Immunology Complement System PDF

complememt system 24 October 2024 10:26 The complememt system consists of several plasma proteins that work together to opsonize microbes, to promote the recruitment of phagogytes to the site of infection, and in some cases, to directly kill the microbes. Complement activation involves proteoly...

complememt system 24 October 2024 10:26 The complememt system consists of several plasma proteins that work together to opsonize microbes, to promote the recruitment of phagogytes to the site of infection, and in some cases, to directly kill the microbes. Complement activation involves proteolytic cascades in which an inactive precursor enzyme, called a zymogen, is altered to become an active protease that cleaves and thereby induces the proteolytic activity of the complement protein in the cascade. The first step in activation of the complement system is recognition of molecules on microbial surfaces but not host cells, and this occurs in three ways: The classical pathway uses e Plasma protein called c1q to detect antibodies bound to the surface of a microbe or other structure. Once C1q binds to the Fc portion of the antibodies, two associated serine proteocases, called C1r and C1s, become active and initate a proteolytic cascade involving other complement proteins. The alternative pathway is triggered when a complement protein called C3 directly recognizes certain microbial surface structures, such as bacterial 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 lectin pathway is triggered by plasma protein called mannose-binding lectin (MBL), which recognizes terminal mannose residues on microbial glycoproteins and glycolipids, similar to the mannose FS receptor on phagocytes. → Recognition of microbes by any of the three complement patliways results in sequential recruitent and assembly of additional complement proteins into protease complexes. → One of these complexes, called C3 convertase, cleaves the central protein of the complement system, C3, producing C3a and C3b. The larger C3b fragment becomes covalently attached to the microbial surface where the complement pathway was activated. The sequential enzymatic activity of complement proteins provides such tremendous ampification that milions of C3b molecules can deposit on the surface of a microbe within 2 or 3 minutes! C3b serves as an opsonin to promote phagocytosis of the microbes. → C3b exposes a thioester domain, which is the one involved in the attachment to membranes, forming thioester bonds. If C3b doesn’t attach to membranes it remains in soluble phase and the thioester bond is quickly hydrolysed, thus inactivating the protein. immunology Pagina 17  protein. → The smaller fragment, C3a, is reicased and stimulates inflammation by acting as a chemoattractant, for neutrophils by inducing mast cell degranulation, and by directly increasing vascular permeability so that plasma proteins and fluid leak into sites of infections. C3b binds other complement proteins to form a protease called C5 convertase that cleaves C5, generating a released peptide (C5a) and a larger fragment (C5b) that remains attached to the microbial cell membranes. C5a exerts the same pro inflammatory effects as C3a and is more potent. C5b initiates the formation of a complex of complemnt proteins C6, C7, C8, and C9, which are assembled into a membrane pore called the membrane attack complex (MAC) that causes lysis of the cells where the complement is activated. Summary for Formation of the Membrane Attack Complex (MAC) → Cleavage of C3: C3 convertase cleaves C3 into C3a and C3b. C3b Deposition: C3b binds to the pathogen surface, amplifying the response. C5 Convertase Formation: C5 Activation: C3b binds to C3 convertase to form C5 convertase (C4b2a3b or C3bBbC3b). C5 Cleavage: C5 convertase cleaves C5 into C5a and C5b. Assembly of MAC: C5b Binding: C5b binds to C6, forming the C5b6 complex. C7 Addition: C7 binds to C5b6, forming C5b67. immunology Pagina 18  C8 Binding: C8 binds to C5b67, forming C5b678. C9 Polymerization: Multiple C9 molecules polymerize to form a pore in the pathogen membrane, resulting in cell lysis. Function of MAC Cell Lysis: The MAC forms a pore in the pathogen membrane, leading to the influx of water and ions, causing cell lysis and death. Effector of Immune Response: The MAC is a key effector of the immune system, targeting and destroying pathogenic cells There are different levels of regulation to control complement activation. Key Steps of Regulation: ⚫ Inhibition of C3 and C5 Convertase Formation: The C3 convertase is essential for cleaving and activating C3, a central step in the complement system that amplifies the immune response. To prevent uncontrolled complement activation, Factor H plays a critical regulatory role by inhibiting the assembly of C3 convertase on host cells. It does this by binding to C3b, which is deposited on cell surfaces as part of complement activation. Inhibiting the binding of Factor B to C3b. Factor B is a component required to form the C3 convertase (C3bBb), so if Factor B can't bind to C3b, the convertase can’t form and activate more complement. ⚫ Host Cell Specific Regulation: Factor H preferentially binds to host cells rather than pathogens because host cells are rich in sialic acid. Sialic acid residues on host cell membranes increase the affinity of Factor H for the cell surface. This feature helps distinguish between self (host cells) and non-self (pathogens or foreign cells), protecting the body’s own cells from complement attack.On pathogens, which typically lack sialic acid or have different surface structures. ⚫ Degradation of C3b by Factor I: Once Factor H binds to C3b on the host cell surface, it serves as a cofactor for Factor I, another regulatory protein. Factor I cleaves C3b into iC3b (inactive C3b), a degradation product that cannot participate in the formation of C3 or C5 convertases. This step effectively shuts down further complement activation at that site. By degrading C3b into iC3b, the immune response is localized and limited to where it is needed, preventing widespread damage. immunology Pagina 19 Anaphylatoxins: Induction of Acute Inflammation: ○ C3a and C5a are potent anaphylatoxins, meaning they can cause rapid and intense inflammation. ○ These molecules bind to receptors on endothelial cells, leading to increased vascular permeability, allowing fluids, proteins, and immune cells to more easily exit the bloodstream and enter infected or injured tissues. Activation of Mast Cells and Release of Vasoactive Mediators: ○ C3a and C5a bind to receptors on mast cells, causing them to release histamine and other vasoactive substances. ○ Histamine is a major mediator of inflammation; it promotes vasodilation (expansion of blood vessels) and further increases vascular permeability. Activation of Neutrophils and Promotion of Respiratory Burst: ○ C5a is a strong chemotactic factor for neutrophils, drawing them to the site of infection or tissue damage. ○ C5a also activates neutrophils, enhancing their ability to adhere to the endothelium via the upregulation of adhesion molecules. ○ Once activated by C5a, neutrophils initiate a respiratory burst, producing reactive oxygen species (ROS). immunology Pagina 20