The complement system consists of more than 30 serum and cell surface proteins. It was first discovered by Jules Bordet, the Belgian Nobel laureate, in 1899. He noted that when serum with antibacterial antibodies was added to a sample containing bacteria, the bacteria underwent lysis by the action of the antibodies. However, when the serum was heated above a certain temperature, lysis ceased to occur. He concluded that since antibodies are heat stable, there must be another substance in the serum that assists or complements the antibodies. Hence the term "complement" was coined.
There are three separate pathways of the complement system: the classical, alternative, and mannose-binding lectin pathways. They differ in the way they are activated but have a common end product, the terminal C5-9, also known as the membrane attack complex (Figure 1).
The classical pathway is activated by antigen-antibody interaction, leading to the activation of C1q, with the subsequent C2- and C4-dependent cleavage of C3 (by C3 conver-tase C4b2a) and cleavage of C5 by the C5 convertase (C4b2a3b).
The lectin pathway is activated when the serum mannose binding lectin (MBL), which is a homolog of C1q, recognizes microbial surface mannose and triggers activation of
MBL-associated proteases (MASP1-3), resulting in the same formation of C3 and C5 as in the classical pathway.
The alternative pathway is activated by the presence of lipopolysaccharide and also spontaneously generated C3b. C3b binds to factor B and forms a complex that is cleaved by factor D to form the alternative C3 convertase, C3(H20)Bb. The complex is stabilized by properdin, which acts as an amplifying activator. This enables the cleavage product C3b to bind to it, forming the alternative C5 convertase (C3b3bBb).
All three pathways use C3 and cleave C5, which leads to the formation of the proinflammatory cleavage products C5a and C5b-9, which are believed to be mainly responsible for ischemia-reperfusion injury. There is cross talk between the three pathways in a few species including mice. The pathways augment each other. C3 is at the intersection of all three pathways and its inhibition will lead to a complete blockade of complement activation and hence the formation of the membrane attack complex. This complex results in
pore formation in the cell membrane, causing abnormal ion transport, altered signaling, and possible cell lysis and eventual death.
In early studies, C3 depletion using cobra venom factor was reported to be protective during ischemia-reperfusion in kidney and heart . Since then, complement inhibition in multiple animal models has been successful in limiting IR injury. In experimental myocardial ischemia, C1 esterase inhibitor administered before reperfusion prevented the deposition of C1q and significantly reduced the area of cardiac muscle necrosis. It was also shown to confer protective effects in models of lung transplantation. Animals genetically deficient in C3 have less local tissue necrosis after skeletal muscle or intestinal ischemia. The protection from local and remote injury accorded to C5 deficient animals in models of ischemia-reperfusion confirmed the central role of the membrane attack complex . These preclinical results highlight the importance of complement activation.
Free radical scavengers have been used in similar studies and showed promise, but results of clinical trials were discouraging. Although the efficacy of complement antagonism in clinical trials cannot be predicted with certainty, these drugs are likely to fare better than the free radical scavengers. Free radical scavengers have never worked when given after the onset of reperfusion. In contrast, an inhibitor of complement activation, soluble crry (complement receptor-related gene Y), was effective against injury when given both prior to and after the onset of murine intestinal reperfusion. The use of a soluble complement receptor 1 (sCR1) in a model of skeletal muscle ischemia also reduced muscle injury when given up to an hour after the start of reperfusion. The complement system has also been shown to mediate intestinal injury after resuscitation from hemor-rhagic shock, which can be viewed as global body ischemia and reperfusion. The inhibition of complement after hemorrhage reduced tissue injury and neutrophil influx and preserved nitric oxide synthase function. The exact complement pathway has yet to be ascertained, but complement inhibition might provide a novel avenue for treating patients with major hemorrhage and prevent the compounding problem of gut ischemia, as well other problems associated with the multiple organ dysfunction syndrome.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.