Disorders of the Complement System

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Chapter 128 Disorders of the Complement System

128.1 Evaluation of the Complement System

Testing for total hemolytic complement activity (CH50) effectively screens for most of the 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 CH50 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), factors D or B of the alternative pathway, or properdin. Deficiency of factors I or H permits consumption of C3, with partial reduction in the CH50 value. When clotted blood or serum sits at room temperature or warms, CH50 activity begins to decline, which leads to values that are falsely low but not zero. It is important to separate the serum and freeze it at −70°C by no more than an hour after blood draw.

In hereditary angioedema, depression of C4 and C2 during an attack significantly reduces the CH50. 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 patients’ 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 due to 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 (AP50) detects deficiency of properdin, factor D, and factor B. Immunochemical methods can be used to quantify individual components of all 3 pathways, guided by results of the screening hemolytic assays. It is possible to analyze the genes encoding many of the components.

A defect of complement function should be considered in any patient with recurrent angioedema, autoimmune disease, chronic nephritis, hemolytic-uremic syndrome (HUS), or partial lipodystrophy, or with recurrent pyogenic infections, disseminated meningococcal or gonococcal infection, or a second episode of bacteremia at any age. A previously well adolescent or young adult with meningococcal meningitis due to an uncommon serotype (not A, B, or C) should undergo screening for a late-component or alternative pathway deficiency with CH50 and AP50 assays.

128.2 Genetic Deficiencies of Complement Components

Congenital deficiencies of all 11 components of the classical-membrane attack pathway and of factor D and properdin of the alternative pathway are described (Table 128-1). All of the components of the classical and alternative pathways except properdin are inherited as autosomal recessive co-dominant traits. Each parent transmits a gene that codes for synthesis of half the serum level of the component. Deficiency results from inheritance of 1 null gene from each parent; the hemizygous parents typically have CH50 levels that are low normal. Properdin deficiency is transmitted as an X-linked trait.

Most patients with primary C1q deficiency have systemic lupus erythematosus (SLE), an SLE-like syndrome without typical SLE serology, a chronic rash that has shown an underlying vasculitis on biopsy, or membranoproliferative glomerulonephritis (MPGN). Some C1q-deficient children have serious infections, including septicemia and meningitis. Individuals with C1r, C1s, combined C1r/C1s, C4, C2, or C3 deficiency also have a high incidence of autoimmune syndromes (see Table 128-1), especially SLE or an SLE-like syndrome in which antinuclear antibody level is not elevated.

C4 is encoded by 2 genes, termed C4A and C4B. C4 deficiency represents absence of both gene products. Complete deficiency of only C4A, present in about 1% of the population, also predisposes to SLE, though C4 levels are only partially reduced. Patients with only C4B deficiency may be predisposed to infection. A few patients with C5, C6, C7, or C8 deficiency have SLE, but recurrent meningococcal infections are much more likely to be the major problem.

The reason for the concurrence of deficiencies of complement components, especially C1, C4, C2, or C3 deficiency, and autoimmune-immune complex diseases is not entirely clear, but deposition of C3 on autoimmune complexes facilitates their removal from the circulation through binding to complement receptor 1 (CR1) on erythrocytes and transport to the spleen and liver. The early components, particularly C1q and C3, expedite the clearance of necrotic and apoptotic cells, which are sources of autoantigens. Inefficiency of either or both of these processes might explain the concurrence of autoimmune disease and complement deficiency.

Individuals with C2 deficiency are predisposed to life-threatening septicemic illnesses, most commonly due to pneumococci. Most have not had problems with increased susceptibility to infection, presumably because of the protective function of the alternative pathway. The genes for C2, factor B, and C4 are situated close to each other on chromosome 6, and a partial depression of factor B levels can occur in conjunction with C2 deficiency. Persons with a deficiency of both proteins may be at particular risk.

Because C3 can be activated by C142 or by the alternative pathway, a defect in the function of either pathway can be compensated for, at least to some extent. Without C3, however, opsonization of bacteria is inefficient, and the chemotactic fragment from C5 (C5a) is not generated. Some organisms must be well opsonized in order to be cleared, and genetic C3 deficiency has been associated with recurrent, severe pyogenic infections due to pneumococci and meningococci.

More than half of the individuals reported to have congenital C5, C6, C7, or C8 deficiency have had meningococcal meningitis or extragenital gonococcal infection. Patients with C9 deficiency retain about one-third normal CH50 titers; some of these patients have also had Neisseria disease. In studies of patients ≥10 yr of age with systemic meningococcal disease, 3-15% have had a genetic deficiency of C5, C6, C7, C8, C9, or properdin. Among patients with infections caused by the uncommon Neisseria meningitidis serogroups (X, Y, Z, W135, 29E, or nongroupable; not A, B, or C), 33-45% have an underlying complement deficiency. It is not clear why patients with a deficiency of 1 of the late-acting components suffer a particular predisposition to Neisseria infections. It may be that serum bacteriolysis is uniquely important in defense against this organism. Many persons with such a deficiency have no significant illness.

A few individuals have been identified with deficiency of factor D