The complement system is under tight regulation because it has potent inflammatory activity and the potential to cause significant damage to host cells. The complement cascade is inherently regulated by the short half-life C4b and C3b and byinstability of the C3 convertases, C4b2a, and C3bBb. C1-inhibitorregulates the cascade by blocking active sites on C1r, C1s, and the MASP. Factor I destabilizes C3 convertase complexes and degrades the active fragments. Other inhibitors include membrane proteins, such as decay accelerating factor, CR1, membrane cofactor protein (MCP), and plasma proteins such as C4b-binding protein and factor H. Formation of the MAC can be blocked by cell surface CD59, protein S, and other plasma proteins. Deficiency of any of these regulatory proteins can result in an inflammatory response, tissue damage, or excessive complement consumption.
Disorders of complement proteins can result from inherited deficiency or can be secondary to increased consumption. The consequences of decreased complement depend on the affected factor (see Table 75-1). Deficiencies of early components of the classic pathway (C1, C2, or C4) are not usually associated with severe infections, although patients with C2 deficiency may present with milder recurrent infections. Patients with C1, C2, or C4 deficiency are susceptible to autoimmune diseases, especially systemic lupus erythematosus. The exact mechanism of this susceptibility is not known but is thought to arise from the role of these early components in clearing immune complexes.
Deficiency of properdin, C3, or the terminal componentspredisposes patients to severe recurrent infections. Deficiency of C3, the major opsonin, due to a genetic defect or secondary to excessive consumption, predisposes patients to infections, especially with encapsulated organisms. Deficiency of one of the terminal components that compose the MAC predisposes patients to infection with Neisseria meningitidis. Complement deficiency may be found in 40% of patients presenting with recurrent neisserial infections. Deficiency of mannose-binding lectin also is associated with an increased frequency of bacterial infections, including sepsis.
Congenital deficiency of C1-inhibitor results in hereditary angioedema, characterized by recurrent episodes of nonpruritic angioedema lasting 48 to 72 hours, which occur spontaneously or after minor trauma, stress, or anxiety. Abdominaledema can cause acute abdominal pain; edema of the upperairway can be life threatening and may necessitate emergencytracheostomy. The disorder is inherited as an autosomal dominant disease and results from a heterozygous deficiency of C1-inhibitor leading to serum levels less than 30% of normal values. Some mutations (type II hereditary angioedema) resultin normal levels of C1-inhibitor with defective function. An acquired form of angioedema results from autoantibodies toC1-inhibitor in lymphoid malignancies or autoimmune disorders but is uncommon in childhood. C1-inhibitor is a regulatorof Hageman factor (clotting factor XIIa), clotting factor XIa,plasma kallikrein, and plasmin in addition to C1r and C1s. Lackof inhibition of the contact system, Hageman factor and plasmakallikrein, is responsible for the development of angioedema.Deficiencies in the complement regulatory proteins factor H,factor I, and MCP result in atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II, and have been linked to age-related macular degeneration.