Possible mechanisms of complement and disease associations

Since only some, but not all, complement-deficient individuals show disease manifestations, it appears legitimate to conclude that the deficiency is the common genetic basis, not the primary cause in the pathogenesis of a given disease. Also, there is no direct evidence for a role of single genetic variants of a given component in the pathogenesis of autoimmune or infectious diseases. However, there are several lines of evidence suggesting an important physiologic role of complement in immune defense:

1. It has been shown that the intact classical pathway is needed to prevent formation of insoluble immune complexes (ICs); the components of the classical pathway play an important role in this function. In cases of deficiency, ICs may not be cleared by the reticuloendothelial system and therefore recirculate until being deposited at capillary or basal membranes, leading eventually to tissue damage. This mechanism could be envisaged in some forms of vasculitis and glomerulonephritis, as well as autoimmune disease in the presence of nuclear antibodies.

2. In the case of viral antigens, small ICs may escape from CRl-mediated clearance by erythrocytes if the individual is C4-deficient. Circulating ICs may even, after years, be deposited in the brain, having passed the blood-cerebrospinal fluid barrier, contributing to cytotoxic effects in the central nervous system, as seen in diseases such as SSPE and AIDS.

3. Deficiency of MAC components may render these individuals more susceptible to recurrent infections with bacteria such as Neisseria. On the other hand, the lack of complement-dependent bacterial lysis protects the patient from massive ievels of bacterial endotoxin, leading to a milder course of disease. Depending upon the structural components of the bacterial membranes, some strains appear to be more resistant to complement-mediated lysis than others.

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