Complement system - Wikipedia
The classical pathway is activated by IgM, complement fixing .. The alternative activation pathway and complement component C3 are critical. This pathway can proceed on The complement component C3 is. Complement component C3 is cleaved by: A. C3b The classical and alternative pathways meet at complement component: A. C3. B. C4.
Jules Bordeta 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.
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.
InPaul Ehrlich renamed the heat-sensitive component "complement. According to this theory, the immune system consists of cells that have specific receptors on their surface to recognize antigens. Upon immunisation with an antigenmore of these receptors are formed, and they are then shed from the cells to circulate in the blood. Those receptorswhich 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.
C3b has most important opsonizing activity Inflammation — by attracting macrophages and neutrophils Membrane attack — by rupturing cell wall of bacteria Overview[ edit ] Most of the proteins and glycoproteins that constitute the complement system are synthesized by hepatocytes. But significant amounts are also produced by tissue macrophagesblood monocytesand epithelial cells of the genitourinary system and gastrointestinal tract. The three pathways of activation all generate homologous variants of the protease C3-convertase.
The classical complement pathway typically requires antigen-antibody complexes for activation specific immune responsewhereas 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. In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causes a cascade of further cleavage and activation events.
C3b binds to the surface of pathogens, leading to greater internalization by phagocytic cells by opsonization. In the alternative pathway, C3b binds to Factor B.
Classical complement pathway - Wikipedia
C5 convertase is also formed by the classical pathway when C3b binds C4b and C2b. C5a is an important chemotactic proteinhelping recruit inflammatory cells. C3a is the precursor of an important cytokine adipokine named ASP although this is not universally accepted  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.
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.
Reaction Cascade of the Complement System: Classical complement pathway The classical and alternative complement pathways The classical pathway is triggered by activation of the C1-complex.
The C1-complex is composed of 1 molecule of C1q, 2 molecules of C1r and 2 molecules of C1s, or C1qr2s2. A single pentameric IgM can initiate the pathway, while several, ideally six, IgGs are needed.
This also occurs 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 molecules.
C1r is a serine protease. They then cleave C1s another serine protease. In this way, the activation of a small number of complement proteins at the start of the pathway is hugely amplified by each successive enzymatic reaction, resulting in the rapid generation of a disproportionately large complement response. As might be expected, there are many regulatory mechanisms to prevent uncontrolled complement activation. The blood coagulation system is another example of a triggered-enzyme cascade.
In this case, a small injury to a blood vessel wall can lead to the development of a large thrombus. There are three distinct pathways through which complement can be activated on pathogen surfaces. These pathways depend on different molecules for their initiation, but they converge to generate the same set of effector molecules Fig.
There are three ways in which the complement system protects against infection. First, it generates large numbers of activated complement proteins that bind covalently to pathogens, opsonizing them for engulfment by phagocytes bearing receptors for complement.
Complement System | British Society for Immunology
Second, the small fragments of some complement proteins act as chemoattractants to recruit more phagocytes to the site of complement activation, and also to activate these phagocytes.
Third, the terminal complement components damage certain bacteria by creating pores in the bacterial membrane. There are three pathways of complement activation: Complement is a system of plasma proteins that interacts with pathogens to mark them for destruction by phagocytes In the early phases of an infection, the complement cascade can be activated on the surface of a pathogen through any one, or more, of the three pathways shown in Fig.
The classical pathway can be initiated by the binding of C1q, the first protein in the complement cascade, directly to the pathogen surface. It can also be activated during an adaptive immune response by the binding of C1q to antibody: The mannan-binding lectin pathway MB-lectin pathway is initiated by binding of the mannan-binding lectin, a serum protein, to mannose-containing carbohydrates on bacteria or viruses.
Finally, the alternative pathway can be initiated when a spontaneously activated complement component binds to the surface of a pathogen.
- Classical complement pathway
Each pathway follows a sequence of reactions to generate a protease called a C3 convertase. The active protease is retained at the pathogen surface, and this ensures that the next complement zymogen in the pathway is also cleaved and activated at the pathogen surface. By contrast, the small peptide fragment is released from the site of the reaction and can act as a soluble mediator.
The early events of all three pathways of complement activation involve a series of cleavage reactions that culminate in the formation of an enzymatic activity called a C3 convertase, more The C3 convertases formed by these early events of complement activation are bound covalently to the pathogen surface. Here they cleave C3 to generate large amounts of C3bthe main effector molecule of the complement system, and C3a, a peptide mediator of inflammation.
The C3b molecules act as opsonins; they bind covalently to the pathogen and thereby target it for destruction by phagocytes equipped with receptors for C3b. These comprise a sequence of polymerization reactions in which the terminal complement components interact to form a membrane-attack complexwhich creates a pore in the cell membranes of some pathogens that can lead to their death.
The nomenclature of complement proteins is often a significant obstacle to understanding this system, and before discussing the complement cascade in more detail, we will explain the conventions, and the nomenclature used in this book. All components of the classical complement pathway and the membrane-attack complex are designated by the letter C followed by a number. The native components have a simple number designation, for example, C1 and C2, but unfortunately, the components were numbered in the order of their discovery rather than the sequence of reactions, which is C1, C4, C2, C3, C5C6, C7C8, and C9.
The products of the cleavage reactions are designated by added lower-case letters, the larger fragment being designated b and the smaller a; thus, for example, C4 is cleaved to C4b, the large fragment of C4 that binds covalently to the surface of the pathogen, and C4a, a small fragment with weak pro-inflammatory properties.
The components of the alternative pathwayinstead of being numbered, are designated by different capital letters, for example factor B and factor D. As with the classical pathwaytheir cleavage products are designated by the addition of lower-case a and b: Finally, in the mannose-binding lectin pathway, the first enzymes to be activated are known as the mannan-binding lectin-associated serine proteases MASP-1 and MASP-2, after which the pathway is essentially the same as the classical pathway.
Activated complement components are often designated by a horizontal line, for example, ; however, we will not use this convention. It is also useful to be aware that the large active fragment of C2 was originally designated C2a, and is still called that in some texts and research papers.
Here, for consistency, we will call all large fragments of complement b, so the large active fragment of C2 will be designated C2b.
The formation of C3 convertase activity is pivotal in complement activation, leading to the production of the principal effector molecules, and initiating the late events. In the classical and MB-lectin pathways, the C3 convertase is formed from membrane-bound C4b complexed with C2b.
In the alternative pathwaya homologous C3 convertase is formed from membrane-bound C3b complexed with Bb. The alternative pathway can act as an amplification loop for all three pathways, as it is initiated by the binding of C3b. It is clear that a pathway leading to such potent inflammatory and destructive effects, and which, moreover, has a series of built-in amplification steps, is potentially dangerous and must be subject to tight regulation.
One important safeguard is that key activated complement components are rapidly inactivated unless they bind to the pathogen surface on which their activation was initiated. There are also several points in the pathway at which regulatory proteins act on complement components to prevent the inadvertent activation of complement on host cell surfaces, hence protecting them from accidental damage.
We will return to these regulatory mechanisms later.
We have now introduced all the relevant components of complement and are ready for a more detailed account of their functions. To help distinguish the different components according to their functions, we will use a color code in the figures in this part of the chapter.
This is introduced in Fig. Functional protein classes in the complement system. The classical pathway is initiated by activation of the C1 complex The classical pathway plays a role in both innate and adaptive immunity.
As we will see in Chapter 9, the first component of this pathway, C1q, links the adaptive humoral immune response to the complement system by binding to antibodies complexed with antigens. C1q can, however, also bind directly to the surface of certain pathogens and thus trigger complement activation in the absence of antibody. C1q is part of the C1 complexwhich comprises a single C1q molecule bound to two molecules each of the zymogens C1r and C1s.
C1q is a calcium-dependent sugar-binding protein, a lectin, belonging to the collectin family of proteins, which contains both collagen-like and lectin domains hence the name collectin.
It has six globular heads, linked together by a collagen-like tail, which surround the C1r: C1s 2 complex Fig.