Complement system Totally Explained

Everything about The Complement System totally explained

The complement system is a biochemical cascade which helps clear pathogens from an organism. It is part of the larger immune system that isn't adaptable and doesn't change over the course of an individual's lifetime; as such it belongs to the innate immune system. However, it can be recruited and brought into action by the adaptive immune system.
The complement system consists of a number of small proteins found in the blood, normally circulating as inactive zymogens. 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 activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex. Over 20 proteins and protein fragments make up the complement system, including serum proteins, serosal proteins, and cell membrane receptors. These proteins are synthesized mainly in the liver, and they account for about 5% of the globulin fraction of blood serum.
Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the mannose-binding lectin pathway.

History

In the late 19th century, blood serum was found to contain a "factor" or "principle" which was capable of killing bacteria. In 1896, Jules Bordet, a young Belgian scientist in Paris at the Pasteur Institute, demonstrated that this principle could be analyzed into two components: a heat-stable and a heat-labile component. (Heat-labile meaning that it lost its effectiveness if the serum was heated.) The heat-stable component was found to confer immunity against specific microorganisms, while the heat-labile component was found to be responsible for the non-specific antimicrobial activity conferred by all normal serum. This heat-labile component is what we now call "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 which have specific receptors on their surface to recognize antigens. Upon immunization with an antigen, more of these receptors are formed, and they're then shed from the cells to circulate in the blood. These receptors, which we now call "antibodies", were called by Ehrlich "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's something in the blood which "complements" the cells of the immune system.
Ehrlich believed that each antigen-specific amboceptor had its own specific complement, while Bordet believed that there's only one type of complement. In the early 20th century, this controversy was resolved when it was understood that complement can act in combination with specific antibodies, or on its own in a non-specific way.

Overview

The three pathways all generate homologous variants of the protease C3-convertase. The classical complement pathway typically requires antibodies for activation (specific immune response), while 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 component C3, creating C3a and C3b and causing a cascade of further cleavage and activation events. 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. Both C3a and C5a have anaphylatoxin activity, directly triggering degranulation of mast cells as well as increasing vascular permeability and smooth muscle contraction. C5b initiates the membrane attack pathway, which results in the membrane 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 other macrophage cell types help clear complement-coated pathogens. As part of the innate immune system, elements of the complement cascade can be found in species earlier than vertebrates; most recently in the protostome horseshoe crab species, putting the origins of the system back further than was previously thought.

Classical pathway

The classical pathway is triggered by activation of the C1-complex (C1q, C1r, and C1s), which occurs when C1q binds to IgM or IgG complexed with antigens (a single IgM can initiate the pathway, while multiple IgG's 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). The C1-complex now binds to and splits C4 and then C2, producing C2a and C4b. The inhibition of C1r and C1s is controlled by C1-inhibitor. C4b and C2a bind to form the classical pathway C3-convertase (C4b2a complex), which promotes cleavage of C3 into C3a and C3b; the latter joins with C2a and C4b (the C3 convertase) to make C5 convertase.
C3-convertase can be inhibited by Decay Accelerating Factor (DAF), which is bound to erythrocyte plasma membranes via a GPI anchor.

Alternative pathway

The alternative pathway is triggered by C3 hydrolysis directly on the surface of a pathogen. It doesn't rely on a pathogen-binding protein like the other pathways. Moreover a common single nucleotide polymorphism in factor H (Y402H) has been associated with the common eye disease 'age related macular degeneration'. Both of these disorders are currently thought to be due to aberrant complement activation on host surfaces.

Modulation by infections

Recent research has suggested that the complement system is manipulated during HIV/AIDS to further damage the body.

Additional images

Image:Droga klasyczna.png|Classical Image:Droga alternatywna.png|Alternative Image:Formowanie MAC.svg Image:Complemento C3 convertasi via classica.gif|Classical Further Information

Get more info on 'Complement System'.

External Link Exchanges

Do you know how hard it is to get a link from a large encyclopaedia? Well we're different and will prove it. To get a link from us just add the following HTML to your site on a relevant page:

<a href="http://complement_system.totallyexplained.com">Complement system Totally Explained</a>

Then simply click through this link from your web page. Our crawlers will verify your link, extract the title of your web page and instantly add a link back to it. If you like you can remove the words Totally Explained and embed the link in article text.
As long as your link remains in place, we'll keep our link to you right here. Please play fair - our crawlers are watching. Your site must be closely related to this one's topic. Any kind of spamming, dubious practises or removing the link will result in your link from us being dropped and, potentially, your whole site being banned.