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The Functions and Components of Complement
This Sqadia video is the demonstration of The Complement System - I. The Complement System is the major effector of the humoral branch of the immune system. Research on complement began in the 1890s. Bordet showed that bacteriolytic activity requires two different substances: specific antibacterial antibodies and heat-sensitive component. Bordet devised a simple test for the lytic activity, the easily detected lysis of antibody-coated red blood cells, called hemolysis. Paul Ehrlich in Berlin independently carried out similar experiments, Coined the term complement defining it as “The activity of blood serum that completes the action of antibody.” Research on complement now includes more than 30 soluble and cell-bound proteins. After initial activation, the various complement components interact, in a highly regulated cascade, to carry out a number of basic functions including lysis of cells, opsonization, binding to specific complement receptors on cells of the immune system and immune clearance. The proteins and glycoproteins that compose the complement system are synthesized mainly by liver hepatocytes, significant amounts are also produced by blood monocytes, tissue macrophages, and epithelial cells of the gastrointestinal and genitourinary tracts. These components constitute 5% of the serum globulin fraction. Most circulate in the serum in functionally inactive forms as proenzymes. The complement-reaction sequence starts with an enzyme cascade.
Complement activation by the classical pathway commonly begins with the formation of soluble antigen-antibody complexes or with the binding of antibody to antigen on a suitable target, such as a bacterial cell. IgM and certain subclasses of IgG activate the classical complement pathway. The initial stage of activation involves C1, C2, C3, and C4, which are present in plasma in functionally inactive forms. The formation of an antigen-antibody complex induces conformational changes in the Fc portion of the IgM molecule that expose a binding site for the C1 component of the complement system. C1 in serum is a macromolecular complex consisting of; C1q and two molecules each of C1r and C1s. The C1q molecule is composed of 18 polypeptide chains. Each C1r and C1s monomer contains a catalytic domain and an interaction domain. An IgG molecule contains only a single C1q-binding site in the CH2 domain of the Fc. A single molecule of IgM bound to RBC can activate the classical complement pathway while 1000 molecules of IgG are required to assure that two IgG molecules are close enough to each other on the cell surface to initiate C1q binding.
The Classical Pathway - I
Intermediates in the Classical Pathway act in the following manner: C1q binds antigen-bound antibody. C1r activates auto-catalytically and activates the second C1r; both activate C1s. C1s cleaves C4 and C2. Cleaving C4 exposes the binding site for C2. C4 binds the surface near C1 and C2 binds C4, forming C3 convertase. C3 convertase hydrolyses many C3 molecules. Some combine with C3 convertase to form C5 convertase. The C3b component of C5 convertase binds C5, permitting C4b2a to cleave C5. C5b binds C6, initiating the formation of the membrane-attack complex.
The Classical Pathway - II
Steps and components of classical pathway includes the binding of C1q to Fc binding sites which induces a conformational change in C1r. C1̅s̅ has two substrates - C4 and C2. The C4 component is the glycoprotein containing three polypeptide chains α,β, and γ. C4 is activated when C1̅s̅ hydrolyzes a small fragment (C4a) from the amino terminus of the chain and exposing a binding site on the larger fragment (C4b). The C4b fragment attaches to the target surface in the vicinity of C1. The C2 proenzyme then attaches to the exposed binding site on C4b. Where the C2 is then cleaved by the neighbouring C1s. The smaller fragment from C4 cleavage – C4a, is an anaphylatoxin, or mediator of inflammation that does not participate directly in the complement cascade. The native C3 component consists of two polypeptide chains, α and β. A single C3 convertase molecule can generate over 200 molecules of C3b. The C3b component of this complex binds C5 and alters its conformation, so that the C4b2a component can cleave C5 into C5a, and C5b. Some of the C3b does not associate with C4̅b̅2̅a̅, diffuses away and then coats immune complexes and particulate antigens.
The Alternative Pathway
The alternative pathway generates bound C5b, the same product that the classical pathway generates. Ab-Ag complexes for initiation are not needed. The alternative pathway is a component of the innate immune system. This major pathway of complement activation involves four serum proteins: C3, factor B, factor D, and properdin. The alternative pathway is initiated in most cases by cell-surface constituents that are foreign to the host. Pathogens and particles of microbial origin that are the initiators of the alternative pathway are many strains of gram-negative bacteria and gram-positive bacteria, some viruses and virus-infected cells and some tumor cells. Nonpathogen initiators are human IgG, IgA, and IgE in complexes, heterologous erythrocytes, and anionic polymers. Intermediates of the Alternative Pathway i.e. C3 hydrolyses spontaneously, C3b fragment attaches to foreign surface. Factor B binds C3a, exposes site acted on by Factor D. Cleavage generates C3bBb, which has C3 convertase activity. Convertase generates C3b; some binds to C3 convertase activating C5' convertase. C5b binds to antigenic surface. In the classical pathway, C3 is rapidly cleaved to C3a and C3b through enzymatic activity of the C3 convertase. In the alternative pathway, serum C3, which contains an unstable thioester bond, is subject to slow spontaneous hydrolysis to yield C3a and C3b. Foreign antigenic surfaces have low levels of sialic acid, so C3b bound to these surfaces remains active for a longer time. Binding to C3b exposes a site on factor B that serves as the substrate. Factor D cleaves the C3b-bound factor B. The C3 convertase activity of C3bBb has a half-life of only 5 minutes. The non-enzymatic C3b component binds C5, the Bb component subsequently hydrolyzes the bound C5 to generate C5a and C5b. The latter binds to the antigenic surface.