which complement protein is first common for the classical and alternative pathway

Full Answer

How are complement proteins activated in the plasma?

These proteins are inactively circulating in the plasma and are functional when cleaved into peptide fragments. The activation of the complement system occurs through three different pathways: the classical pathway, the mannose-binding lectin (MBL) pathway, and the alternative pathway.

How many proteins are in the complement system?

About 50 proteins and protein fragments make up the complement system, including serum proteins, and cell membrane receptors. They account for about 10% of the globulin fraction of blood serum. Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the lectin pathway.

What is the difference between classical and alternative complement pathway?

The classical complement pathway typically requires antigen-antibody complexes for activation (specific immune response), whereas the alternative pathway can be activated by spontaneous complement component 3 (C3) hydrolysis, foreign material, pathogens, or damaged cells.

What are the three pathways of the complement system?

The activation of the complement system occurs through three different pathways: the classical pathway, the mannose-binding lectin (MBL) pathway, and the alternative pathway. What is the classical pathway of the complement system? 1. Soluble regulators: 2. Membrane-bound proteins: What is the classical pathway of the complement system?

Which complement component is found in both the classic and alternative pathways?

CD35 {complement receptor 1 (CR1)}: classical, lectin and alternative pathway. CD35 is a transmembrane glycoprotein that facilitates the decay of C3/C5 convertase in both the classical and alternate pathways and acts as a co-factor for factor I in the degradation of C3b and C4b [81].

Which came first the lectin classical pathway or the alternative pathway of complement?

It is a widely accepted canon of immunology that the alternative pathway is more primitive and hence older in evolutionary terms than the lectin/classical pathway.

Is are the first protein in the classical complement pathway?

C1 is the first protein activated in the classical pathway.

Which complement pathway is most common?

All the pathways converge at C3 (which is the most abundant complement protein found in the blood), resulting in the formation of the activation products, C3a, C3b, C5a and the membrane attack complex (C5b-9).

Which complement pathway evolved first?

classical pathwayThe first protein in the classical pathway of complement activation is C1, which is a complex of C1q, C1r, and C1s.

Is C4 alternative pathway?

As noted, C4 (mixture of C4A and C4B) participates in all three of the complement pathways (classical, alternative, and lectin); the alternative pathway is "triggered spontaneously," while the classical and lectin pathways are elicited in response to the recognition of particular microbes.

Is C3 involved in the classical pathway?

There are at least 21 different serum proteins have been confirmed as components of the classical pathway, in which 11 major protein play the most critical role, including C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, C9.

What is classical and alternative pathway?

The classical complement pathway typically requires antigen—antibody complexes (immune complexes) for activation (specific immune response), whereas the alternative pathway can be activated by C3 hydrolysis, foreign material, pathogens, or damaged cells.

What is the alternative pathway of complement activation initiated by?

The alternative pathway (AP) is slowly activated spontaneously by hydrolysis of the internal C3 thioester bond [12–14] and further triggered by contact with various proteins, lipids and carbohydrate structures on microorganisms and other foreign surfaces [1, 15].

Why is C3 commonly measured complement protein?

By measuring the amount of C3 proteins, your healthcare provider can diagnose infection, disease, immune deficiency and other health conditions, like autoimmune disorders. This test also helps your healthcare provider monitor treatment for autoimmune disease.

What does C3 and C4 complement test for?

C3 and C4 are the most commonly measured complement components. A complement test may be used to monitor people with an autoimmune disorder. It is done to see if treatment for their condition is working. When the complement system is turned on during inflammation, levels of complement proteins may go down.

What is the most abundant complement protein quizlet?

The classical and lectin pathways use the classical C3 convertase (C3bBb), whereas the alternative pathway uses the alternative convertase (C4b2a). C3 is the most abundant complement component in the plasma and circulates as a zymogen, an inactive enzyme.

What is the difference between classical pathway and lectin pathway?

The main difference between classical and alternative pathway is that the initiation of alternative pathways is not dependent on the presence of immune complexes. The lectin pathway is activated following the recognition and binding of pathogen-associated molecular patterns (PAMPs) by mannose-binding lectin (MBL) [27].

How does the lectin pathway start?

The lectin pathway is initiated when pattern-recognition molecules (MBL, CL-K1, and ficolins) bind to the so-called pathogen-associated molecular patterns (PAMPs) (D-mannose, N-acetyl-D-glucosamine, or acetyl groups), on the surface of pathogens or to apoptotic or necrotic cells (9).

What is the alternative pathway of complement activation initiated by?

The alternative pathway (AP) is slowly activated spontaneously by hydrolysis of the internal C3 thioester bond [12–14] and further triggered by contact with various proteins, lipids and carbohydrate structures on microorganisms and other foreign surfaces [1, 15].

How is the classical pathway of complement activation?

The complement pathway. Complement can be activated through three pathways: classical, lectin, and alternative. The classical pathway is activated when C1q binds to antibody attached to antigen, activating C1r and C1s, which cleave C4 and C2.

What is the function of complement proteins?

Immune clearance. The complement system removes immune complexes from the circulation and deposits them in the spleen and liver. Thus it acts as anti-inflammatory function. Complement proteins promote the solubilization of these complexes and their clearance by phagocytes.

What is complement path?

The complement system is a part of the innate immune system, consists of a series of proteins that interact with one another in a highly regulated manner, in order to eliminate pathogens. It helps antibodies and phagocytic cells to clear pathogens and damaged cells;

What is the MBL pathway?

The lectin recognizes and binds the carbohydrate of the target cell which then activates complements. MBL pathway resembles classical pathway as it proceeds through the action of C4 and C2 to produce activated proteins of the complement system. MBL works same as C1q which it resembles in structure. After the MBL binds to carbohydrate residues on ...

What bacteria can activate complement?

Microorganisms inducing MBL pathway are bacteria, such as Salmonella, Listeria, and Neisseria strains , some fungi and some viruses including HIV-1. MBL is an acute phase protein and its concentration increases during inflammation. The lectin recognizes and binds the carbohydrate of the target cell which then activates complements.

What complement fragments activate mast cells?

Activation of mast cells and basophils and enhancement of inflammation. The proteolytic complement fragments, C5a, C4a, and C3a induce acute inflammation by activating mast cells and neutrophils. All three peptides bind to mast cells and induce degranulation, with the release of vasoactive mediators such as histamine.

What can stimulate the complement system?

The complement system can also be stimulated by abnormal stimuli, like persistent microbes, antibodies against self-antigens, or immune complexes deposited in tissues. Even when the system is properly regulated and activated, it can cause significant tissue damage.

What attracts neutrophils and macrophages to the area where the antigen is present?

Complement fragments attract neutrophils and macrophages to the area where the antigen is present. These cell surfaces have receptors for complements, like C5a, C3a, thus, run towards the site of inflammation, i.e. chemotaxis.

What is complement protein?

Complement is the term used to describe a group of serum proteins that are critically important in our defense against infection. There are deficiencies of each of the individual components of complement. Patients with complement deficiencies encounter clinical problems that depend on the role of the specific complement protein in normal function.

What is complement in the immune system?

As part of the innate immune system, complement acts immediately to start the process of removal and resolution of the problem. Complement works with the inflammatory cells of the innate immune system and those of adaptive or acquired immunity. It also interacts with proteins of the coagulation and kinin generating systems along with others.

What are the components of the classical pathway?

Aggregates of immunoglobulins such as cryoglobulins also activate the CP. Components of the CP are C1q, C1r, C1s, C2 and C4. The CP was the first to be discovered, but is the most recent in evolutionary terms. The Lectin Pathway (LP) is similar to the CP except for the first two steps. Mannose binding lectin (MBL), the Ficolins, and Collectin can initiate the LP. Associated with these are enzymes referred to as MASPs (MBL-Associated Serine Proteases). C2 and C4 also participate in the LP. The LP is thought to be the most evolutionarily primitive of the complement pathways and the first to react before the adaptive immune response occurs. The Alternative Pathway (AP) is initiated by fragments of the complement component C3. Other elements of the AP are Factor B, Factor D and properdin. A unique feature of the AP is the presence of the only positive regulator in the complement system, Properdin. Properdin makes it possible for the amplification loop of the alternative pathway to set up a very efficient mechanism for putting lots of C3b onto the surface of the activating cells, protein complexes or particles in the immediate vicinity of the activation site. Because the ability of the C3b to bind to these surfaces decays rapidly, the activation is limited to just the region around the C3 cleavage site. This time-limitation is another control mechanism for the complement pathway. The Terminal Pathway (TP) is the final set of steps in the complement activation process that forms a membrane lesion or hole (membrane attack complex or MAC) that kills susceptible bacteria or other cells that activate complement on their surfaces. The TP is dependent upon at least one of the other pathways to initiate the process that it then completes. The components of the TP are C3, C5, C6, C7, C8 and C9. A fluid phase form of the MAC, called the Terminal Complement Complex (TCC) can be found in the circulation after complement activation occurs and makes a useful laboratory marker for complement activation. Control mechanisms to prevent unregulated activity (and tissue damage) are present in each pathway. C1-esterase inhibitor (C1-inh) is a serine protease inhibitor (SERPIN) that acts by forming a complex with active enzymes to trap and inactivate them. It is important in controlling the C1r and C1s activation in the CP, and the MASPs in the LP along with several enzymes in the coagulation system. The dynamic interplay among the different complement pathways and their control processes involves other plasma protein systems such as enzymes of the coagulation system, enzymes from inflammatory cells, and substances such as histamine released from cells in the local environment. All of these participants affect the outcome of an activation event. Most of the time, the outcome is favorable to the host, with the danger met and the situation returned rapidly to normal. The diseases that accompany uncontrolled activation or inadequate performance of complement’s functions are often the result of inherited deficiency or subtle impairment of one or more of the components.

What is the primary deficiency of C1Q?

Primary deficiency of C1q, C1r, C1s or C4 is closely linked to development of systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), thought to be due in part to the inability of complement to clear immune complexes and dying cells.

What is C1-inh?

C1-esterase inhibitor (C1-inh) is a serine protease inhibitor (SERPIN) that acts by forming a complex with active enzymes to trap and inactivate them. It is important in controlling the C1r and C1s activation in the CP, and the MASPs in the LP along with several enzymes in the coagulation system.

How does the complement system work?

The primary functions of the complement system are to protect from infection , to remove particulate substances , (like damaged or dying cells, microbes or immune complexes) and to help modulate adaptive immune responses. As part of the innate immune system, complement acts immediately to start the process of removal and resolution of the problem. Complement works with the inflammatory cells of the innate immune system and those of adaptive or acquired immunity. It also interacts with proteins of the coagulation and kinin generating systems along with others. Complement activation is tightly regulated and designed to kill invading microbes while producing minimal “collateral damage” that could result in the destruction of host tissues. Complement proteins in the circulation are not activated until triggered by an encounter with a bacterial cell, a virus, an immune complex, damaged tissue or other substance not usually present in the body. Complement activation is a cascading event like the falling of a row of dominoes. It must follow a specific order if the end result is to be achieved. The circulating proteins have been grouped into three activation pathways, based on the types of substances and proteins that initiate the activation. If you visualize a trident, the three tines represent the different initiation routes, while the handle represents the lytic mechanism by which this cascade ultimately destroys the threat, no matter which activation pathway started the response. The diagram in Figure 1 depicts the activation pathways.

What are the symptoms of a lack of complement?

Clinical indications for possible complement deficiencies include recurrent mild or serious bacterial infections, autoimmune disease, or episodes of angioedema (a painless, but often dramatic, swelling under the skin, or swelling in the intestines, which can be extremely painful).

What is the classical complement pathway?

The classical complement pathway (see section 7.5) actually invokes multiple mechanisms of action that can help to clear a targeted antigen. The first is the well-known CDC pathway, in which activation of the complement cascade by IgG 1 or IgG 3 results in a series of reactions culminating in the formation of the membrane attack complex (MAC), which forms a pore through the membrane of the targeted cell. This MAC-mediated, immune cell-independent process results in the killing of the target cell through the disruption of its membrane ( Gasque, 2004; Morgan et al., 2005; Jefferis, 2009b, 2009c; Moore et al., 2010 ). The process by which this occurs is a complex and highly regulated biochemical cascade, as described in detail by Gasque (2004), Morgan et al. (2005), and Ricklin and Lambris (2007). The circulating C1 complex is comprised of C1q, C1r, and C1s. As shown in Figure 8.3, C1q has six “heads” that look like a bunch of tulips, each head of which can bind an IgG. At least two of these heads must be occupied to induce the required conformation for deposition of the components C1r and C1s, a requirement which can be met only in immune complexes and not by circulating monomeric IgG ( Jefferis, 2009b ). IgG 1 or IgG 3 binding to C1q activates C1 to become a protease which cleaves complement component C4 into C4a and C4b. C4a, which is an anaphylatoxin, activates inflammatory immune cells, whereas C4b binds to C1, resulting in the formation of a protease that cleaves C2 into C2a and C2b. Ultimately, the pathway results in the proteolytic generation of components C3a and C3b by C3 convertases, as well as C5a and C5b. Formation of C3b exposes thioester groups that attach to the surface of invading bacteria or apoptotic cells to opsonize them. This is a key step in the complement cascade that ultimately leads to elimination of invading pathogens as well as apoptotic host cells ( Ricklin and Lambris, 2007 ). C3a and C5a, which are pro-inflammatory anaphylatoxins, bind to their cognate receptors, C3aR and C5aR, respectively, resulting in activation of the immune system ( Gasque, 2004; Ricklin and Lambris, 2007 ). Similarly, the generation of C5b contributes that component to the membrane attack complex (MAC, which is comprised of complement components C5b, C6, C7, C8, and C9), which inserts into the cell membranes of bacteria and apoptotic cells and forms a pore that causes lysis ( Gasque, 2004 ).

Which polysaccharide activates both the classical and alternative complement pathways?

All the active pectic polysaccharides activate both the classical and alternative complement pathways. Other acidic polysaccharides such as Plantago mucilage A and paniculatan also activate both pathways. 47,64

What is the C1q activator?

In the CP, complement is activated through the PRM termed C1q [4]. C1q is secreted by brain macroglia, monocytes, macrophages, and immature dendritic cells and functions as an important link between the complement and acquired immune systems. The list of endogenous and exogenous C1q activators continues to grow. Endogenous C1q activators include IgM and IgG immune complexes, surface-bound pentraxins (e.g., C-reactive protein (CRP) and pentraxin 3), β-amyloids fibrils, and tissue damaged elements from apoptotic cells (e.g., phosphatidylserine, double-stranded DNA, glyceraldehyde 3-phosphate dehydrogenase, annexins 2 and 5, and calreticulin) [10–12]. Exogenous C1q activators consist mostly of molecular patterns on pathogen surfaces such as bacterial porins and lipopolysaccharides (LPS) [7]. In circulation, C1q associates with two C1r and two C1s serine proteases to form a C1qC1r 2 s 2 pentamer commonly known as the C1 complex. The C1 complex is able to recognize PAMP or DAMP activators through C1q. Activator binding by C1q initiates a conformational change, allowing C1r to autocleave in order to self-activate and in turn, activate C1s ( Fig. 1) [6]. Activated C1s subsequently cleaves C4 to generate C4a (released to circulation) and C4b (opsonizing) fragments [13]. C4b has a highly reactive thioacyl bond capable of cross-linking to –OH or –NH 2 nucleophiles on complement activating surfaces [14]. As such, C4 cleavage by surface-bound C1 complex leads to PAMP or DAMP becoming tagged with C4b. The surface-bound C4b recruits C2, which in turn is cleaved by the C1 complex to release a C2b fragment (to circulation) and a C2a serine protease fragment which stays associated with C4b [6]. The surface-bound C4bC2a protease complex then becomes a key cascade protease of the complement system, the CP C3 convertase [6,15]. The complement C3 convertase plays a central role in complement signal cascade amplification and activation of the TP [2,3,6,8,13]. First, it cleaves C3 into anaphylatoxin and opsonizing fragments, C3a and C3b, respectively. C3a is an anaphylotoxin and its generation starts a series of inflammation processes. Since all three complement activation pathways converge by assembling a C3 convertase, overall, C3b is the major opsonizing agent of the complement pathway. Similar to C4b, C3b uses a reactive thioester bond to cross-link with complement activators, covalently marking these targets for opsonization and also acting as a surface for complement cascade amplification through FB and FD from the AP ( Fig. 1 ).

What is the role of complement in apoptotic cells?

Complement plays a key role in the clearance of immune complexes. Recent evidence supports a role for complement in the clearance of apoptotic cells. These data support the hypothesis that complement deficiency causes lupus by the impairment of physiological disposal of autoantigens, and apoptotic cells may be an important source of the autoantigens that drive the characteristic spectrum of autoantibodies found in SLE.

What is the mechanism that controls the action of anaphylatoxins?

The action of C5a is further controlled by binding to C5a receptors present on the surfaces of circulating leukocytes. These cells immediately endocytose and digest any C5a engaged by the C5aR, removing it from the circulation.

What are the anaphylatoxins in the complement cascade?

All three anaphylatoxins are single-chain polypeptides of about MW 9000, clipped from the N-terminal ends of their respective parent molecules. It is important to note that the anaphylatoxins can also be generated when the complement components are cleaved by enzymes other than those involved in the complement cascade. Kallikrein, plasmin, lysosomal enzymes, and even certain bacterial proteases can directly cleave free C3, C4, and C5 circulating in the blood, to produce C3a, C4a, and C5a.

What is the IgA class in human sera?

Kiyohara et al. 68 found that normal human sera and human colostrums contained IgM, IgG, immunoglobulin A (IgA), and secretory IgA classes of natural antibodies, which react with the complement-activating pectins, pectic polysaccharides, and arabinogalactans from medicinal herbs by different degrees.

Which biochemical pathway activates the complement system?

Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the lectin pathway. The alternative pathway accounts for the majority of terminal pathway activation and so therapeutic efforts in disease have revolved around its inhibition.

What is the alternative complement pathway?

Accordingly, the alternative complement pathway is one element of innate immunity. Once the alternative C3 convertase enzyme is formed on a pathogen or cell surface, it may bind covalently another C3b, to form C3bBbC3bP, the C5 convertase. This enzyme then cleaves C5 to C5a, a potent anaphylatoxin, and C5b.

What is the C3BBBP complex?

The C3bBb complex is stabilized by binding oligomers of factor P (properdin). The stabilized C3 convertase, C3bBbP, then acts enzymatically to cleave much more C3, some of which becomes covalently attached to the same surface as C3b. This newly bound C3b recruits more B, D and P activity and greatly amplifies the complement activation. When complement is activated on a cell surface, the activation is limited by endogenous complement regulatory proteins, which include CD35, CD46, CD55 and CD59, depending on the cell. Pathogens, in general, don't have complement regulatory proteins (there are many exceptions, which reflect adaptation of microbial pathogens to vertebrate immune defenses). Thus, the alternative complement pathway is able to distinguish self from non-self on the basis of the surface expression of complement regulatory proteins. Host cells don't accumulate cell surface C3b (and the proteolytic fragment of C3b called iC3b) because this is prevented by the complement regulatory proteins, while foreign cells, pathogens and abnormal surfaces may be heavily decorated with C3b and iC3b. Accordingly, the alternative complement pathway is one element of innate immunity.

What is complement in the immune system?

Upon immunization with an antigen, more of these receptors are formed, and they are then shed from the cells to circulate in the blood. Those receptors, which 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.

What is the difference between heat-stable and heat-sensitive?

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. In 1899, Paul Ehrlich renamed the heat-sensitive component "complement.". Ehrlich introduced the term "complement" as part ...

Why is paroxysmal hemoglobinuria caused by complement breakdown?

Paroxysmal nocturnal hemoglobinuria is caused by complement breakdown of RBCs due to an inability to make GPI. Thus the RBCs are not protected by GPI anchored proteins such as DAF.

How is the complement system regulated?

The complement system is regulated by complement control proteins, which are present at a higher concentration in the blood plasma than the complement proteins themselves.

What is the alternative complement pathway?

(Some labels are in Polish.) The alternative pathway is a type of cascade reaction of the complement system and is a component of the innate immune system, a natural defense against infections.

What is complement factor H?

Complement Factor H can inhibit the formation of the C3 convertase by competing with factor B for binding to C3b; accelerate the decay of the C3 convertase; and act as a cofactor for Factor I -mediated cleavage of C3b. Complement factor H preferentially binds to vertebrate cells (because of affinity for sialic acid residues), allowing preferential protection of host (as opposed to bacterial) cells from complement-mediated damage.

What is the C5 convertase?

The C5-convertase of the alternative pathway consists of (C3b) 2 BbP (sometimes referred to as C3b 2 Bb). After the creation of C5 convertase (either as (C3b) 2 BbP or C4b2a3b from the classical pathway), the complement system follows the same path regardless of the means of activation (alternative, classical, or lectin). C5-convertase cleaves C5 into C5a and C5b. C5b binds sequentially to C6, C7, C8 and then to multiple molecules of C9 to form membrane attack complex .

Which protein binds to C3B?

CFHR5 (Complement Factor H-Related protein 5) is able to bind to act as a cofactor for factor I, has decay accelerating activity and is able to bind preferentially to C3b at host surfaces.

Does C3B bind to host cells?

Since C3b is free and abundant in the plasma, it can bind to either a host cell or a pathogen surface. To prevent complement activation from proceeding on the host cell, there are several different kinds of regulatory proteins that disrupt the complement activation process:

Which protein cleaves into Ba and Bb?

This change in shape allows the binding of plasma protein Factor B, which allows Factor D to cleave Factor B into Ba and Bb.

Can C3 convertase cleave C3 proteins?

This convertase, the alternative pathway C3-convertase, although only produced in small amounts, can cleave multiple C3 proteins into C3a and C3b. The complex is believed to be unstable until it binds properdin, a serum protein. The addition of properdin forms the complex C3bBbP, a stable compound which can bind an additional C3b ...

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