A plethora of host factors that determine the outcome of meningococcal infection.

In this issue of the Journal, Domingo et al. (1) sought to determine if the presence of one or another allelic form of the immunoglobulin (Ig) receptor Fc gamma receptor IIA (Fc RIIA), which is expressed constitutively on neutrophils as well as on certain other cells, increased either the risk or severity of meningococcal infection. Fc RIIA (CD32) has two allotypes (2), Fc RIIA-R131 and Fc RIIA-H131, depending on whether arginine (R) or histidine (H) is at position 131of the protein. Previous work showed that the R/R131 form of the receptorbound IgG2 compared poorly with the H/H131 form (3), and was associated with poor opsonization of encapsulated bacteria (4). Since the principal immunoglobulin isotype raised in humans against polysaccharide antigens (including bacterial capsular polysaccharides) is of the IgG2 class, persons who are homozygous or heterozygous for Fc RIIA-R/R131 may be more susceptible to infection by meningococci or might develop more severe disease after infection. The results showed that although the Fc RIIA-R/R131 allotype was not more common in persons with meningococcal infection and thus did not predispose to infection, it was associated with more severe infection (i.e., meningococcemia, fulminant disease, or complications of the infection) (1). Older persons with invasive meningococcal disease were more likely to have the R/R131 allotype (1), similar to two earlier reports that described more severe disease in patients with the R/R131 allotype (5,6). All studies showed that meningococcal meningitis had a relatively benign outcome compared with meningococcal bacteremia, even in patients with the R/R131 allotype. Apparently, poor neutrophil binding of antimeningococcal IgG2 antibodies predisposed to severe meningococcal bacteremia and sepsis. Nonetheless, the results have practical implications; vaccination with polysaccharide-protein conjugates invoke other IgG isotypes in addition to IgG2, thus bypassing the problems posed by the low-affinity IgG2 neutrophil receptor. Many investigators are working on such vaccines for meningococci, principally to circumvent the nonimmunogenicity of the group B meningococcal capsule, and the findings by Domingo et al. provide another reason why the development of such vaccines should be accelerated. The results, however, are somewhat surprising, since prior studies have shown that bactericidal antibodies and complement constitute a main defense against invasive meningococcal disease (7–9). In a classic series of experiments, the likelihood of meningococcal bacteremia or meningitis among new military recruits resulted from colonization of the upper airways by an epidemic strain and the absence of preexisting bactericidal (complementdependent) antibodies to this strain (7,8). This work led to the development of polysaccharide vaccines against all the main capsular serotypes except B, which is not immunogenic in humans because of mimicry of host sialic acids. The importance of complement in protection is evident from the occurrence of meningococcal disease in persons with hereditary deficiencies in the complement pathways, including early components, properdin, and late acting components (9 –12). Moreover, recent evidence suggests strongly that human deficiency in serum mannose– binding lectin predisposes to invasive meningococcal disease, particularly in children and adolescents (13–15). The binding of mannose– binding lectin to meningococci activates complement directly, and its deficiency or alterations of the meningococcal cell surface decreases serum bactericidal activity against meningococci (13). Bactericidal activity due to mannose– binding lectin is likely to be important in the protection of children and adolescents who have lost protective maternal antibodies and who have yet to acquire their own antimeningococcal antibodies. The evidence provided by Domingo et al. (1) that a neutrophil receptor for IgG2, and hence opsonization, is important in protection against the most severe forms of bacteremic meningococcal disease should not be too surprising, since it has long been known that functional asplenia predisposes to fulminant bacteremias by encapsulated bacteria, owing to loss of opsonic functions provided by the spleen (16). Effective host defenses are composed of many parts, just as bacterial virulence is the sum of different bacterial gene products. Undoubtedly, both bactericidal complement– dependent killing and phagocytic killing are important in effective host defense. PaAm J Med. 2002;112:72–74. From the Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Requests for reprints should be addressed to P. Frederick Sparling, MD, Department of Medicine, University of North Carolina School of Medicine, CB 7030, 521 Burnett Womack Building, Chapel Hill, North Carolina 27599.