Complement Deficiencies

Genetic deficiencies have been described for each of the complement components. Homozygous deficiencies in any of the early components of the classical pathway (C1q, C1r, C1s, C4, and C2) exhibit similar symptoms, notably a marked increase in immune-complex diseases such as systemic lupus erythematosus, glomerulonephritis, and vasculitis. These deficiencies highlight the importance of the early complement reactions in generating C3b, and the critical role of C3b in solubilization and clearance of immune complexes. In addition to immune-

FIGURE 13-14

Clearance of circulating immune complexes by reaction with receptors for complement products on erythrocytes and removal of these complexes by receptors on macrophages in the liver and spleen. Because erythrocytes have fewer receptors than macrophages, the latter can strip the complexes from the erythrocytes as they pass through the liver or spleen. Deficiency in this process can lead to renal damage due to accumulation of immune complexes.

complex diseases, individuals with such complement deficiencies may suffer from recurrent infections by pyogenic (pus-forming) bacteria such as streptococci and staphylococci. These organisms are gram-positive and therefore resistant to the lytic effects of the MAC. Nevertheless, the early complement components ordinarily prevent recurrent infection by mediating a localized inflammatory response and opsonizing the bacteria. Deficiencies in factor D and properdin—early components of the alternative pathway—appear to be associated with Neisseria infections but not with immune-complex disease.

Patients with C3 deficiencies have the most severe clinical manifestations, reflecting the central role of C3 in activation of C5 and formation of the MAC. The first patient identified with a C3 deficiency was a child suffering from frequent severe bacterial infections and initially diagnosed as having agammaglobulinemia. After tests revealed normal immuno-globulin levels, a deficiency in C3 was discovered. This case highlights the critical function of the complement system in converting a humoral antibody response into an effective defense mechanism. The majority of patients with C3 deficiency have recurrent bacterial infections and may have immune-complex diseases.

Individuals with homozygous deficiencies in the components involved in the MAC develop recurrent meningococcal and gonococcal infections caused by Neisseria species. In normal individuals, these gram-negative bacteria are generally susceptible to complement-mediated lysis or are cleared by the opsonizing activity of C3b. MAC-deficient individuals rarely have immune-complex disease, which suggests that they produce enough C3b to clear immune complexes. Interestingly, a deficiency in C9 results in no clinical symptoms, suggesting that the entire MAC is not always necessary for complement-mediated lysis.

Congenital deficiencies of complement regulatory proteins have also been reported. The C1 inhibitor (C1Inh) regulates activation of the classical pathway by preventing excessive C4 and C2 activation by C1. Deficiency of C1Inh is an autosomal dominant condition with a frequency of 1 in 1000. The deficiency gives rise to a condition called hereditary angioedema, which manifests clinically as localized edema of the tissue, often following trauma, but sometimes with no known cause. The edema can be in subcutaneous tissues or within the bowel, where it causes abdominal pain, or in the upper respiratory tract, where it causes obstruction of the airway.

Studies in humans and experimental animals with ho-mozygous deficiencies in complement components have been the major source of information concerning the role of individual complement components in immunity. These findings have been greatly extended by studies using knockout mice genetically engineered to lack expression of specific complement components. Investigations of in vivo complement activity in these animals has allowed dissection of the complex system of complement proteins and the assignment of precise biologic roles to each.

SUMMARY

■ The complement system comprises a group of serum proteins, many of which exist in inactive forms.

■ Complement activation occurs by the classical, alternative, or lectin pathways, each of which is initiated differently.

■ The three pathways converge in a common sequence of events that leads to generation of a molecular complex that causes cell lysis.

■ The classical pathway is initiated by antibody binding to a cell target; reactions of IgM and certain IgG subclasses activate this pathway.

■ Activation of the alternative and lectin pathways is antibody-independent. These pathways are initiated by reaction of complement proteins with surface molecules of microorganisms.

■ In addition to its key role in cell lysis, the complement system mediates opsonization of bacteria, activation of inflammation, and clearance of immune complexes.

■ Interactions of complement proteins and protein fragments with receptors on cells of the immune system control both innate and acquired immune responses.

■ Because of its ability to damage the host organism, the complement system requires complex passive and active regulatory mechanisms.

■ Clinical consequences of inherited complement deficiencies range from increases in susceptibility to infection to tissue damage caused by immune complexes.

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