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) result in similar symptoms, notably a marked increase in immune-complex diseases such as SLE, glomerulonephritis, and vasculitis. The effects of these deficiencies highlight the importance of C3b’s role in the clearance of immune complexes. In addition, as described earlier, C1q has been shown to bind apoptotic cells and cell fragments. In the absence of C1q binding, apoptotic cells can act as auto-antigens and lead to the development of autoimmune diseases such as SLE. Individuals with deficiencies in the early complement components may also suffer from recurrent infections with both gram-negative and gram-positive, pyogenic (pus-forming) bacteria such as streptococci and staphylococci. These latter organisms are normally resistant to the lytic effects of the MAC, but the early complement components are important in controlling such infections by mediating a localized inflammatory response and opsonizing the bacteria.
A deficiency in MBL, the first component of the lectin pathway, has been shown to be relatively common, and results in serious pyrogenic (fever-inducing) infections in babies and children. Children with MBL deficiency suffer from recurrent respiratory tract infections. MBL deficiency is also found with a frequency two to three times higher in patients with SLE than in normal subjects, and certain mutant forms of MBL are found to be prevalent in chronic carriers of hepatitis B. 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.
People with C3 deficiencies display serious clinical manifestations, reflecting the central role of C3 in opsonization and in the formation of the MAC. The first person identified with a C3 deficiency was a child suffering from frequent, severe bacterial infections leading to meningitis, bronchitis, and pneumonia, and who was initially diagnosed with agammaglobulinemia. After tests revealed normal immunoglobulin levels, a deficiency in C3 was discovered. This case highlighted the critical role of the complement system in converting a humoral antibody response into an effective host defense mechanism. The majority of people with C3 deficiency have recurrent bacterial infections and may also present with immune-complex diseases.
Levels of C4 vary considerably in the population. The genes encoding C4 are located in the major histocompatibility locus (see Chapter 7), and the number of C4 genes vary among individuals from two to six. Low gene copy numbers are associated with lower levels of C4 in plasma and with a correspondingly higher incidence of SLE, for the reasons described earlier. Patients with complete deficiencies of one or more of the components of the classical pathway, such as C4, contract more frequent infections with bacteria such as S. pneumoniae, Haemophilus influenzae, and N. meningitidis. However, even patients with low copy numbers of the C4 gene appear to be relatively well protected against such infections. Interestingly, C4 exists in two isoforms: C4A and C4B. C4B is more effective in binding to the surfaces of the three bacterial species mentioned above.
Individuals with deficiencies in components of the terminal complement cascade are more likely than members of the general population to suffer from meningitis, indicating that cytolysis by complement components C5 through C9 is of particular relevance to the control of N. meningitidis. This has resulted in the release of public health guidelines that highlight the need for vaccinations against N. meningitidis for individuals deficient in the terminal complement components.
Deficiencies of complement regulatory proteins have also been reported. As described previously, C1INH, the C1 inhibitor, regulates activation of the classical pathway by preventing excessive C4 and C2 activation by C1. However, as a serine protease inhibitor, it also controls two serine proteases in the blood clotting system. Patients with C1INH deficiency suffer from a complex disorder that includes excessive production of vasoactive mediators (molecules that control blood vessel diameter and integrity), which in turn leads to tissue swelling and extracellular fluid accumulation. The resultant clinical condition is referred to as hereditary angioedema. It presents clinically as localized tissue edema that often follows trauma, but sometimes occurs with no known cause. The edema can be in subcutaneous tissues; within the bowel, where it causes abdominal pain; or in the upper respiratory tract, where it can result in fatal obstruction of the airway. C1INH deficiency is an autosomal dominant condition with a frequency of 1 in 1000 in the human population.
Studies in humans and experimental animals with homozygous deficiencies in complement components have provided important information regarding the roles of individual complement components in immunity. These initial observations have been significantly enhanced by studies using knockout mice, genetically engineered to lack expression of specific complement components. Investigations of in vivo complement activity in these animals have allowed dissection of the complex system of complement proteins and the assignment of precise biologic roles to each.