The complement system is a part of the immune system that helps defend against infection by enhancing the ability of antibodies and phagocytic cells to clear microbes and damaged cells, promoting inflammation, and attacking the pathogen`s cell membrane. The complement system consists of a number of small proteins that circulate in the blood as inactive precursors or reside on cell surfaces. When stimulated by one of several triggers, these proteins undergo a series of proteolytic reactions that result in the generation of biologically active products.

There are three main pathways of complement activation: the classical pathway, the alternative pathway, and the lectin pathway. These pathways differ in how they are initiated, but they converge into a common terminal pathway that leads to the formation of the membrane attack complex (MAC), a pore-like structure that lyses target cells.

• The classical pathway is activated by certain isotypes of antibodies (mainly IgM and IgG) bound to antigens on the surface of microbes or other structures. This pathway involves a plasma protein called C1q that recognizes and binds to the Fc portion of the antibodies, activating two associated serine proteases, C1r and C1s, that initiate a cascade of enzyme activation involving other complement proteins. The classical pathway is one of the major effector mechanisms of the humoral arm of adaptive immune responses.
• The alternative pathway is activated by microbial cell surfaces or certain immunoglobulins in the absence of antibody. This pathway involves a complement protein called C3 that directly recognizes and binds to certain microbial structures, such as lipopolysaccharide (LPS) on gram-negative bacteria. C3 is also constantly activated in solution at a low level and binds to cell surfaces, but it is inhibited by regulatory molecules present on mammalian cells. Because microbes lack these regulatory molecules, the spontaneous activation can be amplified on microbial surfaces. Thus, this pathway can distinguish normal self from foreign microbes on the basis of the presence or absence of the regulatory proteins. The alternative pathway is phylogenetically older than the classical pathway and represents an innate defense mechanism against infection.
• The lectin pathway is activated by a plasma protein called mannose-binding lectin (MBL) that recognizes and binds to mannose, fucose, or N-acetylglucosamine residues on microbial glycoproteins and glycolipids. MBL is a member of the collectin family with a hexameric structure similar to C1q. After MBL binds to microbes, two zymogens called MASP1 and MASP2 (MBL-associated serine proteases) associate with MBL and initiate downstream proteolytic steps identical to the classical pathway. The lectin pathway resembles the classical pathway structurally and functionally, but it does not require antibody for activation.

All three pathways result in the generation of enzyme complexes that cleave C3 into C3a and C3b, which are biologically active fragments. C3b becomes covalently attached to microbial surfaces or to antibody-antigen complexes, enhancing their phagocytosis by cells that express receptors for C3b. C3a is an anaphylatoxin that stimulates inflammation by inducing mast cell degranulation and chemotaxis of leukocytes. The cleavage of C3 also leads to the formation of C5 convertase, which cleaves C5 into C5a and C5b. C5a is another anaphylatoxin with similar functions as C3a, while C5b initiates the assembly of MAC on target cell membranes. MAC causes osmotic lysis of foreign cells by creating pores in their membranes.

The complement system is regulated by various factors that prevent excessive activation and damage to host cells. These factors include inhibitors of enzyme activity (such as C1 inhibitor), cofactors for factor I-mediated cleavage of C3b and C4b (such as membrane cofactor protein), decay-accelerating factors that dissociate C3 convertase (such as CD55), and membrane-protective proteins that prevent MAC formation (such as CD59). Deficiencies or dysfunctions of these regulatory factors can result in various diseases involving complement-mediated tissue damage or susceptibility to infection.

The complement system represents the dynamic interplay among different pathways, control processes, and other protein systems and cells in the local environment. Complement activation plays an important role in both innate and adaptive immunity by augmenting antibody responses and immunologic memory, lysing foreign cells, clearing immune complexes and apoptotic cells, stimulating inflammation, and modulating other immune functions.

The classical pathway is one of the three pathways of complement activation. It is activated by certain isotypes of antibodies bound to antigens on the surface of microbes or other structures. The antibodies that can trigger this pathway are mainly IgM and IgG, which are produced by B cells as part of the adaptive immune response. The classical pathway can also be initiated by innate immune system proteins called pentraxins, such as C-reactive protein (CRP), which can bind to C1q and activate the complement cascade.

The first step in the classical pathway is the binding of C1q, a hexameric protein with six globular heads and six collagen-like tails, to the Fc portion of the antibodies or to the pentraxins. This binding induces a conformational change in C1q that activates two associated serine proteases, C1r and C1s. C1r cleaves and activates another C1r molecule, forming a C1r2 complex. The activated C1r2 then cleaves and activates two molecules of C1s, forming a C1s2 complex. The C1 complex, consisting of C1q, C1r2 and C1s2, is now fully active and ready to cleave the next complement proteins in the cascade.

The second step in the classical pathway is the cleavage of C4 and C2 by the C1 complex. The activated C1s2 cleaves C4 into two fragments: C4a, which is released into the fluid phase, and C4b, which binds covalently to the nearby surface through a reactive thioester bond. The bound C4b then binds to C2, forming a complex that is cleaved by C1s2 into two fragments: C2a, which remains attached to C4b, and C2b, which is released into the fluid phase. The C4b2a complex is also known as the classical pathway C3 convertase, because it can cleave C3 into C3a and C3b.

The third step in the classical pathway is the cleavage of C3 by the classical pathway C3 convertase. The bound C3b can then bind to another molecule of C2, forming a complex that is cleaved by C1s2 into two fragments: C2a, which remains attached to C3b, and C2b, which is released into the fluid phase. The resulting complex, called C4b2a3b or classical pathway C5 convertase, can cleave C5 into C5a and C5b.

The fourth step in the classical pathway is the formation of the membrane attack complex (MAC) by the assembly of terminal complement components. The MAC consists of multiple copies of proteins called C6, C7, C8 and C9 that form a pore in the membrane of the target cell, leading to its lysis.

The classical pathway has several biological functions in immunity. It can opsonize microbes by coating them with C3b and/or IgG for enhanced phagocytosis by macrophages and neutrophils. It can stimulate inflammation by releasing anaphylatoxins such as C3a and C5a that attract and activate leukocytes and increase vascular permeability. It can also induce cell lysis by forming MAC on susceptible cells such as bacteria or virus-infected cells.

The classical pathway is regulated by several mechanisms to prevent excessive or inappropriate activation. Some of these mechanisms include:

• The dissociation of the unstable enzyme complexes such as C1 or C4b2a.
• The inhibition of enzyme activity by plasma proteins such as factor I or factor H that cleave or displace bound complement components.
• The binding of soluble or membrane-bound receptors such as CR1 or DAF that interfere with complement binding or assembly.
• The degradation of anaphylatoxins by enzymes such as carboxypeptidase N or carboxypeptidase B that remove their terminal amino acids.

In summary, the classical pathway is a complement activation pathway that is triggered by antibodies or pentraxins bound to antigens on target surfaces. It involves a series of proteolytic reactions that generate enzyme complexes that cleave complement proteins and produce biological effects such as opsonization, inflammation and lysis. It is regulated by various factors that limit its activity and prevent damage to host cells.

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. The alternative pathway is one of three complement pathways that opsonize and kill pathogens.

The alternative pathway is triggered when a complement protein called C3 directly recognizes certain microbial surface structures, such as bacterial lipopolysaccharide (LPS). C3 is also constitutively activated in solution at a low level and binds to cell surfaces, but it is then inhibited by regulatory molecules present on mammalian cells. Because microbes lack these regulatory proteins, the spontaneous activation can be amplified on microbial surfaces. Thus, this pathway can distinguish normal self from foreign microbes on the basis of the presence or absence of the regulatory proteins.

The alternative pathway involves the following steps :

• C3 undergoes spontaneous hydrolysis to form C3(H2O), which exposes a reactive thioester bond.
• C3(H2O) binds to factor B, a plasma protein, which allows factor D, a serine protease, to cleave factor B into Ba and Bb. Bb remains bound to C3(H2O) to form C3(H2O)Bb.
• C3(H2O)Bb is also known as a fluid-phase C3 convertase. This convertase can cleave multiple C3 proteins into C3a and C3b. C3a is an anaphylatoxin that stimulates inflammation. C3b covalently attaches to the surface of the activator (microbe or foreign material) by reacting with hydroxyl or amino groups.
• C3b binds to factor B, which allows factor D to cleave factor B into Ba and Bb. Bb remains bound to C3b to form C3bBb.
• C3bBb is also known as a membrane-bound C3 convertase. This convertase can cleave more C3 proteins into C3a and C3b. The newly formed C3b can bind to another molecule of C3bBb to form C3b2Bb.
• C3b2Bb is also known as a membrane-bound C5 convertase. This convertase can cleave C5 into C5a and C5b. C5a is another anaphylatoxin that stimulates inflammation. C5b initiates the formation of the membrane attack complex (MAC), which lyses the target cell.

The alternative pathway is regulated by several mechanisms to prevent excessive activation and damage to host cells :

• The fluid-phase and membrane-bound C3 convertases are unstable and decay spontaneously over time.
• Factor H, a plasma protein, competes with factor B for binding to C3b and accelerates the decay of the C3 convertases. Factor H also acts as a cofactor for factor I, another plasma protease, which cleaves C3b into inactive fragments (iC3b and C3d).
• Complement receptor 1 (CR1) and decay-accelerating factor (DAF), two membrane proteins expressed on host cells, also compete with factor B for binding to C3b and accelerate the decay of the C3 convertases.
• Membrane cofactor protein (MCP) and CR1 act as cofactors for factor I, which cleaves C3b into inactive fragments on host cell surfaces.
• Properdin, a plasma protein, stabilizes the membrane-bound C3 convertases by binding to them. Properdin also enhances the recognition of microbial surfaces by the alternative pathway.

The alternative pathway plays an important role in innate immunity by opsonizing and killing microbes, stimulating inflammation, and enhancing adaptive immune responses. However, dysregulation or deficiency of the alternative pathway can lead to various diseases, such as atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD), and systemic lupus erythematosus (SLE).

The lectin pathway is another way of activating the complement system without the involvement of antibodies. It is triggered by a type of carbohydrate-binding protein called lectin or collectin that recognizes and binds to specific sugars on the surface of microbes or dying cells .

One of the most important lectins in this pathway is mannose-binding lectin (MBL), which can bind to mannose, glucose, fucose, and N-acetylglucosamine residues that are commonly found on bacterial, fungal, parasitic, and viral pathogens . MBL is produced by the liver and circulates in the blood as a complex with serine proteases called MASP-1, MASP-2, MASP-3, MAp19, and MAp44 .

When MBL binds to a microbe or a dying cell, it activates MASP-1 and MASP-2, which are similar to C1r and C1s of the classical pathway. These proteases then cleave C4 and C2 to form C4b and C2a, which together make up the C3 convertase (C4bC2a) on the target surface . MASP-3, MAp19, and MAp44 are alternative splice products of MASP-1 and MASP-2 genes that may have regulatory roles in this pathway .

The lectin pathway can also be initiated by other collectins such as ficolins and collectin 11 (CL11), which have different sugar specificities and associate with different MASPs . Ficolins can bind to N-acetylglucosamine, acetylated compounds, and sialic acid on microbes, while CL11 can bind to galactose and N-acetylgalactosamine residues . These collectins activate MASP-1 and MASP-2 in a similar manner as MBL .

The lectin pathway shares many similarities with the classical pathway, such as the generation of C3 convertase, C5 convertase, and downstream effector functions. However, it differs in the way it recognizes the activators and initiates the cascade. The lectin pathway is part of the innate immune system that can rapidly respond to microbial invasion without prior exposure or antibody production .

The complement protein C3 is the most abundant and central component of the complement system. It is synthesized in the liver and circulates in the plasma as an inactive precursor. C3 has a molecular weight of about 190 kDa and consists of two polypeptide chains, called α and β, linked by disulfide bonds. The α chain contains a thioester bond that is essential for the biological activity of C3.

The thioester bond is normally hidden within the C3 molecule and protected from hydrolysis. However, when C3 is activated by any of the three pathways, the thioester bond becomes exposed and reacts with hydroxyl or amino groups on nearby molecules. This results in the covalent attachment of C3 to the surface of microbes or other targets, or to fluid-phase molecules such as antibodies. The covalently bound form of C3 is called C3b.

The cleavage of C3 also generates another fragment, called C3a, which is released into the surrounding fluid. C3a is a small peptide of about 9 kDa that has potent inflammatory effects. It can bind to receptors on mast cells, basophils, eosinophils, and phagocytes, and trigger the release of histamine, cytokines, and other mediators. C3a also increases vascular permeability, attracts leukocytes to the site of infection or injury, and enhances their activation.

The generation of enzyme complexes that cleave C3 is the key step in all pathways of complement activation. These enzyme complexes are called C3 convertases. Each pathway has its own mechanism for forming C3 convertases, but they all share a common structure: a protease that cleaves C3 (called Bb or C2a) bound to a recognition molecule that binds to the target surface (called C3b or C4b). The classical and lectin pathways use a similar type of C3 convertase, composed of C4b and C2a (C4b2a), while the alternative pathway uses a different type of C3 convertase, composed of C3b and Bb (C3bBb).

The formation of C3 convertases initiates a positive feedback loop that amplifies the production of more C3b. This is because C3b can bind to the recognition molecules of the existing C3 convertases and form new ones. For example, in the classical pathway, C4b2a can bind to another molecule of C3b and form a new complex called C4b2aC3b. This complex can then cleave more molecules of C3 and generate more C3b. Similarly, in the alternative pathway, C3bBb can bind to another molecule of C3b and form a new complex called C3bBbC3b. This complex can also cleave more molecules of C3 and generate more C3b.

The amplification of C3b production ensures that enough complement proteins are deposited on the target surface to mark it for destruction by phagocytes or by membrane attack complexes (discussed later). However, this amplification also poses a risk of excessive complement activation and damage to host cells. Therefore, there are several regulatory mechanisms that control the formation and stability of C3 convertases and prevent their indiscriminate action on self surfaces. These mechanisms will be discussed in more detail later.

In summary, all pathways of complement activation converge on the generation of enzyme complexes that cleave the complement protein C3 into two fragments: C3a and C3b. The fragment C3a has inflammatory effects, while the fragment C3b covalently attaches to target surfaces or fluid-phase molecules and forms new enzyme complexes that cleave more molecules of C3. This amplifies the production of more C3a and C3b and enhances the biological effects of complement activation.

The complement protein C3 is the most abundant and important component of the complement system. It exists in plasma as a proenzyme that can be cleaved by different enzyme complexes to generate two fragments: C3a and C3b. C3a is a small peptide that acts as an anaphylatoxin, meaning that it induces inflammation by binding to receptors on mast cells, basophils, and phagocytes. C3b is a larger fragment that retains the thioester bond of C3 and can covalently attach to any surface that has hydroxyl or amino groups. This process is called opsonization, and it enhances the recognition and phagocytosis of microbes by phagocytes that express receptors for C3b.

The proteolysis of C3 can be triggered by three different pathways: the classical pathway, the alternative pathway, and the lectin pathway. Each pathway has a distinct mechanism of generating a proteolytic complex called C3 convertase, which is responsible for cleaving C3. The classical pathway uses a complex of C1q, C1r, and C1s to recognize antibodies bound to antigens and activate C4 and C2, which form the classical C3 convertase (C4b2a). The alternative pathway uses a spontaneous hydrolysis of C3 to generate C3(H2O), which binds to factor B and is cleaved by factor D to form the alternative C3 convertase (C3bBb). The lectin pathway uses a complex of mannose-binding lectin (MBL) and MASP1/2 to recognize mannose residues on microbes and activate C4 and C2, which form the same classical C3 convertase as the classical pathway.

The generation of C3b by any of these pathways initiates a positive feedback loop that amplifies the complement activation. This is because C3b can bind to the C3 convertases of both the classical and alternative pathways and act as a cofactor for factor B cleavage by factor D, resulting in the formation of more alternative C3 convertases (C3bBb). These convertases can then cleave more C3 molecules and produce more C3b, creating a self-sustaining cycle of complement activation.

The proteolysis of C3 also leads to the formation of another proteolytic complex called C5 convertase, which cleaves the complement protein C5 into two fragments: C5a and C5b. C5a is another anaphylatoxin that has similar functions as C3a but also acts as a chemotactic factor for neutrophils and monocytes. C5b initiates the assembly of the membrane attack complex (MAC), which consists of complement proteins C6, C7, C8, and multiple copies of C9. The MAC forms pores in the membranes of microbial targets and causes cell lysis.

The proteolysis of C3 is therefore the central event in complement activation because it generates biologically active products that mediate various functions of the complement system, such as opsonization, inflammation, chemotaxis, and lysis. The regulation of this process is crucial for maintaining the balance between host defense and tissue damage.

The main goal of complement activation is to cleave the complement protein C3 into two fragments: C3a and C3b. C3a is a small peptide that acts as an inflammatory mediator, while C3b is a larger fragment that binds covalently to the surface of the activator or to antibodies bound to antigens. C3b can then act as an opsonin, enhancing phagocytosis by cells that express receptors for C3b. C3b can also initiate the formation of another proteolytic complex called C5 convertase, which cleaves the complement protein C5 into C5a and C5b. C5a is another inflammatory peptide, while C5b initiates the assembly of the membrane attack complex (MAC), which forms pores in the membranes of microbial targets and causes cell lysis.

The generation of C3 convertase and C5 convertase is the key step in complement activation, and it is achieved by different mechanisms in each of the three pathways. In the classical pathway, the binding of C1q to antibodies or pentraxins activates two serine proteases, C1r and C1s, which cleave two other complement proteins, C4 and C2. The cleaved fragments of C4 and C2 form a complex called C4b2a, which is the classical pathway C3 convertase. This complex can cleave multiple molecules of C3 into C3a and C3b. Some of the generated C3b molecules bind to the surface of the activator or to antibodies, while others associate with the existing C4b2a complex to form a new complex called C4b2a3b, which is the classical pathway C5 convertase. This complex can cleave multiple molecules of C5 into C5a and C5b.

In the alternative pathway, the spontaneous hydrolysis of a thioester bond in some molecules of C3 exposes a reactive group that can bind to hydroxyl or amino groups on microbial surfaces. This process is called tick-over and it generates a molecule called iC3 (inactive or hydrolyzed C3). iC3 can bind to a plasma protein called factor B, which is then cleaved by another plasma protein called factor D into two fragments: Ba and Bb. The iC3Bb complex is the alternative pathway fluid-phase C3 convertase, which can cleave soluble molecules of C3 into C3a and C3b. Some of these generated C3b molecules bind covalently to microbial surfaces or to iC3Bb, forming a new complex called C3bBb, which is the alternative pathway surface-bound C3 convertase. This complex is stabilized by another plasma protein called properdin (factor P), which prevents its dissociation by regulatory proteins. The surface-bound alternative pathway C3 convertase can cleave more molecules of C3 into C3a and C3b, amplifying the complement activation on microbial surfaces. Some of the generated C3b molecules associate with the existing C3bBb complex to form a new complex called C3bBbC3b, which is the alternative pathway C5 convertase. This complex can cleave multiple molecules of C5 into C5a and C5b.

In the lectin pathway, the binding of MBL or other collectins to mannose residues on microbes activates two serine proteases, MASP1 and MASP2, which are similar to C1r and C1s. These proteases cleave two other complement proteins, C4 and C2, generating fragments that form a complex called C4b2a, which is identical to the classical pathway C3 convertase. This complex can cleave multiple molecules of C3 into C3a and C3b. Some of the generated C3b molecules bind to the surface of the activator or to MBL, while others associate with the existing C4b2a complex to form a new complex called C4b2a3b, which is identical to the classical pathway C5 convertase. This complex can cleave multiple molecules of C5 into C5a and C5b.

Thus, all three pathways converge at the level of C3 convertase and C5 convertase formation, which are responsible for generating biologically active products that mediate various functions of complement system.

Although the three pathways of complement activation are initiated by different mechanisms, they share some common features that allow them to cooperate and amplify each other. The first feature is that they are all triggered by the binding of one of their components to an activator. For the classical pathway, the activator is an antibody-antigen complex; for the alternative pathway, it is a microbial surface structure or a C3b molecule; and for the lectin pathway, it is a mannose residue on a microbe. The binding of these components to their respective activators induces conformational changes that expose active sites for subsequent enzymatic reactions.

The second feature is that they all involve a cascade of enzyme activation. Each pathway has a series of proteolytic steps that generate active fragments from inactive precursors. These fragments then act as enzymes or cofactors for the next step in the cascade. The cascade amplifies the initial signal and ensures a rapid and robust response. The cascade also creates diversity in the biological effects of complement activation, as different fragments have different functions.

The third feature is that they all result in the generation of biological effects. The main biological effects of complement activation are opsonization, inflammation, and lysis. Opsonization is the process of coating microbes with C3b molecules, which facilitates their recognition and phagocytosis by cells that express receptors for C3b. Inflammation is the process of attracting and activating leukocytes and increasing vascular permeability at the site of infection or injury. Inflammation is mediated by anaphylatoxins, which are small peptides derived from C3a and C5a. Lysis is the process of forming pores in the membranes of target cells or microbes, leading to their disruption and death. Lysis is mediated by the membrane attack complex (MAC), which is composed of C5b, C6, C7, C8, and multiple copies of C9.

These three features illustrate how the complement system can sense and respond to various types of activators in a coordinated and efficient manner. By having different initiating pathways, complement can recognize a wide range of foreign or altered structures. By having a common cascade of enzyme activation, complement can amplify its response and generate diverse biological effects. By having multiple biological effects, complement can eliminate or neutralize pathogens and promote tissue repair and immune responses.

Complement activation promotes phagocytosis and stimulates inflammation

One of the main functions of complement activation is to enhance the clearance of microbes and other foreign particles by phagocytic cells. This is achieved by the covalent attachment of C3b to the surface of the target, which acts as an opsonin that facilitates the recognition and engulfment by phagocytes. Phagocytes, such as neutrophils and macrophages, express receptors for C3b and its cleavage product iC3b, such as CR1, CR3 and CR4. These receptors bind to C3b or iC3b on the target and trigger phagocytosis. In addition, some phagocytes also express receptors for C1q, such as cC1qR and gC1qR, which can bind to C1q that is associated with antibodies on the target. This also enhances phagocytosis and links the classical pathway with the humoral immune response.

Another function of complement activation is to induce inflammation, which is a local response to tissue injury or infection that aims to eliminate the cause of damage and restore homeostasis. Inflammation is characterized by increased blood flow, vascular permeability, leukocyte recruitment and activation, and production of inflammatory mediators. Complement activation contributes to inflammation by generating several anaphylatoxins, such as C3a, C4a and C5a, which are small peptides released from the cleavage of C3, C4 and C5. These anaphylatoxins bind to specific receptors on various cell types, such as mast cells, basophils, eosinophils, neutrophils, monocytes, macrophages and endothelial cells. The binding of anaphylatoxins to their receptors triggers a variety of responses that promote inflammation, such as:

• Degranulation of mast cells and basophils, leading to the release of histamine and other vasoactive substances that increase vascular permeability and smooth muscle contraction.
• Chemotaxis of leukocytes, especially neutrophils and monocytes, towards the site of infection or injury.
• Activation of leukocytes, enhancing their phagocytic activity, respiratory burst, cytokine production and expression of adhesion molecules.
• Stimulation of endothelial cells, increasing their expression of adhesion molecules that facilitate the attachment and transmigration of leukocytes across the vascular wall.

Among the anaphylatoxins, C5a is the most potent in inducing inflammation. It also has other effects that modulate the immune response, such as:

• Inhibition of the regulatory action of factor H on C3b, thus amplifying complement activation.
• Enhancement of antibody production by B cells.
• Induction of tolerance or anergy in T cells.

Therefore, complement activation plays a crucial role in linking innate and adaptive immunity by promoting phagocytosis and stimulating inflammation. However, excessive or uncontrolled complement activation can also cause tissue damage and contribute to inflammatory diseases. Thus, complement activation must be tightly regulated by various mechanisms that will be discussed in the next point.

Conclusion: Complement activation represents the dynamic interplay among different pathways, control processes, and other protein systems and cells in the local environment.

The complement system is a complex network of proteins that work together to protect the host from microbial infections and to modulate immune responses. The complement system can be activated by three different pathways: the classical pathway, the alternative pathway, and the lectin pathway. Each pathway has its own mechanism of initiation, but they all converge on the common terminal pathway that leads to the formation of the membrane attack complex (MAC), which lyses target cells. The complement system also generates various fragments that have important biological functions, such as opsonization, inflammation, chemotaxis, and immune regulation.

The complement system is tightly regulated by a number of factors that prevent excessive activation and damage to host cells. These factors include soluble inhibitors, membrane-bound regulators, and receptor-mediated clearance of complement components. The complement system also interacts with other protein systems and cells in the local environment, such as coagulation factors, kinins, cytokines, antibodies, and phagocytes. These interactions can either enhance or inhibit the complement activity, depending on the context and the nature of the stimuli.

The complement system is not a static entity, but a dynamic and adaptable one that responds to different challenges and signals. The complement system can be influenced by genetic variations, environmental factors, disease states, and therapeutic interventions. The complement system can also evolve and adapt to new pathogens and antigens by generating diversity in its components and receptors. The complement system is therefore a vital part of the innate and adaptive immunity that contributes to host defense and homeostasis.

1. The complement system is an important part of the innate and adaptive immune responses. It helps to eliminate pathogens and infected cells, as well as to regulate inflammation and immune activation. However, excessive or uncontrolled complement activation can also cause damage to host tissues and contribute to various diseases, such as autoimmune disorders, sepsis, ischemia-reperfusion injury, and transplant rejection. Therefore, the complement system is tightly regulated by a number of soluble and membrane-bound proteins that inhibit or degrade the complement components or their products. These regulatory proteins include factor H, factor I, C1 inhibitor, decay-accelerating factor (DAF), membrane cofactor protein (MCP), CD59, and others. Some pathogens have also evolved mechanisms to evade or subvert the complement system, such as by binding to host regulatory proteins, mimicking complement inhibitors, or cleaving complement components. Understanding how the complement system is activated and regulated is essential for developing novel therapeutic strategies to modulate its activity in health and disease.

Comparison of the three pathways

The three pathways of complement activation have different triggers, but they share some common features and outcomes. The following table summarizes the main similarities and differences among the classical, alternative, and lectin pathways.

All three pathways converge at the cleavage of C3 into C3a and C3b by the respective C3 convertases. The C3a fragment is an anaphylatoxin that stimulates inflammation and attracts phagocytes. The C3b fragment binds covalently to the microbial surface or the antibody-antigen complex and acts as an opsonin that enhances phagocytosis. The C3b fragment also forms part of the C5 convertase that cleaves C5 into C5a and C5b. The C5a fragment is another anaphylatoxin that has similar effects as C3a. The C5b fragment initiates the formation of the membrane attack complex (MAC) that inserts pores into the microbial membrane and causes lysis.

The complement system is tightly regulated by various inhibitors that prevent excessive activation and damage to host cells. Some of these inhibitors are soluble proteins in plasma (e.g., factor I, factor H), while others are membrane-bound proteins on host cells (e.g., membrane cofactor protein, decay-accelerating factor). These inhibitors act by dissociating or inactivating the enzyme complexes involved in complement activation.

The complement system is a vital part of the innate immune system that cooperates with the adaptive immune system to eliminate pathogens and maintain homeostasis. The three pathways of complement activation provide different mechanisms for recognizing and responding to various types of foreign invaders. By understanding how these pathways work and how they are regulated, we can better appreciate the complexity and versatility of the complement system.

The complement system is a complex network of proteins that work together to protect the host from microbial infections and to modulate immune responses. The complement system can be activated by three different pathways: the classical pathway, the alternative pathway, and the lectin pathway. Each pathway has its own mechanism of initiation, but they all converge on the common terminal pathway that leads to the formation of the membrane attack complex (MAC), which lyses target cells. The complement system also generates various fragments that have biological activities, such as opsonization, inflammation, chemotaxis, and immune regulation.

The complement system is tightly regulated by several factors that prevent excessive activation and damage to host cells. These factors include soluble inhibitors, membrane-bound regulators, and receptors that bind to complement fragments and mediate their clearance or signaling. The complement system also interacts with other protein systems and cells in the local environment, such as coagulation factors, kinins, cytokines, antibodies, and phagocytes. These interactions can either enhance or inhibit the complement functions, depending on the context and the nature of the stimuli.

The complement system is not a static entity but a dynamic one that adapts to different situations and challenges. The complement system can be influenced by genetic variations, environmental factors, microbial evasion strategies, and disease states. The complement system can also influence the outcome of various diseases, such as infections, autoimmune disorders, inflammatory conditions, and cancer. Therefore, understanding the complement system is essential for developing novel diagnostic and therapeutic approaches for various diseases.

Complement activation represents the dynamic interplay among different pathways, control processes, and other protein systems and cells in the local environment.

The complement system is not a linear cascade of reactions, but rather a complex network of interactions that involves multiple components, regulators, receptors, and effectors. The three pathways of complement activation (classical, alternative, and lectin) are not independent of each other, but rather can influence and amplify one another. For example, C3b produced by any pathway can bind to C4b2a (the classical C3 convertase) or C3bBb (the alternative C3 convertase) to form C5 convertases that cleave C5 and initiate the terminal pathway. Similarly, C3b can bind to MBL-associated serine proteases (MASPs) to activate the lectin pathway. Conversely, some components of one pathway can inhibit or regulate another pathway. For example, factor H and factor I can inactivate C3b and C4b, respectively, thus preventing excessive complement activation. Moreover, some complement components can interact with other protein systems or cell types to modulate their functions. For example, C3a and C5a can bind to receptors on mast cells, basophils, eosinophils, neutrophils, monocytes, macrophages, dendritic cells, T cells, and B cells to induce degranulation, chemotaxis, cytokine production, phagocytosis, antigen presentation, and antibody production. Additionally, some complement components can bind to coagulation factors or fibrinogen to influence hemostasis and inflammation. Furthermore, some complement components can bind to apoptotic or necrotic cells to facilitate their clearance by phagocytes or prevent their release of harmful substances.

Thus, complement activation represents the dynamic interplay among different pathways, control processes, and other protein systems and cells in the local environment. This interplay ensures that complement activation is finely tuned to match the nature and intensity of the stimulus, and that complement-mediated effects are coordinated with other immune responses to achieve optimal protection against infections and tissue damage.

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