Complement Components – Definition, Functional categories

What is Complement?

• Complement plays a vital role in our immune system, acting as a powerful defense mechanism against various pathogens. It is a complex system consisting of a set of serum proteins that work together with both the innate and adaptive immune systems to eliminate harmful microorganisms in the blood and tissues.
• The complement system is a crucial part of our body’s innate immune response, which provides immediate defense against pathogens. Unlike the adaptive immune response, which takes time to recognize and respond to specific pathogens, the complement system acts rapidly and non-specifically. It acts as a first line of defense, ensuring that pathogens are neutralized before they can cause significant harm.
• The complement system consists of around 30 proteins, including enzymes, receptors, and regulatory proteins. These proteins circulate in the bloodstream in an inactive form, awaiting activation signals from various triggers, such as the presence of pathogens or immune complexes. Once activated, the complement proteins initiate a cascade of enzymatic reactions, leading to a series of events that result in the elimination of the pathogen.
• One of the primary functions of complement is to promote inflammation. Activation of the complement system leads to the recruitment of immune cells to the site of infection or tissue damage, enhancing the immune response. Complement proteins can also directly destroy pathogens by forming membrane attack complexes that puncture and kill the microbial cells.
• Additionally, complement plays a crucial role in the opsonization process, which enhances the ability of immune cells to recognize and engulf pathogens. Complement proteins coat the surface of pathogens, making them more recognizable to phagocytic cells, such as macrophages and neutrophils. This opsonization process facilitates the efficient clearance of pathogens from the body.
• Furthermore, complement contributes to the adaptive immune response by linking the innate and adaptive immune systems. It aids in the clearance of immune complexes and apoptotic cells, preventing the development of autoimmune responses. Complement proteins also interact with immune cells and modulate their activity, influencing the initiation and regulation of adaptive immune responses.
• In summary, complement is a set of serum proteins that collaborates with both the innate and adaptive immune systems to eliminate blood and tissue pathogens. Its functions range from promoting inflammation and directly killing pathogens to facilitating opsonization and linking the innate and adaptive immune responses. The complement system serves as a crucial defense mechanism, playing a pivotal role in maintaining our overall health and protection against infections.

Functional categories of Complement Components

Complement components can be classified into seven functional categories:

1. Initiator complement components

• Initiator complement components play a crucial role in initiating the complement cascade by binding to specific soluble or membrane-bound molecules. These components recognize and interact with their activating ligands, leading to conformational changes that result in altered biological activity and the initiation of the complement response. Two notable examples of initiator complement components are the C1q complex and Mannose-Binding Lectin (MBL).
• The C1q complex is a key initiator of the classical pathway of the complement system. It is composed of six C1q molecules, each consisting of three polypeptide chains. C1q binds to antibodies that are bound to antigens on the surface of pathogens or to certain other molecules, such as C-reactive protein (CRP). This binding triggers a conformational change in C1q, which then interacts with and activates the associated C1r and C1s proteases. The activated C1s cleaves other complement components, leading to the amplification and progression of the complement cascade.
• Mannose-Binding Lectin (MBL) is part of the lectin pathway, another important initiation pathway of the complement system. MBL is a soluble pattern recognition receptor that recognizes specific sugar structures on the surface of pathogens. When MBL binds to these sugar structures, it undergoes a conformational change and forms complexes with MBL-associated serine proteases (MASPs), similar to the C1 complex. The activated MASPs cleave downstream complement components, triggering the subsequent activation of the complement cascade.
• Both the C1q complex and MBL are capable of recognizing a wide range of pathogens and aberrant molecules, allowing for the initiation of the complement response in response to various types of infections and cellular abnormalities. Their binding to specific ligands triggers a series of enzymatic reactions, leading to the recruitment and activation of other complement components, amplifying the immune response against the identified target.
• The initiation of the complement cascade by these components is a crucial step in the immune response. It sets in motion a complex series of events that ultimately lead to the elimination of pathogens, the clearance of immune complexes, and the modulation of inflammatory and immune responses. Understanding the function and activation of initiator complement components is essential for comprehending the overall functioning of the complement system and its importance in immune defense.

2. Enzymatic mediators

• Enzymatic mediators play a vital role in the complement system by cleaving and activating other complement components, thereby amplifying and regulating the complement cascade. These mediators include proteolytic enzymes such as C1r, C1s, MASP2, and factor B.
• These enzymes can be activated through different mechanisms. Some proteases undergo conformational changes and become active upon binding to specific macromolecules. This binding event triggers their enzymatic activity and allows them to cleave and activate downstream complement components. Examples of such proteases include C1r and C1s, which are activated upon binding to the C1q complex, and MASP2, which is activated upon binding to Mannose-Binding Lectin (MBL).
• On the other hand, some complement proteases are initially inactive and exist as zymogens. These zymogens require cleavage by another protease enzyme to activate their enzymatic function. Zymogens are proteins that are activated by proteolytic cleavage. Factor B is an example of a complement component that functions as a zymogen. Upon cleavage by the enzyme factor D, it is converted into its active form, allowing it to participate in the complement cascade.
• Of particular importance in the complement cascades are the enzyme complexes known as the C3 and C5 convertases. The C3 convertase cleaves complement component C3, while the C5 convertase cleaves complement component C5. These convertases are essential for the generation of the small complement fragments C3a and C5a, which act as anaphylatoxins and participate in various immune functions.
• The C3 convertase can be formed through different pathways, including the classical, lectin, and alternative pathways. In the classical and lectin pathways, C3 convertase is generated by the sequential cleavage of C4 and C2 by the C1 complex or MASP2, respectively. In the alternative pathway, C3 convertase is formed through the spontaneous hydrolysis of C3, which is then stabilized by factors B, D, and properdin.
• Similarly, the C5 convertase can be formed through multiple pathways. Once C3 convertase is formed, it can bind to C3b and recruit additional complement components, leading to the formation of the C5 convertase. The C5 convertase cleaves C5 to generate C5a and initiate downstream events in the complement cascade.
• In summary, enzymatic mediators in the complement system are proteolytic enzymes that cleave and activate other complement components, playing a crucial role in amplifying and regulating the complement cascade. They can be activated through conformational changes, binding to macromolecules, or proteolytic cleavage. The C3 and C5 convertases are enzyme complexes of central importance in the complement cascades, cleaving C3 and C5, respectively. Understanding the function and regulation of these enzymatic mediators is essential for comprehending the intricate workings of the complement system and its role in immune defense.

3. Membrane-binding components or opsonins

• Membrane-binding components, also known as opsonins, play a crucial role in the complement system by enhancing phagocytosis and promoting the clearance of pathogens. These opsonins are formed when complement components, such as C3 and C4, are cleaved into two fragments upon activation of the complement cascade.
• The larger fragments generated from the cleavage of C3 and C4 are called C3b and C4b, respectively. These fragments serve as opsonins, which are molecules that coat the surface of microbial cells and facilitate their recognition and uptake by phagocytic cells.
• Opsonization is a process that marks pathogens for phagocytosis, the engulfment and destruction of foreign particles or microorganisms by specialized immune cells called phagocytes. When C3b or C4b binds to the surface of a microbial cell, it acts as a binding target for phagocytic cells that express specific receptors for these opsonins.
• Phagocytes, including macrophages and neutrophils, possess receptors that recognize and bind to C3b or C4b on the surface of pathogens. This binding triggers a series of events that lead to the internalization of the opsonized pathogen into the phagocyte, followed by its degradation and elimination.
• The opsonization process enhances phagocytosis in several ways. Firstly, the binding of opsonins to the surface of pathogens promotes their recognition by phagocytic cells, increasing the efficiency of target identification. This recognition allows phagocytes to distinguish between self and non-self, facilitating the selective removal of foreign invaders.
• Secondly, opsonization enhances the adherence of phagocytes to opsonized pathogens. The binding of opsonins to the microbial surface provides phagocytes with a stable point of attachment, enabling them to engulf the pathogen more effectively.
• Additionally, opsonization promotes the activation of various phagocytic mechanisms within the phagocytes, such as the release of antimicrobial substances and the production of reactive oxygen species. These mechanisms contribute to the destruction and elimination of the internalized pathogens.
• C3b and C4b are not only involved in opsonization but also play roles in other complement processes. They can participate in the formation of the membrane attack complex (MAC), which leads to the lysis of pathogens, and contribute to the recruitment and activation of immune cells through interactions with specific receptors.
• In summary, membrane-binding components or opsonins, such as C3b and C4b, play a crucial role in the complement system by enhancing phagocytosis. These opsonins coat the surface of pathogens, promoting their recognition and uptake by phagocytic cells. Opsonization improves the efficiency of phagocytosis, enhances pathogen adherence, and activates phagocytic mechanisms for effective elimination of the engulfed pathogens. By functioning as opsonins, C3b, and C4b contribute to the immune system’s defense against invading microorganisms and maintain immune homeostasis.

4. Inflammatory mediators

• Inflammatory mediators play a critical role in the complement system by promoting and regulating the inflammatory response. Certain small fragments generated during complement activation act as these mediators. Examples of these fragments, known as anaphylatoxins, include C3a, C5a, and C4a.
• Anaphylatoxins are named so because they can induce anaphylaxis, a severe allergic reaction characterized by widespread inflammation. However, in normal physiological conditions, these fragments play important roles in immune defense and tissue homeostasis.
• One of the key functions of anaphylatoxins is their ability to enhance the blood supply to the site of their release. When C3a, C5a, or C4a bind to specific receptors on endothelial cells lining the small blood vessels, they trigger a series of events that lead to an increase in capillary diameter. This process, known as vasodilation, promotes the delivery of immune cells and necessary molecules to the inflamed area. Increased blood supply helps in the removal of harmful agents and facilitates the arrival of immune cells to combat infections or initiate tissue repair.
• In addition to enhancing blood flow, anaphylatoxins also play a role in recruiting and activating immune cells. They act as chemoattractants, signaling molecules that attract immune cells to the site of tissue damage or infection. Anaphylatoxins promote the migration of immune cells, such as neutrophils, monocytes, and macrophages, to the inflamed area. These immune cells are essential for eliminating pathogens, removing debris, and promoting tissue repair.
• Furthermore, anaphylatoxins can activate immune cells upon binding to their respective receptors. Activation of immune cells leads to the release of additional inflammatory molecules and the amplification of the immune response. This activation can enhance phagocytosis, respiratory burst (production of reactive oxygen species), and the release of inflammatory cytokines, all of which contribute to the elimination of pathogens and the resolution of inflammation.
• While anaphylatoxins are crucial for immune defense, excessive or uncontrolled release can lead to harmful effects. Excessive vasodilation can result in hypotension (low blood pressure) and tissue damage. Inflammatory mediators, when produced in excess, can contribute to chronic inflammation and tissue pathology.
• In summary, anaphylatoxins, including C3a, C5a, and C4a, are small fragments generated during complement activation that serve as inflammatory mediators. They enhance blood supply by inducing vasodilation, attracting immune cells to the site of inflammation, and activating these immune cells. While these mediators are essential for immune defense and tissue repair, their excessive release can lead to harmful effects. Understanding the regulation and balance of inflammatory mediators is crucial for maintaining immune homeostasis and preventing detrimental outcomes associated with excessive inflammation.

5. Membrane attack proteins

• Membrane attack proteins, also known as the membrane attack complex (MAC), play a crucial role in the complement system’s ability to eliminate invading microorganisms. These proteins are responsible for forming transmembrane channels that insert into the cell membranes of pathogens, leading to their lysis and destruction. The components of the MAC include C5b, C6, C7, C8, and multiple copies of C9.
• Once the complement cascade is activated, the formation of the MAC represents the cytolytic end product of the cascade. The MAC assembles in a stepwise manner on the surface of the target cell. It begins with the binding of C5b to the target cell membrane, followed by sequential recruitment of C6, C7, and C8. Finally, multiple copies of C9 are incorporated into the complex, resulting in the formation of a transmembrane channel.
• The MAC’s transmembrane channel is crucial for its cytolytic activity. It functions by creating pores or holes in the pathogen’s cell membrane. These pores disrupt the integrity of the membrane, leading to the uncontrolled influx of water, ions, and molecules into the cell. This disruption causes osmotic imbalances, leading to cell swelling and ultimately lysis of the target cell. By lysing the pathogen, the MAC effectively eliminates the invader and contributes to the immune system’s defense against infections.
• The membrane attack proteins are particularly important in the late stages of the complement cascade. While other complement components have various roles, such as opsonization or inflammation, the MAC’s primary function is to directly destroy pathogens. The formation of the MAC is tightly regulated to ensure that it targets only foreign cells and does not harm the host’s own cells.
• It is worth noting that the MAC’s lytic activity is not limited to microorganisms. The complex can also target infected host cells, cancer cells, and certain other types of abnormal cells. This ability highlights the versatile nature of the complement system in recognizing and eliminating various threats to the body.
• In summary, membrane attack proteins, or the membrane attack complex (MAC), play a vital role in the complement system’s defense mechanism. By inserting into the cell membranes of invading microorganisms, the MAC forms transmembrane channels that cause osmotic lysis of the pathogen. The components of the MAC work together to create pores that disrupt the integrity of the target cell’s membrane, leading to its destruction. The MAC’s ability to directly lyse pathogens is a crucial aspect of the complement system’s role in the immune response against infections.

6. Complement receptor proteins

• Complement receptor proteins play a vital role in the recognition and response to pathogens within the immune system. These receptors are part of the complement system, which is an essential component of the innate immune response. Unlike antibodies, complement receptors detect pathogens through mechanisms that are not antibody-mediated.
• Complement receptors are located on the surfaces of various cells and bind to specific complement proteins, initiating specific cellular functions. One example is the complement receptor 1 (CR1), which binds to complement component C3b on the surface of pathogens. This interaction triggers a process called phagocytosis, where immune cells engulf and eliminate the C3b-bound pathogen. Phagocytosis is a critical mechanism for clearing pathogens from the body.
• Another example is the binding of complement component C5a to C5aR receptors on neutrophils, which are a type of white blood cell involved in immune defense. This binding stimulates a process called neutrophil degranulation, in which neutrophils release granules containing enzymes and other molecules. Neutrophil degranulation leads to inflammation, an important response that helps recruit immune cells to the site of infection or tissue damage.
• Complement receptors are named with the suffix “R,” such as CR1, CR2, and C5aR. These receptors have specific binding affinities for complement components, allowing for selective recognition and activation of particular immune responses. The binding of complement proteins to their respective receptors triggers intracellular signaling pathways, leading to the activation of specific cellular functions necessary for immune defense.
• It is important to note that complement receptor proteins are not limited to immune cells. They are also found on various other cell types, including endothelial cells, epithelial cells, and platelets. These receptors enable non-immune cells to contribute to the immune response by recognizing and responding to complement proteins.
• Overall, complement receptor proteins are crucial in the detection and response to pathogens by the complement system. They play a key role in initiating phagocytosis, promoting inflammation, and coordinating immune defense mechanisms. By binding to complement components, these receptors help coordinate the innate immune response and contribute to the overall protection of the body against invading pathogens.

7. Regulatory complement components

• Regulatory complement components are essential for preventing unintended damage to host cells during complement activation. These components act as safeguards to protect host cells from complement-mediated lysis. They include both membrane-bound and soluble regulatory proteins that work together to control and regulate the complement system.
• One important regulatory protein is factor I. It plays a crucial role in the degradation of complement component C3b, which is a key step in regulating the complement cascade. Factor I works in conjunction with other cofactors, such as factor H and factor H-like protein 1 (FHL-1), to enzymatically cleave and inactivate C3b. This prevents the amplification of the complement response and helps prevent excessive complement activation on host cells.
• Another regulatory protein is Protectin, also known as CD59 or membrane inhibitor of reactive lysis (MIRL). Protectin is a glycoprotein that is present on the surface of host cells. Its primary function is to inhibit the formation of the membrane attack complex (MAC) on host cells. The MAC is a cytolytic complex formed during complement activation, which can lead to the lysis of target cells. Protectin acts by binding to the C8 and C9 components of the MAC, preventing their incorporation into the complex and thereby blocking MAC-mediated lysis.
• These regulatory complement components play a crucial role in maintaining the delicate balance between effective immune defense and self-tolerance. By degrading C3b and inhibiting MAC formation, they protect host cells from unintended complement-mediated damage. Without these regulatory mechanisms, the complement system could potentially harm healthy cells and tissues.
• Furthermore, mutations or deficiencies in these regulatory proteins can lead to complement dysregulation and are associated with certain complement-mediated diseases. For example, deficiencies in factor I or mutations in factor H are linked to diseases such as atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD), where uncontrolled complement activation can lead to tissue damage and inflammation.
• In summary, regulatory complement components play a critical role in protecting host cells from unintended complement-mediated lysis. Factors such as factor I and Protectin work together to degrade complement components and inhibit the formation of the MAC on host cells. This ensures that complement activation is tightly controlled and limited to the appropriate targets, preventing damage to healthy tissues. Understanding and studying these regulatory mechanisms are essential for gaining insights into complement-related diseases and developing therapeutic interventions.

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