The complementary system is part of the immune system that enhances the ability of antibodies and phagocytic cells to cleanse microbes and damage cells from an organism, increase inflammation, and attack pathogen cell membranes. It is part of the innate immune system, which can not adapt and remain unchanged during one's lifetime. Complementary systems can, however, be recruited and brought into action by the antibodies produced by the adaptive immune system.
The complement system consists of a number of small proteins found in the blood, synthesized by the liver, which circulates as an inactive precursor (pro-protein). When stimulated by one of several triggers, the protease in the system divides the specific protein to release the cytokine and initiates a further magnification cavity. The end result of complementary activation or supplementary fixation cascade is phagocyte stimulation to clean out alien and damaged material, inflammation to attract additional phagocytes, and activation of cell-killing membranes invades the complex. More than 30 proteins and protein fragments form a complement system, including serum proteins, and cell membrane receptors. They account for about 10% of the blood serum globulin fraction.
Three biochemical pathways activate complementary systems: classic complementary pathways, alternative complementary pathways, and lectin pathways.
Video Complement system
History
In 1888, George Nuttall discovered that sheep blood serum had a mild killing activity against the bacteria that caused Anthrax. The killing activity disappears when he heats the blood. In 1891, Hans Ernst August Buchner, noted the same nature of blood in his experiments, named the property of the "alexin murder", which means "parry" in Greek. In 1884, several laboratories have shown that serum from guinea pigs that have recovered from cholera kill the cholera bacteria in vitro . Serum heating destroys his murderous activity. However, the heat-activated serum, when injected into a marmot exposed to cholera bacteria, retains its ability to protect animals from disease. Jules Bordet, a Belgian young scientist in Paris at the Pasteur Institute, concluded that this principle has two components, which retain the "sensitization" effect after heating and one (alexin) whose toxic effects are lost after heating. The heat stable component is responsible for immunity to certain microorganisms, whereas the heat-sensitive component is responsible for the non-specific antimicrobial activity provided by all normal serum. In 1899, Paul Ehrlich renamed the heat-sensitive "compass" component.
Ehrlich introduced the term "complementary" as part of his larger theory of the immune system. According to this theory, the immune system consists of cells that have specific receptors on the surface to recognize the antigen. After immunization with antigens, more of these receptors are formed, and they are then released from the cells to circulate in the blood. These receptors, which we now call "antibodies," are called by Ehrlich "amboceptors" to emphasize their bifunctional binding capacity: They recognize and bind to specific antigens, but they also recognize and bind the hot-labile antimicrobial component of fresh serum.. Ehrlich, therefore, named this heat-labile component "complementary," because it is something in the blood that "complements" the immune system cells. Ehrlich believes that any antigen-specific amboceptor has its own particular complement, while Bordet believes that there is only one type of complement. At the beginning of the 20th century, this controversy was solved when it was understood that the supplement could act in combination with specific antibodies, or by itself in non-specific ways.
Maps Complement system
Function
Complementary trigger the following immune functions:
- Phagocytosis - by opsonizing the antigen. C3b has the most important opsonizing activity
- Inflammation - by pulling macrophages and neutrophils
- An attack membrane - by breaking the bacterial cell wall
Overview
Most proteins and glycoproteins which are complementary systems are synthesized by hepatocytes. But significant amounts are also produced by tissue macrophages, blood monocytes, and epithelial genitourinary system cells and gastrointestinal tract. The three activation pathways all produce a homologous variant of the C3-convertase protease. Classical complementary pathways usually require antigen-antibody complexes for activation (specific immune responses), whereas alternative pathways may be activated by spontaneous C3 hydrolysis, foreign material, pathogens, or damaged cells. Mannose-binding lectin pathways may be activated by hydrolysis or C3 antigens in the absence of antibodies (non-specific immune responses). In all three paths, C3-convertase cuts and activates C3 components, creates C3a and C3b, and causes cascade division and event activation further. C3b binds the surface of the pathogen, leading to greater internalization by phagocytic cells by opsonization.
In alternative pathways, C3b binds Factor B. Factor D releases the Ba Factor from Factor B bound to C3b. Complex C3b (2) Bb is a protease that cuts C5 into C5b and C5a. C5 convertase is also formed by the Classical Path when C3b binds C4b and C2a. C5a is an important chemotactic protein, helping to recruit inflammatory cells. C3a is a precursor of an important cytokine (adipokine) called ASP (although it is not universally accepted) and is usually rapidly cleaved by carboxypeptidase B. Both C3a and C5a have anaphyloxoxin activity, directly triggering mast cell degranulation and increasing vascular permeability and smooth muscle contraction. C5b initiates the path of the membrane attack, resulting in a membrane attack complex (MAC), which consists of C5b, C6, C7, C8, and C9 polymers. MAC is a cytolytic endproduct of a complement cascade; forming a transmembrane channel, which causes the osmotic lysis of the target cell. The Kupffer cell and other macrophage cell types help clear the plated complementary pathogens. As part of the innate immune system, complement cascade elements can be found in species earlier than vertebrates; most recently in the protostome horseshoe crab species, puts the origin of the system back farther than previously thought.
Classic path
The classic pathway is triggered by C1-complex activation. C1-complex consists of 1 molecule C1q, 2 molecules C1r and 2 molecules C1, or C1qr 2 s 2 . This occurs when C1q binds to IgM or IgG complexed with antigens. A single pentameric IgM can initiate a path, while some, ideally six, IgG are required. 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 split C1 (other serine proteases). The C1r 2 s 2 component now divides C4 and then C2, resulting in C4a, C4b, C2a, and C2b (catalyze C4). C4b and C2a bind to form the classical C3-convertase pathway (C4b2a complex), which encourages the cleavage of C3 to C3a and C3b. C3b then merged with C4b2a to make C5 convertase (C4b2a3b complex).
Alternate path
Alternate paths continue to be activated at a low level, analogous to idle car engines, as a result of spontaneous C3 hydrolysis due to internal thioester bond breakdown (C3 is somewhat unstable in aqueous environments). Alternative pathways do not depend on pathogen-binding antibodies such as other pathways. C3b produced from C3 by C3 converting enzyme complexes in the liquid phase is rapidly inactivated by factor H and factor I, such as C3b-like C3 which is a spontaneous cleavage product of the internal thioester. Conversely, when the internal thioester C3 reacts with the hydroxyl or amino group of a molecule on the surface of the cell or pathogen, C3b is now covalently bonded to the surface protected from the inactivation of the mediated H factor. C3b that is bonded on the surface can now bind factor B to form C3bB. This complex before the D factor will be split into Ba and Bb. Bb will remain in contact with C3b to form C3bBb, which is an alternative C3 convertase path.
The C3bBb complex is stabilized by binding the oligomers of the P factor (Properdin). The stable C3 convertase, C3bBbP, then acts enzymatically to split more C3, some of which become covalently attached to the same surface as C3b. The newly bound C3b recruits more B, D, and P activities and strongly reinforces complement activation. When the complement is activated on the cell surface, activation is limited by endogenous complementary regulating proteins, which include CD35, CD46, CD55 and CD59, depending on the cell. Pathogens, in general, do not have complementary regulatory proteins (there are many exceptions, which reflect the adaptation of pathogenic microbes for the defense of vertebrate immunity). Thus, alternative complementary pathways are able to distinguish themselves from non-self on the basis of surface expression of complementary control proteins. The host cell does not accumulate the surface of C3b cells (and the proteolytic fragments of C3b called iC3b) because these are prevented by complementary regulatory proteins, while foreign cells, pathogens and abnormal surfaces may be greatly adorned with C3b and iC3b. Thus, an alternative complementary pathway is one of the elements of innate immunity.
Once an alternative C3 convertase enzyme is formed on a pathogen or cell surface, it may bind another covalent C3b, to form C3bBbC3bP, convertase C5. This enzyme then cuts C5 to C5a, strong anaphyloxoxine, and C5b. The C5b then recruits and assembles C6, C7, C8 and some C9 molecules to assemble complex membrane attacks. It creates holes or pores in membranes that can kill or damage pathogens or cells.
Pathway
The lectin pathway is homologous with the classical pathway, but with opsonin, mannose-binding lectin (MBL), and ficolins, not C1q. This pathway is activated by binding MBL to the mannose residue on the pathogen surface, which activates the associated serine protease MBL, MASP-1, and MASP-2 (very similar to C1r and C1s, respectively), which can then break down C4 into C4a and C4b and C2 becomes C2a and C2b. C4b and C2b then bind together to form a classic C3-convertase, as in the classical path. Fikolin is homologous with MBL and works through MASP in the same way. Several single nucleotide polymorphisms have been described in M-ficolin in humans, with effects on ligand binding ability and serum levels. Historically, the larger C2 fragment is named C2a, but is now referred to as C2b. In invertebrates without adaptive immune systems, the ficolins are expanded and the specificity of binding is diversified to compensate for the lack of pathogen-specific introduction molecules.
Complete the protein fragment nomenclature
Immunological textbooks have used different naming naming for smaller and larger C2 fragments as C2a and C2b. The preferred task seems to be that smaller fragments are defined as C2a: as early as 1994, a well-known book suggests that larger C2b fragments should be designated C2b. However, this is reinforced in their 4th edition of 1999, to say that: "It is also useful to realize that the larger C2 active fragments were initially designated C2a, and are still mentioned in some texts and research papers. consistency, we will call all major parts of the complement b , so that a larger fragment of C2 will be designated C2b.In the classical path and lectin the C3 convertase enzyme is formed from membrane-bound C4b with C2b. "
This nomenclature is used in other literature: "(Note that, in older texts, smaller fragments are often called C2b, and larger ones are called C2a for historical reasons.)" Assignments are mixed in the last literature, though. Some sources indicate larger and smaller fragments as C2a and C2b respectively while other sources apply the opposite. However, due to the widely defined convention, C2b here is a larger fragment, which, in the classical path, forms C4b2b (classically C4b2a). It may be worth noting that, in a series of Janeway's book editions, 1-7, in the latest edition they drew an attitude to show the larger C2b fragment as C2b.
Viral inhibition
The fixation of MBL proteins on the surface of the virus has also been shown to increase the neutralization of viral pathogens.
Review
Complement activation by antigen-related antibody
On the classical path, C1 binds the C1q subunit to the fragment Fc (created from region CH2) of IgG or IgM, which has formed a complex with antigens. C4b and C3b can also bind to IgG or IgG-related antigens, to its Fc section.
The binding of the immunoglobulin-mediated complement may be interpreted as a complement using the immunoglobulin ability to detect and bind the non-self antigen as a guide stick. The complement itself can bind non-self pathogens after detecting molecular patterns associated with pathogens (PAMP), however, by using the specificity of the antibodies, the complement can detect non-self enemies more specifically.
Some components have various binding sites. On the classical pathway, C4 binds to Ig-associated C1q and C1r 2 s 2 enzymes cutting C4 to C4b and 4a. C4b binds C1q, Ig-related antigens (especially to Fc parts), and even to the surface of microbes. C3b binds Ig associated antigen and to the microbial surface. C3b's ability to bind Ig-associated antigens will work effectively against the antigen-antibody complex to make it dissolve.
Rule
Complementary systems have the potential to damage the host network, which means that activation must be strictly regulated. The complement system is regulated by the complement control protein, which is present at higher concentrations in the blood plasma than the complementary protein itself. Some complementary control proteins are present on the membrane of independent cells that prevent them from being a complementary target. One example is CD59, also known as protectin, which inhibits C9 polymerization during the formation of a membrane attack complex. The classical pathway is inhibited by C1-inhibitors, which bind C1 to prevent activation.
C3-convertase can be inhibited by Decay accelerating factor (DAF), which is bound to the erythrocyte plasma membrane through GPI anchors.
Role in disease
Complementary deficiency
It is thought that complementary systems may play a role in many diseases with immune components, such as Barraquer-Simons Syndrome, asthma, lupus erythematosus, glomerulonephritis, various forms of arthritis, autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, paroxysmal. nocturnal hemoglobinuria, atypical hemolytic uremic syndrome and ischemic-reperfusion injury, and transplant organ rejection.
The complement system also becomes increasingly involved in diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions such as spinal cord injury.
Lack of terminal pathways affects both autoimmune diseases and infections (especially Neisseria meningitidis, due to the complex role of membrane attack ("MAC") attacking Gram-negative bacteria).
Infection with N. meningitidis and N. gonorrhoeae is the only known condition associated with a complement component MAC deficiency. 40-50% of those with MAC deficiency have recurrent infections with N. meningitidis .
Disadvantages in regulatory complements
Mutations in the complement of factor H regulators and membrane cofactor proteins have been associated with atypical hemolytic uremic syndrome. In addition, single common nucleotide polymorphisms in factor H (Y402H) have been associated with common eye diseases of age-related macular degeneration. Complementary component polymorphism 3, complementary factor B, and complementary factor I, as well as the elimination of complementary factors H-3 and H-1 complement factors also affect a person's risk of developing age-related macular degeneration. Both of these disorders are presently thought to be due to complementary activation that deviates on the surface of the host cell.
Mutations in the C1 inhibitor gene may cause hereditary angioedema, a genetic condition resulting from a reduction in bradykinin regulation by C1-INH.
Paroxysmal nocturnal hemoglobinuria is caused by impairment of red blood cells due to the inability to make GPI. Thus red blood cells are not protected by GPI anchored proteins such as DAF.
Diagnostic tools
Diagnostic tools for measuring complementary activities include total activity test activities.
The presence or absence of a complementary fixation on the challenge can indicate whether certain antigens or antibodies are present in the blood. This is the principle of complementary fixation test.
Modulation by infection
Recent research has shown that the complement system is manipulated during HIV/AIDS, in a way that further damages the body.
References
Source of the article : Wikipedia
0 Comments