The role of Fc gamma receptor polymorphisms and C3 in the immune defence against Neisseria meningitidis in complement-deficient individuals

Individuals with either a late (C5-9) complement component deficiency (LCCD ) or properdin deficiency are at increased risk to develop meningococcal di sease, often due to serogroups W135 and Y. Anti-meningococcal defence in bo th LCCD persons and properdin-deficient individuals without bactericidal an tibodies depends mainly on phagocytosis. Three types of opsonin receptors a re involved in phagocytosis by polymorphonuclear cells (PMN). These represe nt the polymorphic Fc gamma RIIa (CD32) and Fc gamma RIIIb (CD16b) receptor s, and the C3 receptor CR3 (CD11b/CD18). When the distribution of Fc gamma RIIa and Fc gamma RIIIb allotypes was assessed in 15 LCCD and in 15 properd in-deficient patients with/without previous meningococcal disease, we found the combination of Fc gamma RIIa-R/R131 with Fc gamma RIIIb-NA2/NA2 alloty pes to be associated with previous meningococcal disease (odds ratio 13.9, Fisher's test P = 0.036). No such relation was observed in the properdin-de ficient patients. The importance of Fc gamma RIIa allotypes was also demons trated using in vitro phagocytosis assays. PMN from Fc gamma RIIa-R/R131 ho mozygous donors internalized IgG2 opsonized meningococci W135 significantly (P < 0.05) less than PMN from Fc gamma RIIa-H/H131 donors. When properdin- deficient serum was tested, it was observed that reconstitution with proper din resulted in enhanced PMN phagocytosis of the W135 meningococci (P = 0.0 01). This enhanced phagocytosis was parallelled by an increase in C3 deposi tion onto the opsonized meningococci W135 (r = 0.6568, P = 0.01). We conclu de that the occurrence of meningococcal disease in LCCD patients is associa ted with certain Fc gamma R allotypes. Properdin-deficient individuals are susceptible to meningococcal disease because of an insufficient C3 depositi on on the surface of meningococci, resulting in insufficient phagocytosis.