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 found 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 C1q, C2, and C4 deficiencies develop systemic lupus erythematosus. The reason for this association of complement defects and an autoimmune immune complex disease is unknown, but it may be related to inadequate clearance of circulating immune complexes because of defects in complement activation. 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 autoimmunity results. Some patients with C2 or C4 deficiency show increased susceptibility to infections, and others are asymptomatic. Deficiency of C3 is associated with frequent serious pyogenic bacterial infections that may be fatal, illustrating the central role of C3 in opsonization, enhanced phagocytosis, and destruction of these organisms.
• Deficiencies in components of the alternative pathway result in increased susceptibility to meningococcal infections. Factor B and Factor D deficiencies are rare, but X-linked recessive properdin deficiency is more common. Genetic variants of the genes encoding MBL and MASP2 contribute to immunodeficiency in some patients; this is discussed in Chapter 21.
• Deficiencies in the terminal complement components, including C5, C6, C7, C8, and C9, have also been described. Interestingly, as mentioned earlier, the only consistent clinical problem in these patients is a propensity for disseminated infections by Neisseria bacteria, including Neisseria meningitidis and Neisseria gonorrhoeae. Complement-mediated bacterial lysis is particularly important for defense against these thin-walled organisms.
• Deficiencies in complement regulatory proteins are associated with abnormal complement activation and a variety of related clinical abnormalities.
• Deficiencies of C1-INH and decay accelerating factor causing hereditary angioedema were mentioned earlier.
• 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 by-products.
• A form of hemolytic-uremic syndrome involves defective complement regulation, and the most common mutations in this condition are in the Factor H gene. The other gene that is mutated in many patients is the MCP gene. In this disease, children present with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, all triggered by endothelial cell injury caused by hyperactivation of the alternative pathway of complement. Mutant Factor H or MCP binds less well to C3b and C4b on endothelial surfaces, and as a result there is excessive complement activation, leading to the formation of microthrombi and vascular damage.
• The effects of a lack of Factor I or Factor H are similar to the effects of an autoantibody called C3 nephritic fac tor (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 defective clearing of circulating immune complexes.
• Specific allelic variants of Factor H are strongly associated with age-related macular degeneration. Excessive inflammation in the absence of complement regulation contributes to the disruption of photoreceptor cells in the macular region and consequent blindness.
• Mutations in the PIG-A (phosphatidylinositol glycosyl transferase-A) gene result in paroxysmal nocturnal hemoglobinuria, as discussed earlier, as a result of defective GPI anchors for CD59 and DAF. Rare germline mutations in the genes encoding CD55 and CD59 have also been described.
• Deficiencies in complement receptors include the absence of CR3 and CR4, both resulting from rare mutations in the β chain (CD18) that is shared by the CD11/CD18 family of integrin molecules. The disease caused by this gene defect is called leukocyte adhesion deficiency. 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.
