Complement system
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.
[4] In 1888, George Nuttall found that sheep blood serum had mild killing activity against the bacterium that causes anthrax.
Nevertheless, the heat-inactivated serum, when injected into guinea pigs exposed to the cholera bacteria, maintained its ability to protect the animals from illness.
[11] According to this theory, the immune system consists of cells that have specific receptors on their surface to recognize antigens.
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.
But significant amounts are also produced by tissue macrophages, blood monocytes, and epithelial cells of the genitourinary system and gastrointestinal tract.
The classical complement pathway typically requires antigen-antibody complexes for activation (specific immune response), whereas the alternative pathway can be activated by spontaneous complement component 3 (C3) hydrolysis, foreign material, pathogens, or damaged cells.
The mannose-binding lectin pathway can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response).
C3a is the precursor of an important cytokine (adipokine) named ASP (although this is not universally accepted [13]) and is usually rapidly cleaved by carboxypeptidase B.
Both C3a and C5a have anaphylatoxin activity, directly triggering degranulation of mast cells as well as increasing vascular permeability and smooth muscle contraction.
[14] MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes osmotic lysis of the target cell.
[15] 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).
Several single-nucleotide polymorphisms have been described in M-ficolin in humans, with effect on ligand-binding ability and serum levels.
[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.
[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.
[33] 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.
Ability of C3b to bind to antigen-associated Ig would work effectively against antigen-antibody complexes to make them soluble.
[citation needed] The complement system has the potential to be extremely damaging to host tissues, meaning its activation must be tightly regulated.
[35] Another example, is a plasma protein called, Factor H (FH), which has a key role in down-regulating the alternative pathway.
C3-convertase also can be inhibited by decay accelerating factor (DAF), which is bound to erythrocyte plasma membranes via a GPI anchor.
Improper alternative complement pathway activation may mediate recurrent immune-mediated fetal loss.
[47] Mutations in the genes of complement regulators, especially factor H, have been associated with atypical hemolytic uremic syndrome,[4][48][49] and C3 glomerulopathy.
[4][50] 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.
