The system of the complement is a biochemical cascade complexes Immune system, involving a Cytolyse, a Chimiotaxie, a Opsonisation and a Inflammation; it can mark organizations Pathogène S for their Phagocytose. The system of the complement consists of more than 35 Protéine S. Among them, 12 are directly implied in metabolic ways of the complement, whereas the remainder has regulating functions. There are three biochemical ways which activate the system of the complement: the traditional Way of the complement, the alternative Way of the complement and the Way of the lectines binding the mannanes.

General information

The system of the complement is a whole of proteins circulating or membrane of blood, mainly secreted by the liver. Their role initially recognized was to supplement the action of serum immunoglobulins, from where them name. In the absence of proteins Thermolabile S (which lose their qualities at a given temperature), the specific immunoglobulins Thermostable S are unable to involve the lysis of their target. The proteins of the complement account for approximately 5% of the plasmatic globulines. The various proteins of the complement are inactive proenzymes and which are activated in cascade by cleavage. Cleavage releases a fraction having an enzymatic activity of protease, and a small fragment which often has a role on the inflammatory cells.

The system of the complement has several important functions: the cytolysis of a cell or an disease-causing agent, the activation of the immune system by the small pro-inflammatory fragments of cleavage, the opsonisation of certain agents allowing their phagocytosis, and the metabolism of the complexes circulating immunes thanks to the receivers of the fragments of the complement.

The various ways activating the complement lead to the formation of a C3 Convertase , starting point of the common effector way which destroys the target by forming a transmembrane channel, allowing the entry of water molecules in the cell. The principal proteins of the complement are noted of C1 with C9, they migrate in electrophoresis in the fraction of Globulines Beta and have a molecular weight from 100 to 200 kDa.

� alternate way, traditional way � C3 controls both � C3a and C5a is the `anaphylatoxines': release histamine and C5a have a chimiotaxic activity important � C5a activates the way of the lipooxygénases and increase leucocytic adhesion C3b and C3bi function like opsonins � C5-9 forms the `membrane attack complex: MAC', the active element in the lysis of the cells

Traditional way

Activation

The traditional way is activated by the complex antigen-antibody. Only IgG1, IgG3, IgM, and slightly IgG2 are able to involve the cascade of the events. The fixing of two or several immunoglobulins of IgG or a pentameric molecule of IgM, the surface of a micro-organism, makes it possible their area FC to fix the first component of the traditional way: C1. C1 is a large complex, composed of three under-components: C1q, C 1r and C1s. When C1q binds the complex antigen-antibody, it activates C 1r, which becomes proteolytic, and cleaves C1s to start the cascade of proteolysis. It is necessary to notice that C1q is composed of 6 identical units, each one comprising a globular head which fixes the antibody, and a tail of the collagenous type .

In fact indeed globular heads will interact with fragments FC of immunoglobulins having bound the antigen. Activated C1 cleaves C4 then C4 cleaves C2, to form a C4b2a complex still called C3-convertase , traditional, in this case. This convertase form C4b2a3b or C5-convertase. Each cleavage releases a small fragment: C4a, C2b and C3a which act on the inflammatory cells.

Regulation

It is carried out by the inhibiter of C1 estérase, C1 Inh and protein binding C4, C4bpG. Actually, the actvity of the complement results from a suspension of the inhibiting activity of C1 Inh. The deficit in C1 Inh is responsible for a disease, the hereditary edema angioneurotic.

Common effector way

In both cases, we will see the way alternates then, the early components locally activate C3, which is the factor pivot of the complement, and whose cleavage leads not only to the assembly of the complex which attacks the membrane, but also to the recruitment of the various white globules.

C3b, which is the largest fragment of the lysis of C3 by C3-convertase, binds in a covalent way to surface of the cell. The smallest fragment, C3a, act as for him as diffusible signal which causes an inflammatory answer, by stimulating the migration of the white globules towards the site of the infection. The C3b fragment fixed at the membrane, produces at the same time by the traditional way and the alternate way, and even the way of the lectines, starts the cascade of the reactions which leads to the formation of the membrane complex of attack, starting from the late components of the complement. It is thus fixed on the membrane in a covalent way, and it cleaves the C5 factor in C5a and C5b. C5b slightly remains related to C3b and is assembled quickly in C6 and C7 to form the C567 complex which will be anchored to the membrane via C7. This complex binds then C8, to form the C5678 complex. The connection of the C9 factor, which exposes a hydrophobic area after change of conformation, involves its insertion in the plasmic membrane of the cell. It follows then a chain reaction where C9 of new conformation will bind of C9 of old, involving the conformational change which enables them to form part of the lipidic double-layer. Thus it is formed a channel through the cellular membrane. Consequently, the permeability of the cell is disturbed, the small molecules penetrate and leave the cell in the vicinity of these pores, and through those. The macromlécules cannot however pass. So the cellular mechanism controlling the balance of the exchanges is upset. Water enters by osmosis the cell, making increase its volume until lysis. One observes this same phenomenon of lysis with red globules in hypotonic solution. This system is very effective since it was observed that the presence of only one of these canals allows the lysis of a red globule.

The alternate Way

The alternate way is the first defense appeared during the evolution and is the first concerned one during an infection by an unknown germ of the organization infected before a specific answer immune.

Activation

It is activated as for it by cellular surfaces of bacteria Gram-plus or gram-, some cells infected by a virus, some yeasts, and parasites. Also by polysaccharides, like the zymosan or inulin, by the LPS (lipopolysaccharides) bacterial, and various substance, like asbestos fibers, the gluten, hemoglobin, certain products of iodized contrast fortements and some tumoral cells. It should be noted that a cellular membrane is all the more activatrice of the alternate way which it is low in acid sialic. The alternate way of activation results from the fixing of C3b on a site acceptor. Permanently of small quantities of C3 are cleaved spontaneously in C3a and C3b. This last has, during a very short moment, a highly reactive site able to be fixed on chemical groupings present on virtually all biological surfaces, mainly bacterial. In the absence of this site acceptor, C3b reacts with water and gives soluble C3b. C3b fixed at a surface can then bind the factor B which is cleaved, in the presence of Mg2+ ions, by the factor D in Bb and Ba, forming alternate C3-convertase, or C3bBb. This C3-convertase cleaves molecules of C3 to form a complex C3bBbC3b, or alternate C5-convertase.

Regulation

It is carried out thanks to various proteins:

• the factor H which acts on the dissociation of the alternate C3/C5 convertase and as cofactor of factor I in the inactivation of C3b in C3bi. The factor H intervenes to control the activation of the alternate way in liquid phase.

• the factor I which inactive C3b in C3bi then in C3c and C3dg, in the presence of factor H
• the properdin or factor P which stabilizes the complex C3bBbC3b

On the level of the membranes, the regulation of the activation of the way alternates is done thanks to various membrane proteins: the receiver of C, CR1, the factor of acceleration of dissociation (DAF), the protein cofactor of membranbe (MCP) or CD46. These proteins act as cofactor of factor I to degrade C3b and C4b or as accelerating of the dissociation of the C3/C5 convertase alternate or traditional (CR1 and DAF).

Sees Lectine S

A globular protein, the Mannose Binding Protein (MBP) of the family of the collectines, can interact with the residues mannose or N-acétylglucosamine (GlcNac) of the micro-organisms. Its structure is homologous in C1q. Its fixing on mannoses of bacteria activates 2 serine-proteases MASP1 and MASP2 or MASP3 which cleave and activate C4 and C2, thus joining the traditional way.

Role in the diseases

The diseases related to a deficit in complement are rare:

• protein deficits of the traditional way: C1q, C2, C4, appear by a lupus

• the protein deficits of the way of the mannanes: MBP, give infection low registers and repeating
• the protein deficits of the alternate way: B, D, Properdin, give serious bacterial infections
• the protein deficits of the membrane complex of attack: C5, C6, C7, C8, are accompanied by infections with Neisseria
• the deficits in inhibiters: H, I give infections with urticaria, weakens haemolytic, glomerulopathy or the deficits in CD55 and CD59 give Hémogloginurie Paroxystique Night (disease of Marchiafava and Michelli) or the deficits in C1inh (edema angio-neurotic).
• of the deficits in CR1 and CR3 was also described.

The diseases accompanied by dysfunctions of the complement are numerous.

Although some disease-causing agents are capable of inactiver the complement, the greatest majority cannot it, and on the contrary, the alternate way of C3 convertase activates. These disease-causing agents support the production of the molecules of the alternate way of activation, in particular C3a, C3b, C5a and the membrane complex of attack C56789. This one being formed on the site of C3-convertase, its activity of degradation is exerted on the pathogenic ones and not on the cells of the host. The soluble fragments of the complement C3a and C5a which are formed have pro-inflammatory properties. For example, the connection of C5a to the receivers of the cells endothéliales increases the vascular permeability and the infiltration of plasmatic proteins in ignited fabrics.

Simple: Complement

Random links:

Acámbaro | Peninsula of Setúbal | Kouakou | Geai with black face | Cnaeus Cornelius Cossus