on the membranes of self-cells preventing them from being targeted by complement. One example is CD59, also known as protectin, which inhibits C9 polymerization during the formation of the membrane attack complex. The classical pathway is inhibited by C1-inhibitor, which binds to C1 to prevent its activation.[35] Another example, is a plasma protein called, Factor H (FH), which has a key role in down-regulating the alternative pathway.[36] Factor H, along with another protein called Factor I, inactivates C3b, the active form of C3. This process prevents the formation of C3 convertase and halts the progression of the complement cascade. C3-convertase also can be inhibited by decay accelerating factor (DAF), which is bound to erythrocyte plasma membranes via a GPI anchor.[35]
Modulation of the body by complement with infection[edit]
Excessive complement activity contributes to severe Covid-19 symptoms and disease.[51] Although complement is intended to protect the body systems, under stress there can be more damage than protection. Research has suggested that the complement system is manipulated during HIV/AIDS, in a way that further damages the body.[52]
Role in the brain[edit]
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]
