Immunologic Aspects of Organ Transplantation

Susan Smith MN, PhD

Disclosures

June 17, 2002

Complement Activation

The complement system consists of a complex set of approximately 20 interacting proteolytic enzymes and regulatory proteins found in the plasma and body fluids.[6] Complement proteins are effector molecules that modulate inflammatory responses. Inflammatory cells, APCs, and lymphocytes have receptors for complement stimulation and activation. Conceptually, the complement system is similar to the coagulation system in that complement proteins react sequentially in a series of enzymatic reactions in a cascading manner. Several factors are responsible for activation of the complement system: the formation of insoluble antigen-antibody complexes, aggregated immunoglobulin, platelet aggregation, release of endotoxins by gram-negative bacteria, the presence of viruses or bacteria in the circulation, and the release of plasmin and proteases from injured tissues. Complement proteins can mediate the lytic destruction of cells, including RBCs, WBCs, platelets, bacteria, and viruses.

Complement is activated via 1 of 2 pathways: the lectin/alternative or classical pathway. The lectin alternative pathway is triggered in response to antigen, usually bacteria, alone to ensure that antigen cleanup begins immediately. The classical pathway is triggered when antibody in the plasma leaks into the tissue space and finds the bacterium for which it bears specificity, forming an antigen-antibody complex.

Regardless of which activation pathway activates the complement system, different complement components bind to either the surface of the bacterium or the stem of the antibody molecule that is bound to the bacterium (Figure 9). This binding triggers the cleavage and fixation of additional complement proteins, eventually leading to the activation of complement component C3. Activation of C3 is the critical event in complement activation, which triggers subsequent events that lead to bacterial elimination. Certain fragments of complement are chemotactic for phagocytes: C5a, C4a, and C3a. In this way, complement attracts more phagocytes to the site of antigen entry. Other complement fragments stimulate phagocytosis by coating the surface of bacteria with opsonins, making them "tastier" for phagocytes, to enhance the rate of bacterial clearance. The importance of C3 to immunity is underscored by the fact that while several other complement protein deficiencies have been identified clinically, C3 deficiency does not exist. That is, the absence of C3 is incompatible with life.

A third mechanism of bacteria clearance by complement is the generation of MAC. The MAC is an assembly of complement fragments on the surface of a bacterium that effectively forms a hole in the bacterial membrane, leading to osmotic lysis and death of the bacterium. MAC is triggered when antibody binds to a bacterium for which it bears specificity. Complement components become fixed to the stem of the antibody molecule, triggering the attachment of additional components in the cascade. Eventually, fragments C5b through C9 arrange themselves in a doughnut shape in the membrane of the bacterium, causing lysis and death. In this way, complement is also responsible for the death of cells contained in an organ allograft.

Complement activation leads to the massive production of complement molecules that act as enzymes for subsequent chemical reactions, resulting in cell lysis, phagocyte chemotaxis, and opsonization. Complement inactivators present in the liver and spleen "turn off" the complement cascade to prevent damage to normal tissue.

The body calls on the innate immune mechanisms as the first line of defense against threatening foreign antigens. However, if these mechanisms are not entirely successful, a second set of defenses, collectively referred to as the acquired immune system, is activated to work in concert with the innate immune system. The acquired immune system is composed of lymphocytes and other lymphoid structures necessary for specific immune responses.

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