Alternative Pathway (AP)
※ Download: Classical pathway of complement activation
Formation of the membrane-attack complex seems to be important only for the killing of a few pathogens, although, as we will see in Chapter 13, it might have a major role in immunopathology. There are three pathways of complement activation: the , which is triggered directly by pathogen or indirectly by antibody binding to the pathogen surface; the MB-lectin pathway; and the , which also provides an amplification loop for the other two pathways. This results in formation of the C3 convertase, C3b,Bb see. The molecules of C3b that bind the C3 convertase itself initiate the late events, binding C5 to make it susceptible to cleavage by C2b or.
The altered C1r cleaves C1s. The binding of B by C3 H 2O then allows a plasma protease called factor D to cleave factor B to Ba and , the latter remaining associated with C3 H 2O to form the C3 H 2O Bb complex. Blom, in , 2018 Abstract C4b-binding protein C4BP is the main fluid-phase inhibitor of the classical complement pathway.
Classical pathway - Lippincott's Illustrated Reviews: Immunology, 320p. This local variation in the regulation of complement may allow fine-tuning of tissue levels expressed without alteration of circulating levels.
Classical complement pathway Complement system is a major effector of the humoral branch of the immune system, acting to protect the host from microorganisms such as bacteria. Complement components are designated by numerals C1 - C9 , by letter symbols e. Peptide fragments formed by activation of a component are denoted by small letters ,. In most cases, the smaller fragment resulting from cleavage of a Complement component is designated 'a' and the larger fragment designated 'b' e. Larger fragments bind to targets near activation sites, while smaller fragments, called anaphylatoxins, diffuse from the site and may initiate localized inflammatory responses by binding to specific receptors, such as Complement component 3a receptor 1 CR3aR and Complement component 5a receptor 1 CR5aR , ,. Complement fragments named opsonins, i. Complement fragments interact with each another to form functional complexes. Complement activation by the classical pathway commonly begins with the formation of soluble antigen-antibody complexes immune complexes or with the binding of antibody Immunoglobulins such as IgG1 and IgM to antigen on a suitable target, such as a bacterial cell. Initial stage of activation involves Complement component s C1, C2, C3 and C4, which are present in plasma in functionally inactive forms. Formation of an antigen-antibody complex induces conformational changes in the Fc part of the IgM molecule that expose a binding site for the Complement component C1. C1 in serum is represented by a macromolecular complex also called C1qr2s2. It consists of three protein subunits Complement component 1 q subcomponent C1q , Complement component 1 r subcomponent C1r and Complement component 1 s subcomponent C1s. Components of complex are stabilized by Ca 2+ ions ,. Serpin peptidase inhibitor clade G member 1 C1 inhibitor inhibits activated C1r and C1s and thus regulates complement activation. C1r cleaves and activates C1s, which translates the activation of the Complement component C1 complex into complement activation via cleavage of C4 and C2 to form a C3 convertase C2aC4b. C3 convertase C2aC4b cleaves C3. C5 convertase C2aC4bC3b involved in classical pathway is assembled of two proteins, C4b and C2a, and additional C3b molecules. Factor I is a major regulator of complement. As a protease it has very restricted specificity, cleaving only C3b or C4b in the presence of a cofactor such as Complement factor H Factor H. Cleavage of C3b by Factor I yields iC3b, a major opsonin. CD46 molecule, complement regulatory protein MCP is a cofactor for the Factor I -mediated degradation of C3b and C4b deposited on host cells. Smaller fragments resulting from complement cleavage, C3a and C5a, called anaphylatoxins, bind to their cognate receptors CR3aR and CR5aR on the surface of mast cells and blood basophils and induce degranulation, upon release of histamine and other biologically active mediators. The terminal sequence of complement activation involves Complement components C5b, C6, C7, C8, and C9, which interact sequentially to form a macromolecular structure called Membrane attack complex. This complex creates pores in the cell membrane and induces cell lysis. It inserts into the lipid bilayer of cell membranes, where it becomes a high-affinity receptor for C8 molecules C8alpha, C8beta, C8gamma. This fully active Membrane attack complex forms a large channel through the membrane of the target cell, enabling ions and small molecules to diffuse freely across the membrane. The latest step of complement activation is also controlled by the membrane-associated complement regulatory protein CD59 that prevents the formation of the Membrane attack complex at the terminal step of complement activation cascade ,.
Among these processes is myeloid cell activation leading to enhanced engulfment of apoptotic cells and the regulation of proinflammatory cytokine production which is thought to be important in the prevention of autoimmunity. Like C3a, C5a is also an anaphylatoxin with interacts with its cognate C5a receptor C5aR to attract leukocytes. Complement activation represents the dynamic interplay among the different pathways, the control processes, and other protein systems and cells in the local environment. These act on different stages of the complement cascade, dissociating complexes or catalyzing the enzymatic degradation of covalently bound The thioester bond of activated C3 and C4 classical pathway of complement activation extremely reactive and has no mechanism for distinguishing an acceptor hydroxyl or amine group on a host cell from a similar group on the surface of a pathogen. Not surprisingly, overexpression of complement regulatory proteins in mice markedly ameliorated nephrotoxic serum nephritis. C1s cleaves C2 to produce the large fragment C2b, which is itself a serine protease.
