The diseases discussed so far are mainly due to disturbances of the adaptive immune system. In the next few sections we look at some immunodeficiency diseases that affect cells and molecules of the innate immune system. We start with the complement system, which can be activated by any of three pathways that converge on the cleavage and activation of complement component C3, allowing it to bind covalently to pathogen surfaces, where it acts as an opsonin (discussed in Chapter 2). Not surprisingly, the spectrum of infections associated with complement deficiencies overlaps substantially with that seen in patients with deficiencies in antibody production. In particular, there is increased susceptibility to extracellular bacteria that require opsonization by antibody and/or complement for efficient clearance by phagocytes (Fig. 13.11). Defects in the activation of C3 by any of the three pathways, as well as defects in C3 itself, are associated with increased susceptibility to infection by a range of pyogenic bacteria, including S. pneumoniae, emphasizing the role of C3 as a central effector that promotes the phagocytosis and clearance of capsulated bacteria.
In contrast, defects in the membraneattack components of complement (C5C9) downstream of C3 activation have more limited effects, and result almost exclusively in susceptibility to Neisseria species. A similar susceptibility to Neisseria species is found in patients with defects in the alternative complement pathway components factor D and properdin, indicating that defense against these bacteria, which can survive intracellularly, is largely mediated via antibodyindependent extracellular lysis by the membraneattack complex. Data from largepopulation studies in Japan, where endemic N. meningitidis infection is rare, show that the risk each year of infection with this organism is approximately 1 in 2,000,000 to a normal person. This compares with a risk of 1 in 200 to a person in the same population with an inherited deficiency of one of the membraneattack complex proteins—a 10,000fold increase in risk.
Membrane-attack components C5 C6 C7 C8 C9 Deÿciency leads to infection with Neisseria spp. only C3b deposition C3 Deÿciency leads to infection with pyogenic bacteria and Neisseria spp. Sometimes immune-complex disease C3 convertase Deÿciency leads to immune-complex disease Deÿciency leads to infection with pyogenic bacteria and Neisseria spp. but no immune-complex disease Deÿciency of MBL leads to bacterial infections, mainly in childhood MBL MASP1 MASP2 C2 C4 C1 C2 C4 Factor D Factor P CLASSICAL PATHWAY ALTERNATIVE PATHWAY MBL PATHWAY
The early components of the classical complement pathway are particularly important for the elimination of immune complexes (discussed in Section 1020) and apoptotic cells, which can cause significant pathology in autoimmune diseases such as systemic lupus erythematosus. This aspect of inherited complement deficiency is discussed in Chapter 15. Deficiencies in mannosebinding lectin (MBL), which initiates complement activation independently of antibody (see Section 26), are relatively common (found in 5% of the population). MBL deficiency may be associated with a mild immunodeficiency that results in an increased incidence of bacterial infection in early childhood. A similar phenotype is found in patients with defects in the gene that encodes the MBLassociated serine protease2 (MASP2).