Disorders of the Complement System

Evaluation of the Complement System

Richard B. Johnston

Testing for total hemolytic complement activity (CH ₅₀ ) effectively screens for most of the common diseases of the complement system. A normal result in this assay depends on the ability of all 11 components of the classical pathway and membrane attack complex to interact and lyse antibody-coated sheep erythrocytes. The dilution of serum that lyses 50% of the cells determines the end-point. In congenital deficiencies of C1 through C8, the CH ₅₀ value is 0 or close to 0; in C9 deficiency the value is approximately half-normal. Values in the acquired deficiencies vary with the type and severity of the underlying disorder. This assay does not detect deficiency of mannose-binding lectin (MBL), factor D or B of the alternative pathway, or properdin ( Fig. 160.1 ). Deficiency of factor I or H permits persistence of the classical and alternative pathway convertase and thus consumption of C3, with reduction in the CH ₅₀ value. When clotted blood or serum sits at room temperature or warms, CH ₅₀ activity begins to decline, leading to values that are falsely low but not zero. It is important to separate the serum and freeze it at −70°C (−94°F) by no more than 1 hr after blood draw.

In hereditary angioedema , depression of C4 and C2 during an attack significantly reduces the CH ₅₀ . Typically, C4 is low and C3 normal or slightly decreased. Concentrations of C1 inhibitor protein will be normal in 15% of cases; but C1 acts as an esterase, and the diagnosis can be established by showing increased capacity of the patient's sera to hydrolyze synthetic esters.

A decrease in serum concentration of both C4 and C3 suggests activation of the classical pathway by immune complexes. Decreased C3 and normal C4 levels suggest activation of the alternative pathway. This difference is particularly useful in distinguishing nephritis secondary to immune complex deposition from that caused by NeF (nephritic factor). In the latter condition and in deficiency of factor I or H, factor B is consumed and C3 serum concentration is low. Alternative pathway activity can be measured with a relatively simple and reproducible hemolytic assay that depends on the capacity of rabbit erythrocytes to serve as both an activating (permissive) surface and a target of alternative pathway activity. This assay, AP ₅₀ , detects deficiency of properdin, factor D, and factor B. Immunochemical methods can be used to quantify individual components and split products of all 3 pathways, guided by results of the screening hemolytic assays.

A defect of complement function should be considered in any patient with recurrent angioedema, autoimmune disease (especially SLE), chronic nephritis, hemolytic-uremic syndrome, or partial lipodystrophy, or with recurrent pyogenic infections, disseminated meningococcal or gonococcal infection, or a 2nd episode of bacteremia at any age. A previously well adolescent or young adult with meningococcal meningitis caused by an uncommon serotype (not A, B, or C) should undergo screening for a late-component or alternative pathway deficiency with CH ₅₀ and AP ₅₀ assays.

Genetic Deficiencies of Complement Components

Richard B. Johnston