Another set of complementrelated diseases is caused by defects in complementcontrol proteins (Fig. 13.12). Deficiencies in decayaccelerating factor (DAF) or protectin (CD59), membraneassociated control proteins that protect the surfaces of the body’s cells from complement activation, lead to destruction of red blood cells, resulting in the disease paroxysmal nocturnal hemoglobinuria, as discussed in Section 216. Deficiencies in soluble complementregulatory proteins such as factor I and factor H have various outcomes. Homozygous factor I deficiency is a rare defect that results in uncontrolled activity of the alternative pathway C3 convertase, leading to a de facto C3 deficiency (see Section 216). Deficiencies in MCP, factor I, or factor H can also cause a condition known as atypical hemolytic–uremic syndrome, so called because it leads to lysis of red blood cells (hemolysis) and impaired kidney function (uremia).
A striking consequence of the loss of a complementregulatory protein is seen in patients with C1inhibitor defects, which cause the syndrome known as hereditary angioedema (HAE) (see Section 216). Deficiency of C1 inhibitor results in a failure to regulate both the blood clotting and complement activation pathways, leading to excessive production of vasoactive mediators that cause fluid accumulation in the tissues (edema) and local laryngeal swelling that can result in suffocation.
13-15 Defects in phagocytic cells permit widespread bacterial infections.
Deficiencies in phagocyte numbers or function can be associated with severe immunodeficiency; indeed, a total absence of neutrophils is incompatible with survival in a normal environment. Phagocyte immunodeficiencies can be grouped into four general types: deficiencies in phagocyte production, phagocyte adhesion, phagocyte activation, and phagocyte killing of microorganisms (Fig. 13.13). We consider each in turn.
Inherited deficiencies of neutrophil production (neutropenias) are classified either as severe congenital neutropenia (SCN) or cyclic neutropenia. In severe congenital neutropenia, which can be inherited as a dominant or recessive trait, the neutrophil count is persistently less than 0.5 ×109 per liter of blood (normal numbers are 3 ×109 to 5.5 × 109 per liter). Cyclic neutropenia is characterized by fluctuation in neutrophil numbers from near normal to very low or undetectable with an approximate cycle time of 21 days, resulting in periodicity of infectious risk. The most common causes of SCN are sporadic or autosomal dominant mutations of the gene that encodes neutrophil elastase (ELA2), a component of the azurophilic, or primary, granules involved in the degradation of phagocytosed microbes. Altered targeting of defective elastase 2 to granules causes apoptosis of developing myelocytes and a developmental block at the promyelocyte–myelocyte stage. Some mutations of ELA2 cause