Complement

Chapter 4 Complement




Summary




Complement is central to the development of inflammatory reactions and forms one of the major immune defense systems of the body. The complement system serves as one of the links between the innate and adaptive arms of the immune system.


Complement activation pathways have evolved to label pathogens for elimination. The classical pathway links to the adaptive immune system through antibody. The alternative and lectin pathways provide antibody-independent ‘innate’ immunity, and the alternative pathway is linked to and amplifies the classical pathway.


The complement system is carefully controlled to protect the body from excessive or inappropriate inflammatory responses. C1 inhibitor controls the classical and lectin pathways. C3 and C5 convertase activity are controlled by decay and enzymatic degradation. Membrane attack is inhibited on host cells by CD59.


The membrane attack pathway results in the formation of a lytic transmembrane pore. Regulation of the membrane attack pathway by CD59 reduces the risk of ‘bystander’ damage to adjacent host cells.


Many cells express one or more membrane receptors for complement products. Receptors for fragments of C3 are widely distributed on different leukocyte populations. Receptors for C1q are present on phagocytes, mast cells, and platelets. C5 fragment receptors are present on many cell types. The plasma complement regulator fH binds leukocyte surfaces.


Complement has a variety of functions. Its principal functions include opsonization, chemotaxis and cell activation, lysis of target cells, and priming of the adaptive immune response.


Complement deficiencies illustrate the homeostatic roles of complement. Classical pathway deficiencies result in tissue inflammation. Deficiencies of mannan-binding lectin (MBL) are associated with infections in infants and the immunosuppressed. Alternative pathway and C3 deficiencies are associated with bacterial infections. Terminal pathway deficiencies predispose to Gram-negative bacterial infections. C1 inhibitor deficiency leads to hereditary angioedema. Deficiencies in alternative pathway regulators produce a secondary loss of C3.



Complement and inflammation


The complement system was discovered at the end of the 19th century as a heat-labile component of serum that augmented (or ‘complemented’) its bactericidal properties.


Complement is now known to comprise some 16 plasma proteins, together constituting nearly 10% of the total serum proteins, and forming one of the major immune defense systems of the body (Fig. 4.1). In addition to serving as a key component of the innate immune system, complement also interfaces with and enhances adaptive immune responses. More than a dozen regulatory proteins are present in plasma and on cells to control complement. The functions of the complement system include:




In evolutionary terms the complement system is very ancient and antedates the development of the adaptive immune system: even starfish and worms have a functional complement system.


The importance of complement in immune defense is readily apparent in individuals who lack particular components – for example, children who lack the central component C3 are subject to overwhelming bacterial infections.


Like most elements of the immune system, when overactivated or activated in the wrong place, the complement system can cause harm.


Complement is involved in the pathology of many diseases, provoking a search for therapies that control complement activation.



Complement activation pathways


One major function of complement is to label pathogens and other foreign or toxic bodies for elimination from the host. The complement activation pathways have evolved to serve this purpose, and the multiple ways in which activation can be triggered, together with intrinsic amplification mechanisms, ensure efficient recognition and clearance.


Moreover, there are several different ways to activate the complement system, so providing a large degree of flexibility in response (Fig. 4.2).



The first activation pathway to be discovered, now termed the classical pathway, is initiated by antibodies bound to the surface of the target. Although an efficient means of activation, it requires an adaptive immune response: that is, the host must have previously encountered the target microorganism in order for an antibody response to be generated.


The alternative pathway, described in the 1950s, provides an antibody-independent mechanism for complement activation on pathogen surfaces.


The lectin pathway, the most recently described activation pathway, also bypasses antibody to enable efficient activation on pathogens.


All three pathways – classical, alternative, and lectin pathways:



Thus a small initial stimulus can rapidly generate a large effect. Figure 4.3 summarizes how each of the pathways is activated.



All activation pathways converge on a common terminal pathway – a non-enzymatic system for causing membrane disruption and lytic killing of pathogens.


The immune defense and pathological effects of complement activation are mediated by the fragments and complexes generated during activation:



The details of complement activation, the nomenclature, and the ways in which the pathways are controlled are shown in Figure 4.4.


image

Fig. 4.4 Overview of the complement activation pathways


The proteins of the classical and alternative pathways are assigned numbers (e.g. C1, C2). Many of these are zymogens (i.e. pro-enzymes that require proteolytic cleavage to become active). The cleavage products of complement proteins are distinguished from parent molecules by suffix letters (e.g. C3a, C3b). The proteins of the alternative pathway are called ‘factors’ and are identified by single letters (e.g. factor B, which may be abbreviated to fB or just ‘B’). Components are shown in green, conversion steps as white arrows, and activation/cleavage steps as red arrows. The classical pathway is activated by the cleavage of C1r and C1s following association of C1qr2s2 with classical pathway activators (see Fig. 4.3), including immune complexes. Activated C1s cleaves C4 and C2 to form the classical pathway C3 convertase image. Cleavage of C4 and C2 can also be effected via MASP-2 of the lectin pathway, which is associated with mannan-binding lectin (MBL) or ficolin. The alternative pathway is activated by the cleavage of C3 to C3b, which associates with factor B and is cleaved by factor D to generate the alternative pathway C3 convertase image. The initial activation of C3 happens to some extent spontaneously, but this step can also be affected by classical or alternative pathway C3 convertases or a number of other serum or microbial proteases. Note that C3b generated in the alternative pathway can bind more factor B and generate a positive feedback loop to amplify activation on the surface. Note also that the activation pathways are functionally analogous, and the diagram emphasizes these similarities. For example, C3 and C4 are homologous, as are C2 and factor B. MASP-2 is homologous to C1r and C1s. Either the classical or alternative pathway C3 convertases may associate with C3b bound on a cell surface to form C5 convertases, image, or image, which split C5. The larger fragment C5b associates with C6 and C7, which can then bind to plasma membranes. The complex of C5b67 assembles C8 and a number of molecules of C9 to form a membrane attack complex (MAC), C5b–9.



The classical pathway links to the adaptive immune system



The classical pathway is activated by antibody bound to antigen and requires Ca2+


Only surface-bound IgG and IgM antibodies can activate complement, and they do so via the classical pathway. Surface binding is the key:




The first component of the pathway, C1, is a complex molecule comprising a large, 6-headed recognition unit termed C1q and two molecules each of C1r and C1s, the enzymatic units of the complex (Fig. 4.5). Assembly of the C1 complex is Ca2+-dependent, and the classical pathway is therefore inactive if Ca2+ ions are absent.









The alternative and lectin pathways provide antibody-independent ‘innate’ immunity



The lectin pathway is activated by microbial carbohydrates


The lectin pathway differs from the classical pathway only in the initial recognition and activation steps. Indeed, it can be argued that the lectin pathway should not be considered a separate pathway, but rather a route for classical pathway activation that bypasses the need for antibody.


The C1 complex is replaced by a structurally similar multimolecular complex, comprising a C1q-like recognition unit, either mannan-binding lectin (MBL) or ficolin (actually a family of three proteins in man), and several MBL-associated serine proteases (MASPs). MASP-2 provides enzymatic activity. As in the classical pathway, assembly of this initiating complex is Ca2+-dependent.


C1q and MBL are members of the collectin family of proteins characterized by globular head regions with binding activities and long collagenous tail regions with diverse roles (see Fig. 6.w3image). Ficolins are structurally similar but the head regions comprise fibrinogen-like domains.


MBL binds the simple carbohydrates mannose and N-acetyl glucosamine, while ficolins bind acetylated sugars and other molecules; these ligands are abundant in the cell walls of diverse pathogens, including bacteria, yeast, fungi, and viruses, making them targets for lectin pathway activation. Binding induces shape changes in MBL and ficolins that in turn induce autocatalytic activation of MASP-2. This enzyme can then cleave C4 and C2 to continue activation exactly as in the classical pathway.


The lectin pathway is not the only means of activating the classical pathway in the absence of antibody. Apoptotic cells, released DNA, mitochondria and other products of cell damage can directly bind C1q, triggering complement activation and aiding the clearance of the dead and dying tissue.




The image complex is the C3 convertase of the alternative pathway


Once bound to C3(H2O) or C3b, fB becomes a substrate for an intrinsically active plasma enzyme termed factor D (fD). fD cuts fB in the C3bB complex:



The image complex is the C3 cleaving enzyme (C3 convertase) of the alternative pathway. C3b generated by this convertase can be fed back into the pathway to create more C3 convertases, thus forming a positive feedback amplification loop (Fig. 4.7). Activation may occur in plasma or, more efficiently, on surfaces.




Specific features of host cell surfaces, including their surface carbohydrates and the presence of complement regulators (see below), act to protect the host cell from alternative pathway activation and risk of being destroyed, and such surfaces are termed non-activating.


On an activating surface such as a bacterial membrane, amplification will occur unimpeded and the surface will rapidly become coated with C3b (see Fig. 4.7). In a manner analogous to that seen in the classical pathway, C3b molecules binding to the C3 convertase will change the substrate specificity of the complex, creating a C5 cleaving enzyme, image.


Cleavage of C5 is the last proteolytic step in the alternative pathway and the C5b fragment remains associated with the convertase.



Jun 18, 2016 | Posted by in IMMUNOLOGY | Comments Off on Complement

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