Genetic deficiencies of complement proteins and regulatory proteins are the causes of various human diseases. Inherited and spontaneous deficiencies in many of the complement proteins have been described in humans.
• Genetic deficiencies in classical pathway components, including C1q, C1r, C4, C2, and C3, have been described; C2 deficiency is the most common human complement deficiency. More than 50% of patients with C2 and C4 deficiencies develop systemic lupus erythematosus. The reason for this association is unknown, but defects in complement activation may lead to failure to clear circulating immune complexes. If normally generated immune complexes are not cleared from the circulation, they may be deposited in blood vessel walls and tissues, where they activate leukocytes by Fc receptor-dependent pathways and produce local inflammation. Complement may also play an important role in the clearance of apoptotic bodies containing fragmented DNA. These apoptotic bodies are likely sources of the nuclear antigens that trigger autoantibody responses in lupus. In addition, complement proteins regulate antigen-mediated signals received by B cells; in their absence, self antigens may not induce B cell tolerance, and autoimmu-nity results. Somewhat surprisingly, C2 and C4 deficiencies are not usually associated with increased susceptibility to infections, which suggests that the alternative pathway and Fc receptor-mediated effector mechanisms are adequate for host defense against most microbes. Deficiency of C3 is associated with frequent serious pyogenic bacterial infections that may be fatal, illustrating the central role of C3 in opsoniza-tion, enhanced phagocytosis, and destruction of these organisms.
• Deficiencies in components of the alternative pathway, including properdin and factor D, result in increased susceptibility to infection with pyogenic bacteria. A mutation of the gene encoding the mannose-binding lectin (MBL) contributes to immunodeficiency in some patients; this is discussed in Chapter 20.
• Deficiencies in the terminal complement components, including C5, C6, C7, C8, and C9, have also been described. Interestingly, as mentioned before, the only consistent clinical problem in these patients is a propensity for disseminated infections by Neisseria bacteria, including Neisseria meningitidis and Neisseria gonorrhoeae, indicating that complement-mediated bacterial lysis is particularly important for defense against these organisms.
• Deficiencies in complement regulatory proteins are associated with abnormal complement activation and a variety of related clinical abnormalities. Deficiencies in C1 inhibitor and decay-accelerating factor are mentioned earlier in the text. In patients with factor I deficiency, plasma C3 is depleted as a result of the unregulated formation of fluid-phase C3 convertase (by the normal tickover mechanism). The clinical consequence is increased infections with pyogenic bacteria. Factor H deficiency is rare and is characterized by excess alternative pathway activation, consumption of C3, and glomerulonephritis caused by inadequate clearance of immune complexes and renal deposition of complement byproducts. An atypical form of the hemolytic-uremic syndrome involves defective complement regulation, and the most common mutations in this condition are in the factor H gene. Specific allelic variants of factor H are strongly associated with age-related macular degeneration. The effects of a lack of factor I or factor H are similar to the effects of an autoantibody called C3 nephritic factor (C3NeF), which is specific for alternative pathway C3 convertase (C3bBb). C3NeF stabilizes C3bBb and protects the complex from factor H-mediated dissociation, which results in unregulated consumption of C3. Patients with this antibody often have glomerulonephritis, possibly caused by inadequate clearing of circulating immune complexes.
• Deficiencies in complement receptors include the absence of CR3 and CR4, both resulting from rare mutations in the P chain (CD18) gene common to the CD11CD18 family of integrin molecules. The congenital disease caused by this gene defect is called leukocyte adhesion deficiency (see Chapter 20). This disorder is characterized by recurrent pyogenic infections and is caused by inadequate adherence of neutrophils to endothelium at tissue sites of infection and perhaps by impaired iC3b-dependent phagocytosis of bacteria.
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