COMPLEMENT LEVELS IN DISEASE
The complement proteins have some of the highest turnover rates of any of the plasma components. At any one time, the level of a complement component is a direct function of its catabolic and synthetic rates. There are many factors that cause the increased production of complement components by the liver and from cells present at local sites of inflammation. In tissue culture models, the addition of cytokines, such as interleukin-1α , interferon-γ , and especially tumor necrosis factor- α, upregulate C3 synthesis. Interleukin-1 α, interleukin-6, and especially interferon-γupregulate factor B synthesis. Interestingly, tumor necrosis fac-tor-α and interferon-γ concomitantly increase DAF expression on host cells (e.g., vascular endothelial cells) in order to protect the host from bystander complement attack, especially in areas where the membrane attack complex is inadvertently being deposited (e.g., on the vascular endothelium) during localized inflammation.
The catabolic rates of the complement system are primarily a function of the extent of complement activation by all the pathways involved. Therefore, the levels of complement proteins are influenced by the levels of complement activators (i.e., immune complexes), the class and subclass of immunoglobulin within the immune complexes, the release of direct complement-activating bacterial products, and, in certain chronic inflammatory diseases, the presence of autoantibody to complement components (immunoconglutinins).
The synthetic rates of complement glycoproteins vary widely in disease states and during the course of a given disease. In the end, the level of a complement component is a function of its metabolic rate (synthesis versus catabolism) and the type and course of the inflammatory reaction. Elevated levels of a given complement component in a disease state probably means that there is both a rapid synthetic and catabolic rate. Lower overall com-plement levels indicate that consumption is greater than synthesis at that particular time, usually in association with acute inflammation or an exacerbation of a chronic inflamma-tory process. Severe complement depletion, on the other hand, is usually associated with impaired hepatic synthesis (e.g., as in liver failure).
The development of immune complex diseases is believed to be a consequence of the in-ability to properly eliminate immune complexes from the kidney and/or from the basement membrane of dermal tissues. As previously mentioned in our discussion of the classical pathway, activation of a normal complement system by immune complexes will eventually lead to partial dissolution of the immune complex. This phenomenon is due to the deposi-tion of large complement fragments such as C4b and C3b on the antigen and on the Fab re-gion of the antibody, which interferes with the antigen-antibody binding reaction. If a defi-ciency in the early complement components exists, there will likely be a corresponding defect in the production and binding of C4b and C3b to the immune complex. As a result, the rate of formation of new immune complexes surpasses the inefficient rate of immune complex dissolution and/or phagocytic clearance, and the generation of pro-inflammatory complement fragments will be possible for a longer period of time. The reasons for the lower levels of early complement components (i.e., C1q, C4, and/or C2) are multiple and include not only genetic factors but also a variety of metabolic control mechanisms mentioned above.
In patients with systemic lupus erythematosus (SLE), a reduction in the levels of CR1 on erythrocytes has been reported. As previously discussed, the binding of complement-coated immune complexes to erythrocytes is an important physiological mechanism of im- mune complex removal from the circulation. Small- to medium-sized immune complexes are not taken up as efficiently by CR1 and tend to persist longer in circulation. However, when the number of CR1 receptors on erythrocyte membranes is decreased, even large-sized (complement-coated) immune complexes may persist for longer periods in circula-tion and may have a greater opportunity to be deposited in organs and tissues thereby caus-ing inflammation. The depleted number of CR1 per erythrocyte may be due in part to the overwhelming utilization of the erythrocyte CR1 in SLE and subsequent CR1 catabolism as the complement-coated immune complexes are presented to phagocytic cells in the liver and spleen.
Deficiencies of several of the components of the complement system are associated with two types of clinical situations: chronic bacterial infections, caused by capsulated organ-isms such as Neisseria species, and autoimmune disease, mimicking systemic lupus ery-thematosus .
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