Chapter 136. Meningococcal Infections (Part 5)

Host Defense MechanismsPreventing meningococcal growth in blood requires bactericidal and opsonic antibodies, complement, and phagocytes (Fig. 136-3). The major bactericidal antibodies are IgM and IgG, which (except for serogroup B) bind to the capsular polysaccharide. Immunity to meningococci is therefore serogroup specific. Antibodies to other surface (subcapsular) antigens may confer crossserogroup protection. PorA, PorB, Opc, and LOS appear to be major targets of cross-reactivity and of serogroup B bactericidal antibodies. Infants are protected from meningococcal disease during the first months of life by passively transferred maternal IgG antibodies. As maternal antibody levels wane, the attack rate increases, peaking at...
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Chapter 136. Meningococcal Infections (Part 5) Chapter 136. Meningococcal Infections (Part 5) Host Defense Mechanisms Preventing meningococcal growth in blood requires bactericidal andopsonic antibodies, complement, and phagocytes (Fig. 136-3). The majorbactericidal antibodies are IgM and IgG, which (except for serogroup B) bind tothe capsular polysaccharide. Immunity to meningococci is therefore serogroupspecific. Antibodies to other surface (subcapsular) antigens may confer cross-serogroup protection. PorA, PorB, Opc, and LOS appear to be major targets ofcross-reactivity and of serogroup B bactericidal antibodies. Infants are protectedfrom meningococcal disease during the first months of life by passivelytransferred maternal IgG antibodies. As maternal antibody levels wane, the attackrate increases, peaking at 3–9 months of age. Disease incidence declines asprotective antibodies are induced by colonization with nonpathogenic bacteria thathave cross-reactive antigens. In addition to N. lactamica, which frequentlycolonizes young children, some enteric bacteria have antigens that cross-react withthose of meningococci. One theory relates the occurrence of some cases ofmeningococcal disease to the presence of high levels of IgA antibodies tomeningococci, since these antibodies can block the bactericidal activity of IgM. Figure 136-3 Protection from meningococcal disease involves bothantimeningococcal immunoglobulins and complement. Activation ofcomplement by antimeningococcal IgM or IgG promotes bacterial lysis via themembrane attack complex (C5–C9), while C3b [produced by alternative,mannose-binding lectin (MBL), or classic pathway activation] andantimeningococcal IgG2 cooperate to produce effective opsonophagocytosis. Aneutrophil defect in binding IgG2 (the FcγRIIA R131 allele) has been associatedwith more severe meningococcal disease. CR1, complement receptor 1; LOS,lipooligosaccharide. Complement is required for bactericidal activity and for efficientopsonophagocytosis. Individuals deficient in any of the late complementcomponents (C5–C9) cannot assemble the membrane-attack complex (MAC)needed to kill Neisseria. Although the incidence of meningococcal disease ishigher among those with late-complement-component deficiencies, these personstypically develop less severe disease than complement-sufficient individuals, do soat an older age, and tend to have disease due to uncommon serogroups (W-135, X,Y, Z, and 29E). Although only one-half of individuals with known late-complement-component deficiency ever experience meningococcal disease, someaffected persons have several episodes. Deficiency of each of the terminalcomplement components is inherited in an autosomal recessive fashion. Properdindeficiency, in contrast, is X-linked; some affected males develop overwhelmingmeningococcal disease, an observation indicating that the alternative complementpathway is also needed for antimeningococcal host defense. Disease onset inproperdin-deficient individuals typically occurs in the teens or twenties. There isalso recent evidence that inherited differences in the mannose-binding lectin(MBL) pathway of complement activation may influence the risk of acquiringmeningococcal disease in childhood. Alleles that decrease MBL synthesis havebeen associated with increased risk in the few studies reported to date. Activation of the classic pathway of complement by antigen-antibodycomplexes or of the alternative pathway by LOS or capsular polysaccharide isimportant for producing and maintaining C3b (Fig. 136-3). Without C3b, neitherbactericidal lysis nor phagocytosis can proceed effectively. When C3b isgenerated, meningococcal growth is probably checked by the MACs bactericidalactivity (induction of bacterial lysis) and by robust phagocytosis andopsonophagocytic killing of the bacterium due to complement deposition. MostIgG antibodies to the meningococcal polysaccharide are of the IgG 2 isotype; aphagocytic cell defect (the FcγRIIA R131 allele) that impairs the phagocytosis ofIgG2-coated particles has been associated with more severe meningococcaldisease. This allele has also been associated with a more severe clinical course inpatients with late-complement-component deficiency; thus effective phagocytosismay contribute to the relatively mild meningococcal disease usually observed inthese individuals. The results of studies of gene polymorphism–disease associations aresummarized in Figs. 136-1 and 136-3. In individuals who lack bactericidalantibodies, protection from acquiring meningococcal bacteremia may be provided,at least in part, by innate immune mechanisms such as the MBL pathway foractivating c ...