Alternative Complement Pathway
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Alternative Complement Pathway
The complement system refers to a series of proteins circulating in the blood and bathing the fluids surrounding tissues. The proteins circulate in an inactive form, but in response to the recognition of molecular components of microorganism, they become sequentially activated, working in a cascade where in the binding of one protein promotes the binding of the next protein in the cascade. There are 3 complement pathways that make up the complement system: the classical complement pathway, the lectin pathway, and the alternative complement pathway. The pathways differ in the manner in which they are activated and ultimately produce a key enzyme called C3 convertase (Ref.1).

The alternative complement pathway constitutes the humoral component of natural defence against infections, which can operate without antibody participation. Six proteins, C3, B, D, H, P, by themselves and I perform the functions of initiation, recognition, and amplification of the pathway, which results in the formation of the activator-bound C3/C5 convertase. A variety of activators of this pathway have been described such as certain particulate polysaccharides, for example, bacterial (LPS), yeast (zymosan), or plant (inulin) polysaccharides, fungi, bacteria, viruses and certain mammalian cells. Antibody, independent of its role in activating the classical complement pathway, is able to function in the alternative complement pathway. Metastable C3B is capable of binding directly to IgG (Immunoglobulin-G). The role of immunoglobulin in alternative pathway function is important because C3B covalently bound to IgG displays relative resistance to inactivation by H and I when compared to free C3B. The resistance appears to be entirely due to the reduced affinity of for H, and this confers on the complex an enhanced capacity to activate C3 in serum. It seems that a number of immunoglobulins are able to activate the alternative complement pathway and play an important role in host defence in the infective process. Aggregated IgG and aggregated IgM both activate the pathway, as well as some aggregated IgA myeloma proteins and some IgE myelomas; although the immunoglobulin concentration required for such activation is actually relatively high (Ref.2).

The first step in the alternative pathway is the binding of C3B to an activator. C3 contains a thioester bond, which reacts with almost anything that exposes -OH or -NH2 groups, by spontaneously "ticking over". C3B is continuously generated in small quantities in the circulation but in the free state it is rapidly inactivated by the serum protein factors H and I. Bound C3B which is protected from such inactivation interacts with a serum protein called Factor B (C3 proactivator) to form a magnesium dependent complex C3B, Factor B. This complex is cleaved by another serum protein Factor D (C3 proactivator convertase). The resultant cleavage of Factor B causes the release of Factor-BA, a 30kD fragment and the formation of C3 (H2O) Factor-BB(Mg), the initial C3 convertase, which is confined to the fluid phase. Factor-BB, a 60kD fragment, is the second formed as a result of the cleavage of Factor B. The initial C3 convertase is under positive regulation by Factor-P (Properdin), whose function in the alternative pathway is to bind to cell-bound C3B and to stabilize the C3/C5 convertase. Fragment Factor-BA is released into the medium. Fragment Factor-BBremains bound to C3B, forming the esterase C3B, Factor-BBcomplex, which is the alternative C3 convertase. The C3B, Factor-BBcomplex is homologous in both structure and function to C4B,2B (classical C3 convertase). It cleaves C3 molecules, exposing their thioester bonds to attack by water, plasma proteins and more importantly components of microbial surface. The cleavage and activation of C3 by C3B, Factor-BBis an accelerating reaction with positive feedback, because the product of the reaction itself forms more enzyme. By the end of the reaction, most of the C3B fragments that now saturate the surface of the pathogen close to the initiating antigen: antibody complex are due to the action of the C3 convertase of the alternative pathway (Ref.3).

The C3 convertase can function as a C5 convertase provided that an additional C3B molecule is available in close proximity. The role of this second C3B molecule is to bind C5 and to modify it for cleavage by Factor-BB. At this stage factor I cannot inactivate C3B in the bimolecular C3 convertase, C3B, Factor-BB, although it is able to inactivate the additional C3B which converts the C3B, Factor-BBcomplex to the C5 convertase, C3B, Factor-BB, C3B, also, that factor H augments the rate of inactivation of C3B by dissociating Bb from the complex C3B, Factor-BB. The C3/C5 convertase is physically stabilized by the cyclic protein, Properdin. At this point the alternative pathway proceeds in the same manner as the classical pathway, recruiting additional complement factors (C6, C7, C8 and C9) to ultimately form the MAC (Membrane Attack Complex) and lyse the associated cell. As a major effector mechanism of the complement cascade, the MAC is responsible for direct complement-dependent serum bactericidal activity (Ref.4). Recent evidence suggests that it may also participate in tissue injury in a wide range of diseases. Perhaps for this reason, a small percentage (approx. 5%) of reported individuals with LCCD (Late Complement Component Deficiency) have evidence of immune complex or rheumatologic disease. Host cell-associated regulatory proteins serve as formidable protectors against autologous complement attack. Both DAF (Decay-Accelerating Factor) and MCP (Membrane Cofactor Protein) are regulators with a wide tissue distribution. They are functionally complementary in that DAF prevents assembly of the C3 convertase and dissociates the formed enzyme, whereas MCP has cofactor activity for I mediated C3B degradation. CR1, which has a more limited tissue distribution, also has cofactor activity. Together, these membrane proteins provide a large measure of protection against C3B deposition on self-tissue (Ref.5).