Alternative pathway of the complement system

The complement system is a part of the innate immune system that helps to eliminate pathogens and promote inflammation. It consists of a series of proteins that circulate in the blood and can be activated by different triggers. The complement system has three main pathways of activation: the classical pathway, the lectin pathway, and the alternative pathway.

The alternative pathway is unique among the complement pathways because it does not require antibodies or other specific recognition molecules to initiate. Instead, it relies on the spontaneous activation of a key protein called C3, which can bind to foreign surfaces such as bacteria, viruses, or parasites. The alternative pathway can also amplify the activation of the other complement pathways by generating more C3 molecules.

The alternative pathway is important for host defense against various infections, especially those caused by encapsulated bacteria that can evade antibody responses. It also plays a role in inflammation, tissue repair, and immune regulation. However, excessive or uncontrolled activation of the alternative pathway can cause damage to host cells and tissues, leading to diseases such as atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD), and systemic lupus erythematosus (SLE).

In this article, we will explore the steps and mechanism of the alternative pathway, the three distinct pathways to initiate it, the regulators that control it, and the applications and significance of it in health and disease.

The alternative pathway of the complement system is a cascade of enzymatic reactions that can be activated by various triggers, such as foreign surfaces, properdin, or proteases. The main components of this pathway are C3, factor B, factor D, and properdin. The steps and mechanism of the alternative pathway are as follows:

• The first step is the spontaneous hydrolysis of the internal thioester bond in C3, which produces C3(H2O), a conformationally altered form of C3 that can bind to factor B. This process is called tickover and occurs at a low rate in plasma.
• The second step is the formation of C3(H2O)Bb, a C3 convertase that can cleave more C3 molecules into C3a and C3b. This occurs when factor B binds to C3(H2O) and is cleaved by factor D, a serine protease. Factor Bb remains bound to C3(H2O), while Ba is released into the fluid phase. C3a is an anaphylatoxin that mediates inflammation, while C3b can bind to foreign surfaces or to other C3 molecules.
• The third step is the amplification loop, which generates more C3 convertases and increases the production of C3a and C3b. This occurs when C3b binds to factor B and is cleaved by factor D, forming C3bBb, another C3 convertase. This complex can also bind to properdin, a positive regulator that stabilizes the convertase and enhances its activity. Alternatively, properdin can also initiate the alternative pathway by binding to foreign surfaces and recruiting C3b and factor B.
• The fourth step is the formation of C5 convertases, which cleave C5 into C5a and C5b. This occurs when another C3b molecule binds to the existing C3 convertases (C3(H2O)Bb or C3bBb), forming C3(H2O)BbC3b or C3bBbC3b. These complexes can cleave C5 into C5a and C5b. C5a is another anaphylatoxin that mediates inflammation, while C5b initiates the formation of the membrane attack complex (MAC).
• The fifth step is the formation of MAC, which induces cell lysis by creating pores in the target cell membrane. This occurs when C5b binds to C6, forming a complex that binds to C7. The C5b67 complex then inserts into the membrane and binds to C8, which recruits multiple copies of C9. The assembly of C9 molecules forms a cylindrical structure that perforates the membrane and allows the influx of water and ions, leading to cell lysis.

The alternative pathway of the complement system is a powerful innate immune defense mechanism that can recognize and eliminate various pathogens and foreign particles. However, it also requires tight regulation to prevent damage to host cells and tissues. Several regulators of the alternative pathway will be discussed in point 4.

The alternative pathway can be initiated by three different mechanisms that involve the binding of C3b to different activators on the surface of pathogens or foreign materials. These are:

• The alternative tickover pathway, which is the spontaneous hydrolysis of C3 to C3(H2O) in the plasma. C3(H2O) can bind factor B and be cleaved by factor D to form C3(H2O)Bb, a fluid-phase C3 convertase. This convertase can then cleave more C3 molecules to generate C3b, which can bind to microbial surfaces and initiate the alternative pathway.
• The alternative properdin-activated pathway, which is the direct binding of properdin, a serum protein that stabilizes C3 convertases, to certain microbial surfaces such as Neisseria meningitidis and Streptococcus pneumoniae. Properdin can also bind C3b and factor B in the presence of Mg2+, forming a properdin-C3bBb complex that can act as a C3 convertase.
• The alternative protease-activated pathway, which is the cleavage of C3 and C5 by proteases of the blood coagulation or fibrinolytic systems, such as thrombin and plasmin. These proteases can generate C3a and C5a fragments that have inflammatory and chemotactic activities, as well as C3b and C5b fragments that can bind to microbial surfaces and initiate the alternative pathway.

These three pathways converge at the formation of C3bBbP, a stable C3 convertase that can cleave more C3 molecules and amplify the alternative pathway. The C3b molecules generated by this convertase can then bind another C3b molecule to form C3b2BbP, a C5 convertase that can cleave C5 and initiate the formation of the membrane attack complex (MAC). The MAC is responsible for lysing the target cells by creating pores in their membranes.

Some possible sentences to conclude point 3 are:

• Thus, the alternative pathway can be activated by different triggers that result in the generation of C3b molecules that bind to microbial surfaces and form C3 and C5 convertases.
• The alternative pathway provides a rapid and versatile defense mechanism against a variety of pathogens and foreign materials by producing C3b molecules that opsonize them and form C3 and C5 convertases that lead to their lysis.
• The alternative pathway is an important component of the innate immune system that can recognize and eliminate pathogens and foreign materials by generating C3b molecules that coat them and form C3 and C5 convertases that activate the MAC.

As this pathway does not require any immune response and is activated independently upon encountering foreign particles, it must be rigorously controlled to prevent unwanted host cell attacks. There are several regulators of the alternative pathway that can inhibit or enhance the formation and activity of the C3 and C5 convertases. These regulators can be classified into soluble or membrane-bound factors.

Soluble regulators

• Complement factor H (CFH): It is a plasma protein that binds to C3b and acts as a cofactor for its cleavage by complement factor I (CFI), resulting in the formation of iC3b, which is an inactive form of C3b. CFH also competes with factor B for binding to C3b, preventing the formation of the C3 convertase. CFH deficiency or dysfunction can lead to uncontrolled activation of the alternative pathway and cause kidney diseases such as atypical hemolytic uremic syndrome (aHUS) or age-related macular degeneration (AMD).
• Complement factor I (CFI): It is a plasma protease that cleaves C3b and C4b in the presence of cofactors such as CFH, membrane cofactor protein (MCP), or complement receptor 1 (CR1). CFI prevents the reassembly of the C3 and C4 convertases by inactivating their subunits. CFI deficiency can result in excessive complement activation and consumption, leading to recurrent infections or autoimmune disorders.
• Properdin: It is a plasma protein that stabilizes the C3 convertase by binding to C3bBb complex and preventing its dissociation. Properdin can also initiate the alternative pathway by binding to microbial surfaces and recruiting C3b and factor B. Properdin deficiency can increase the susceptibility to infections by Neisseria meningitidis or other encapsulated bacteria.

Membrane-bound regulators

• Membrane cofactor protein (MCP): It is a glycoprotein expressed on various cell types that serves as a cofactor for CFI-mediated cleavage of C3b and C4b. MCP protects host cells from complement-mediated damage by removing C3b and C4b from their surfaces.
• Decay-accelerating factor (DAF): It is a glycosylphosphatidylinositol (GPI)-anchored protein expressed on many cell types that accelerates the decay of the C3 and C4 convertases by dissociating their subunits. DAF protects host cells from excessive complement activation and inflammation.
• Complement receptor 1 (CR1): It is a transmembrane protein expressed on various immune cells that binds to C3b and C4b and acts as a cofactor for their cleavage by CFI. CR1 also facilitates the clearance of immune complexes by phagocytic cells. CR1 deficiency or polymorphism can impair the regulation of complement activation and increase the risk of autoimmune diseases or infections.

These are some of the main regulators of the alternative pathway that modulate its activity and prevent unwanted damage to host cells. The alternative pathway is a vital part of the innate immune system that provides protection against pathogens, but it also requires tight regulation to avoid excessive inflammation or tissue injury.

The alternative pathway of the complement system is an important component of the innate immune system that provides protection against infections. The alternative pathway has several applications and significance in health and disease, such as:

• It monitors pathogen invasion in normal physiological conditions by continuously activating low-level C3b production.
• It enhances the clearance of microorganisms and neutralizes viruses by opsonization and lysis.
• It recruits and activates inflammatory cells to the site of infection by generating anaphylatoxins C3a and C5a.
• It stimulates the adaptive immune system by promoting B cell activation and antibody production.
• It removes harmful immune complexes from the body by binding to C3b and facilitating their phagocytosis.

The alternative pathway can also be involved in various pathological conditions when it is dysregulated or deficient. Some examples are:

• Paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disorder caused by a mutation in the PIGA gene that leads to the absence of membrane inhibitors of complement on red blood cells, resulting in their lysis by the alternative pathway.
• Atypical hemolytic uremic syndrome (aHUS), a life-threatening condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure, caused by genetic or acquired defects in the regulation of the alternative pathway.
• Age-related macular degeneration (AMD), a leading cause of blindness in elderly people, associated with polymorphisms in genes encoding alternative pathway proteins such as factor H, factor B, and C3.
• Systemic lupus erythematosus (SLE), a chronic autoimmune disease that affects multiple organs, associated with low levels of alternative pathway components and impaired clearance of immune complexes.

Therefore, the alternative pathway of the complement system is a vital part of the host defense mechanism that can also contribute to various diseases when aberrant. Understanding the molecular mechanisms and regulation of the alternative pathway can help to develop novel diagnostic and therapeutic strategies for complement-mediated disorders.

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