Complement system
The complement system is a system of plasma proteins, which may be activated during the immune response to many surfaces of microorganisms. It was originally discovered as a supplementary ( complementing ) portion of the antibody response, but it is now known that it is also involved in the innate immune system. The more than 30 proteins of the human complement system are dissolved in the blood plasma or cell- bound and serve the defense against microorganisms ( eg, bacteria, fungi, parasites ), but also have strong cytocidal properties and can, if they act unregulated, over the course of many diseases (eg, glomerulonephritis, hemolytic uremic syndrome, myocardial infarction, systemic lupus erythematosus, rheumatoid arthritis) to be responsible for tissue damage.
The term " complement" was introduced around 1890 by Paul Ehrlich. According to his theory of the immune system cells consisted with specific receptors that recognize antigens. After antigen contact these receptors are formed and released into the blood for distribution. These receptors nowadays known as antibodies were appointed by Ehrlich as amboceptor, on the one hand recognize the antigen and other, indicate a heat - sensitive component of the blood serum, the Ehrlich called the complement, as they complement the function of the cellular immune defense. Although Ehrlich coined the term complement, the actual description of the complement to Jules Bordet goes back, who discovered that complement both in conjunction with antibodies as can also act alone.
Operation
The main role of the complement system is to cover the surface of pathogens, so as to enable the phagocytes and the destruction of those pathogens that would otherwise not recognize ( opsonization ). In addition, it triggers a series of inflammatory reactions that support the fight against the infection. The fragments of some complement proteins act as chemokines that attract other phagocytes to the site of infection. Another function is the direct destruction of bacteria by the insertion of pores in the cell membranes.
A lot of the complement proteins are called zymogens. These are proteins, proteases in this case, which in turn are activated by limited proteolysis. These zymogens usually occur anywhere in the body, without causing a response. In case of infection but are locally activated and activate other zymogens their cleavage. Thus, a cascade of zymogen activations is triggered, and many are later activated from a few early activated molecules, which leads to an amplification of the response.
Components of the complement system
The complement C1 to C9, the mannose -binding lectin ( MBL) and MBL -bonded C1 and serine proteases C1r and C1s and MASP -1 to 3 ( Sheet MBL -associated: directly involved in the signaling pathways of the complement proteins are the following serine proteases ). By protease -mediated cleavage of the complement C1 to C5 and bearings together with the factors of C6 to C9 is produced a variety of proteins and protein complexes. These include, for example, the anaphylatoxins C3a, C4a and C5a with vasodilator, bronchoconstrictor and chemotactic activity ( inflammation ) and the membrane attack complex ( engl. membrane attack complex (MAC) ). Negative regulators of the system are the C1 inhibitor, Factor H, Factor I, C4bp, CD35, CD46, CD55, CD59, and vitronectin. As activators act properdin and Cobra Venom Factor.
Process and effect of the complement activation
There are three ways by which the complement system is activated:
The product of all three routes is designated as C3 convertase on the surface of the serine protease of the target cell. Triggered by the cleavage of their cascade leads to chemotactic attraction of leucocytes (particularly macrophages), increased phagocytosis, and ultimately lysis of the target cell. Cleavage products of the complement factors C1 to C5, resulting in the individual paths, additionally act as anaphylatoxins and mediate inflammation.
The classic way
At the classical activation pathway of the complement nine glycoproteins (C1 - C9) are involved. These have molecular masses of 24-410 kDa and after formation in the liver, secreted into small extent in lymphocytes, macrophages and fibroblasts, into the bloodstream, where they make up about 10% of the globulin fraction. The complement factor C1 is the first complement protein of the classical pathway and consists of the six-member Kollektin C1q and two molecules of C1s and two molecules of C1r (Fig. below ). C1q has a plurality of binding domains of antigen -bound antibodies (IgG and IgM). For the activation of C1q bound to serine proteases ( C1r and C1s ) two 40 nm from each other remote Ig Fc regions are necessary. Therefore sufficient for IgM antibodies to a molecule, wherein the IgG antibody on the other hand at least two molecules are needed; IgA, IgE or IgD antibodies can not activate the classical pathway. Free antibodies therefore not lead to activation. However C1q can also bind directly to the surface of pathogens and initiate the classical pathway so without the help of antibodies.
The classical activation can be triggered by DNA, collagen, and CRP (C-reactive protein).
Once activated, the serine protease C1s catalysed then the two start reactions of the classical pathway. Cleavage of C2 C2a and C2b and in another of C4 C4a and C4b in. C2b and C4b deposited on C4b2b complex, thus forming the "C3 convertase of the classical pathway ". C4b2b3b forming C5 convertase, which cleaves C5 into C5a and C5b. C3a and C5a diffuse and act in turn as anaphylatoxin.
In the classical activation of the complement component C4d is also removed in addition to C4a and C4b, in a further sequence, that can covalently bind to the endothelium where the complement reaction has taken place. The function of C4d is not yet understood, but it serves as a marker in the biopsy and the diagnostic method of antibody -induced graft rejection.
The activation of C1 is controlled by a plasma protein, the C 1 inhibitor binds to the enzyme active part of C1 ( C1r / s), thereby separating it from C1q. The factors I, H and C4b -binding protein activated cleave C3.
The lectin pathway
In the lectin pathway, the mannose - binding lectin (MBL ) binds to mannose or N-acetylglucosamine at Fikolin on the surface pathogenic (e.g. bacterial peptidoglycan ) and activates the MBL associated serine proteases MASP -1, MASP -2 and MASP -3. These catalyze the same reactions as in the classical way. Again, C4b and C2b form a heterodimer C4b2b and thus also the "C3 convertase of the classical pathway ".
The alternative pathway
The alternative pathway leads to the formation of the "C3 convertase of the alternative pathway ." This pathway is triggered by the spontaneous decay of the unstable complement factor C3 in C3a and C3b. C3a diffuses and has a chemotactic and pro-inflammatory effect as anaphylatoxin. C3b binds covalently to the cell surface. Free C3b is inactivated by factor H and factor I. C3b binds to endogenous cells, it is also relatively rapidly inactivated or degraded by regulatory proteins. On pathogenic surfaces it, however, remains active and binds factor B, which is of factor D ( plasma protease ) is cleaved into Ba and Bb. The resulting complex C3bBb is referred to as " C3 - convertase of the alternative pathway ." It is very unstable and breaks down when it is not stabilized by properdin.
C3 convertase induced reactions
The formed in the alternative, classical and lectin pathway C3 convertases, C3bBb and C4b2b, now split with high activity in C3 C3b and C3a. The resulting C3b molecules have now essentially three options:
The two products of the C5 cleavage act both as anaphylatoxin and chemotactic attractant ( C5a ) and on the other hand they lead the formation of the membrane attack complex ( MAC ) is a ( C5b ). Here C5b recruits the "anchor" one after the other factors C6, C7 and C8. The resulting complex C5b678 then starts the polymerization of C9. After the assembly of up to 18 C9 monomers, the C5b678poly9 complex represents the final membrane attack complex, which attacks the target cell, among others, by pore formation in the cell membrane and leads to their lysis.
The soluble complement fragments C3a, C4a and C5a trigger a local inflammatory reaction. Run by binding to complement receptors of basophils to which release of histamine, heparin and leukotrienes. The activation of complement receptors on endothelial cells, smooth muscle cells, monocytes, eosinophils, and mast cells leads to bronchoconstriction, vasodilation, increase in vascular permeability and recruitment ( by C5a ) of granulocytes and monocytes to vessel walls, which is the prerequisite for immigration into the inflamed area. C3a promotes this predominantly tissue repair mechanisms. C5a stimulates the inflammatory response. Thus, the anaphylatoxins form an important link between innate and adaptive immune defense.
Medical importance
Many of the functions of complement have been detected by the occurrence of diseases in deficiencies in complement factors or regulators:
- C1 inhibitor: A congenital or acquired C1 -INH deficiency can lead to excessive complement reaction as ( ( AAE) Hereditary angioedema (HAE ), acquired angioedema) plays a role in the occurrence of angioedema. Through strong release of anaphylatoxins ( C3a, C5a ), there is swelling of the airways, skin and intestines are also affected.
- C2 and C4: immune complex diseases occur in persons with C2 deficiencies or defects in the "early" components C1q, C1r, C1s or C4. A complete congenital lack C1q is the strongest genetic risk factor for the development of systemic lupus erythematosus (SLE).
- C3: A deficiency of component C3 leads to frequent occurrence of bacterial infections (eg Neisseria ).
- Factor H is absent due to a mutation, results in uncontrolled activation of the alternative pathway to the basement membrane of the glomeruli and in the Bruch's membrane of the eye. The C3 deposits lead to chronic kidney disease ( Membranoproliferative glomerulonephritis type II), which may also be accompanied by visual disturbances. A common cause of this condition is an autoantibody which is directed against the C3bBb complex is stabilized, and this activates the alternative pathway.