8.1 Complement activation pathways
2 min read•july 25, 2024
Complement activation pathways are crucial defense mechanisms in our immune system. They trigger a cascade of protein interactions that help eliminate pathogens and promote . The three main pathways - classical, alternative, and lectin - each have unique activation triggers but converge on formation.
convertase is the key player in amplifying the complement cascade. It cleaves C3 into C3a and C3b, leading to and formation of the . Regulation of complement activation is essential to prevent damage to host cells and maintain immune homeostasis.
Complement Activation Pathways
Complement activation pathways
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- Classical pathway triggers antibody-dependent activation initiated by antigen-antibody complexes on pathogen surfaces (IgG and IgM)
- enables antibody-independent activation spontaneously activating on microbial surfaces (bacterial cell walls)
- activates when mannose-binding lectin (MBL) recognizes carbohydrate patterns on pathogens (bacterial capsules)
Steps in complement activation
- Classical pathway:
- C1 complex (, C1r, C1s) binds to antibody-antigen complexes
- C4 and C2 cleavage forms C3 convertase (C4b2a)
- Alternative pathway:
- Spontaneous hydrolysis of C3 to C3(H2O)
- Factor B binds C3(H2O), cleaved by Factor D
- Forms C3 convertase (C3bBb)
- Lectin pathway:
- MBL binds to pathogen carbohydrates (mannose residues)
- MBL-associated serine proteases (MASPs) activate
- C4 and C2 cleavage forms C3 convertase (C4b2a)
Role of C3 convertase
- C3 convertase cleaves C3 into C3a and C3b amplifying complement cascade
- C3b functions include opsonization of pathogens enhancing phagocytosis and formation of more C3 convertase
- Amplification loop creates exponential increase in complement activation:
- C3b joins C3 convertase to form
- C5 convertase cleaves C5, initiating membrane attack complex (MAC) formation
- Process results in rapid pathogen elimination and inflammation
Regulation of complement activation
- Membrane-bound regulators prevent excessive activation on host cells:
- (DAF) accelerates C3 convertase decay
- Membrane cofactor protein (MCP) acts as cofactor for Factor I
- Complement receptor 1 (CR1) facilitates C3b/C4b degradation
- Fluid-phase regulators control activation in plasma:
- Factor H inhibits alternative pathway C3 convertase
- C4-binding protein regulates classical and lectin pathways
- Enzymatic inactivation by Factor I cleaves C3b and C4b limiting their activity
- Natural decay of C3 convertase occurs spontaneously
- Host cell protection mechanisms like CD59 prevent MAC formation on healthy cells
Key Terms to Review (19)
Alternative pathway: The alternative pathway is one of the three main pathways of complement activation, which plays a crucial role in the innate immune system. Unlike the classical and lectin pathways that require specific antibodies or carbohydrate structures for activation, the alternative pathway can be spontaneously activated by pathogens or foreign surfaces, providing a rapid response to infection. This pathway amplifies the immune response by leading to the formation of C3 convertase, ultimately promoting inflammation and opsonization of pathogens.
Anaphylatoxins: Anaphylatoxins are small peptide fragments that are generated during the complement activation process, specifically from the cleavage of complement proteins C3 and C5. They play a crucial role in promoting inflammation and recruiting immune cells to sites of infection or injury, amplifying the immune response.
C1q: c1q is a protein that plays a crucial role in the classical pathway of complement activation, a part of the immune system that enhances the ability to clear pathogens. It is part of the complement system, where it recognizes and binds to antibodies or other targets, leading to a cascade of immune responses. c1q's function is vital for opsonization, clearance of immune complexes, and the promotion of inflammation.
C3: C3 is a central component of the complement system, which plays a crucial role in the immune response by promoting opsonization, inflammation, and cell lysis. It exists in an inactive form in the bloodstream and becomes activated during the complement activation pathways, leading to its cleavage into C3a and C3b, which have distinct biological functions in the immune defense mechanism.
C3 Convertase: C3 convertase is an enzyme complex that plays a crucial role in the complement system, specifically in the activation of the complement protein C3. This enzyme complex cleaves C3 into C3a and C3b, which are essential for opsonization, inflammation, and the formation of the membrane attack complex. Understanding C3 convertase is key to grasping how the complement system enhances the immune response against pathogens.
C5 convertase: C5 convertase is an enzyme complex that plays a crucial role in the complement system, specifically in the activation of the complement component C5. It is responsible for cleaving C5 into C5a and C5b, which are important for promoting inflammation and forming the membrane attack complex, respectively. This process is a key step in enhancing the immune response against pathogens and contributes to the overall function of the complement activation pathways.
CD55: CD55, also known as decay-accelerating factor (DAF), is a membrane protein that plays a crucial role in regulating the complement system by preventing the formation of the C3 convertase enzyme complex. It protects host cells from damage by inhibiting complement activation, thus maintaining homeostasis and preventing unwanted inflammation. CD55's function is essential for distinguishing between self and non-self, helping to prevent autoimmunity and ensuring that the immune response is appropriately directed.
Chemotaxis: Chemotaxis is the movement of cells towards or away from a chemical stimulus, often used by immune cells to locate sites of infection or inflammation. This process is crucial for the functioning of the immune system, as it directs leukocytes to areas where they are needed most to fight off pathogens and initiate repair processes.
Complement deficiencies: Complement deficiencies refer to a group of immunological disorders characterized by the insufficient or absent production of complement proteins, which play a critical role in the immune system's ability to fight infections and clear pathogens. These deficiencies can lead to increased susceptibility to infections, particularly with encapsulated bacteria, as well as autoimmune conditions due to impaired regulation of immune responses.
Complement inhibitors: Complement inhibitors are proteins that regulate the complement system, preventing excessive activation and protecting host tissues from damage. These inhibitors play a critical role in maintaining homeostasis and preventing autoimmune reactions by controlling the complement pathways, which can be activated through various triggers such as pathogens or immune complexes.
Complement receptors: Complement receptors are specialized proteins found on the surface of immune cells that bind to complement proteins, facilitating various immune responses. These receptors play a crucial role in linking the complement system to cellular activities, enhancing the ability of immune cells to recognize and eliminate pathogens effectively. By interacting with complement components, these receptors help modulate inflammation and activate immune responses, connecting them to complement activation pathways and overall immune functions.
Decay-Accelerating Factor: Decay-accelerating factor (DAF) is a protein that plays a critical role in regulating the complement system by preventing the formation of the C3 convertase enzyme complex. By inhibiting this enzyme's activity, DAF helps to control complement activation, protecting host cells from damage that can occur due to excessive or uncontrolled complement activity. It is particularly important for maintaining self-tolerance and preventing damage to healthy tissues during immune responses.
Hemolytic uremic syndrome: Hemolytic uremic syndrome (HUS) is a serious condition characterized by the combination of hemolytic anemia, acute kidney failure, and thrombocytopenia (low platelet count). It often results from infection, particularly with certain strains of Escherichia coli, leading to the activation of the complement system, which plays a crucial role in immune response and inflammation.
Immune complex clearance: Immune complex clearance refers to the process by which the immune system removes immune complexes, which are formed when antibodies bind to antigens. This mechanism is crucial for maintaining homeostasis and preventing tissue damage, as the accumulation of these complexes can lead to inflammation and autoimmune diseases. The complement system plays a vital role in this process, facilitating the recognition, opsonization, and subsequent removal of immune complexes by phagocytic cells.
Inflammation: Inflammation is a biological response of the immune system to harmful stimuli, such as pathogens, damaged cells, or irritants. It serves to protect the body by initiating healing processes, recruiting immune cells to the site of injury or infection, and facilitating the removal of harmful agents. This complex response can be acute or chronic and is crucial for maintaining homeostasis and defense mechanisms.
Lectin pathway: The lectin pathway is one of the complement activation pathways that helps the immune system identify and eliminate pathogens. This pathway is triggered when lectins, which are proteins that bind to carbohydrates, recognize specific sugar patterns on the surfaces of microbes, leading to a cascade of reactions that activate the complement system. It plays a crucial role in the innate immune response, complementing other pathways like the classical and alternative pathways.
Lysis: Lysis refers to the breakdown or destruction of cells, often through the action of enzymes or external forces. In the context of the immune system, lysis is a critical mechanism by which pathogens are eliminated, particularly during complement activation pathways where antibodies and proteins work together to target and destroy invading microorganisms. This process helps maintain homeostasis and protect the body from infections.
Membrane Attack Complex: The membrane attack complex (MAC) is a structure formed on the surface of pathogen cells, primarily by the complement system, that creates pores in the membrane, leading to cell lysis and death. This complex plays a crucial role in the innate immune response, providing a means for the body to directly eliminate invading microorganisms as part of the first line of defense against infections.
Opsonization: Opsonization is the process by which pathogens are marked for destruction by immune cells, making them more recognizable to phagocytes. This enhances the efficiency of the immune response by promoting the binding of these pathogens to immune cells, facilitating their ingestion and elimination. Opsonization connects to various immune mechanisms, including innate immunity, antibody function, antigen-antibody interactions, and complement activation pathways.