Complement Pathway
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Complement Pathway
The C (Complement) system consists of about twenty plasma proteins that function either as enzymes or as binding proteins. In addition to these plasma proteins, the complement system includes multiple distinct cell-surface receptors that exhibit specificity for the physiological fragments of complement proteins and that occur on inflammatory cells and cells of the immune system. Activation of the complement system initiates a series of enzymatic reactions in which the proteolytic cleavage and activation of successive complement proteins leads to the covalent bonding or fixing of complement fragments to the pathogen surface. A major consequence of this is the uptake and destruction of complement coated microbes by phagocytes that bear receptors for these complement fragments (Ref.1).

Most complement proteins exist in plasma as inactive precursors called zymogens. In the course of complement activation, individual components are activated by highly selective proteolytic cleavage, usually at a single site. The activation of complement takes place in the blood and in the tissues, into which complement proteins leak from the blood. Complement system consists of 9 major components C1-C9. The fraction C1 occurs in serum as a calcium ion dependent complex, which on chelation with EDTA (Ethylene Diamine Tetra Acetic acid) yields three protein subunits called C1Q, C1R and C1S. Thus C is made up of a total of 11 different proteins. C fractions are named C1 to C9 in the sequence of the cascading reaction, except that C4 comes after C1, before C2. Of all the complement components,C3 is supremely important and the most abundant. The complement system uses three different strategies for recognizing microorganisms, each of which initiates a pathway of complement activation that leads to the covalent bonding of complement proteins to microbial surfaces. These initiation pathways include: the Classical, the Lectin, and the Alternative pathway (Ref.2).

The classical pathway of the complement activation is triggered by antibodies bound to antigens on a microbial surface. In this pathway, which was the first to be discovered, the complement proteins work together with antibodies to enhance the clearance of antigen: antibody complexes from the body. In the first part of classical pathway, a series of proteases is activated, each enzyme cleaving and activating the next in the pathway. Cleavage usually produces two fragments, a larger, enzymatically active, fragment and a smaller fragment that often has an inflammatory effect. The larger fragments generally join the cascade. The smaller fragments which are released, often possess biological effects which contribute to defence mechanisms by amplifying the inflammatory process, increasing vascular permeability, inducing smooth muscle contraction, causing chemotaxis of leucocytes, promoting virus neutralization, detoxifying endotoxins and effecting the release of histamine from mast cells (Ref.3).

The two other pathways provide for complement activation in the absence of antibody and are considered part of the innate immune defenses. They are the alternate pathway of complement activation, which is triggered directly by constituents of bacterial cell surfaces, and the lectin-mediated pathway, which is activated by the binding of a MBP1 (Mannose-Binding Protein 1) present in the blood plasma to mannose-containing proteoglycans on the surfaces of bacteria and yeast. All these pathways are distinct in the initiation of the proteolytic cascade but share most of their components and all three lead to the formation of a C3A convertase enzyme that cleaves C3 into C3B and C3A fragments. The C3B fragment becomes covalently bound to the pathogen surface. Macrophage and Neutrophils bear receptor for C3B and so the opsonization of a pathogen with complement facilitates its phagocytosis and destruction in the same way, as does opsonization with antibody. Other inflammatory cells such as eosinophil also bear receptors for complement components; complement-coated pathogens can therefore also activate and recruit these cells into the inflammatory response to infection. Inflammation is also produced in the course of the response. Complement deposited on the surface of certain pathogens can also lead directly to the lysis of the coated cells through the assembly of a complex of the terminal complement components, known as MAC (Membrane Attack Complex), that makes a hole in the cell membrane and destroys its integrity. In addition to providing a key part of the response to bacterial infection, the complement system can be involved in the response to fungi, viruses and protists. There are also several regulatory membrane proteins that function to prevent autologous complement activation and protect host cells from accidental complement attack (Ref.4).

Twelve different proteins have been identified that inhibit complement activation to control the system, including Factor H, Factor I and C1 inhibitor. Deficiencies in components of the complement system have been identified in humans that cause a variety of immune related disorders. C3 deficiency is associated with recurrent bacterial infections, while a lack of C2 can cause antibody-antigen complexes to accumulate and cause the autoimmune disorder systemic lupus erythematosus. People lacking C1 inhibitor have also been identified and found to be prone to uncontrolled complement activation and dangerous swelling through production of C3A and C5A anaphylotoxins. The list of diseases associated with inappropriate complement activation is long. It includes experimental allergic neuritis, type II collagen-induced arthritis, myasthenia gravis, hemolytic anemia, glomerulonephritis, immune complex-induced vasculitis, and multiple sclerosis. Complement is also thought to contribute to the cellular destruction that occurs in adult respiratory distress syndrome, stroke, heart attack, and burn injuries. Activation of complement may also occur when blood comes into contact with bioincompatible surfaces such as the tubing of a cardiopulmonary bypass oxygenator, initiating "whole body" inflammation; or when the body encounters incompatible transplanted tissue, initiating hyperacute rejection (Ref.5).