Chapter 136. Meningococcal Infections (Part 5) ppt

Meningococcal Infections Part 5 Host Defense Mechanisms Preventing meningococcal growth in blood requires bactericidal and opsonic antibodies, complement, and phagocytes Fig.. One theo

Chapter 136 Meningococcal Infections

(Part 5)

Host Defense Mechanisms

Preventing 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 cross-serogroup 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 3–9 months of age Disease incidence declines as protective antibodies are induced by colonization with nonpathogenic bacteria that

have cross-reactive antigens In addition to N lactamica, which frequently

colonizes young children, some enteric bacteria have antigens that cross-react with

those of meningococci One theory relates the occurrence of some cases of meningococcal disease to the presence of high levels of IgA antibodies to meningococci, since these antibodies can block the bactericidal activity of IgM

Figure 136-3

Protection from meningococcal disease involves both antimeningococcal immunoglobulins and complement Activation of

complement by antimeningococcal IgM or IgG promotes bacterial lysis via the membrane attack complex (C5–C9), while C3b [produced by alternative, mannose-binding lectin (MBL), or classic pathway activation] and antimeningococcal IgG2 cooperate to produce effective opsonophagocytosis A neutrophil defect in binding IgG2 (the FcγRIIA R131 allele) has been associated

with more severe meningococcal disease CR1, complement receptor 1; LOS, lipooligosaccharide

Complement is required for bactericidal activity and for efficient opsonophagocytosis Individuals deficient in any of the late complement components (C5–C9) cannot assemble the membrane-attack complex (MAC)

needed to kill Neisseria Although the incidence of meningococcal disease is

higher among those with late-complement-component deficiencies, these persons typically develop less severe disease than complement-sufficient individuals, do so

at 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, some affected persons have several episodes Deficiency of each of the terminal complement components is inherited in an autosomal recessive fashion Properdin deficiency, in contrast, is X-linked; some affected males develop overwhelming meningococcal disease, an observation indicating that the alternative complement pathway is also needed for antimeningococcal host defense Disease onset in properdin-deficient individuals typically occurs in the teens or twenties There is also recent evidence that inherited differences in the mannose-binding lectin (MBL) pathway of complement activation may influence the risk of acquiring meningococcal disease in childhood Alleles that decrease MBL synthesis have been associated with increased risk in the few studies reported to date

Activation of the classic pathway of complement by antigen-antibody complexes or of the alternative pathway by LOS or capsular polysaccharide is important for producing and maintaining C3b (Fig 136-3) Without C3b, neither bactericidal lysis nor phagocytosis can proceed effectively When C3b is generated, meningococcal growth is probably checked by the MAC's bactericidal activity (induction of bacterial lysis) and by robust phagocytosis and opsonophagocytic killing of the bacterium due to complement deposition Most IgG antibodies to the meningococcal polysaccharide are of the IgG2 isotype; a phagocytic cell defect (the FcγRIIA R131 allele) that impairs the phagocytosis of IgG2-coated particles has been associated with more severe meningococcal disease This allele has also been associated with a more severe clinical course in patients with late-complement-component deficiency; thus effective phagocytosis may contribute to the relatively mild meningococcal disease usually observed in these individuals

The results of studies of gene polymorphism–disease associations are summarized in Figs 136-1 and 136-3 In individuals who lack bactericidal antibodies, protection from acquiring meningococcal bacteremia may be provided,

at least in part, by innate immune mechanisms such as the MBL pathway for activating complement, complement factor C4b, and the TLR4 pathway for LOS recognition Other genes may influence meningococcal survival in vivo [FcγIIA (CD32)], while still others seem to regulate the host inflammatory (IL-1β, IL-1Ra,

TNF-α, angiotensin-converting enzyme) and clotting (PAI-1) responses to invading meningococci Although many of these associations await confirmation

in other populations of patients, in sum they point to important genetic influences

on the acquisition and severity of meningococcal disease This conclusion is supported by the overrepresentation of ABO blood group nonsecretors among patients with meningococcal disease and by the striking variability in meningococcal disease incidence among different racial groups