The role of Fcγreceptor polymorphisms and C3 in the immune defence againstNeisseria meningitidisin complement-deficient individuals

Abstract

SUMMARYIndividuals with either a late (C5±9) complement component deficiency (LCCD) or properdin deficiency are at increased risk to develop meningococcal disease, often due to serogroups W135 and Y. Anti-meningococcal defence in both LCCD persons and properdin-deficient individuals without bactericidal antibodies depends mainly on phagocytosis. Three types of opsonin receptors are involved in phagocytosis by polymorphonuclear cells (PMN). These represent the polymorphic FcgRIIa (CD32) and FcgRIIIb (CD16b) receptors, and the C3 receptor CR3 (CD11b/CD18). When the distribution of FcgRIIa and Fcg RIIIb allotypes was assessed in 15 LCCD and in 15 properdin-deficient patients with/ without previous meningococcal disease, we found the combination of FcgRIIa-R/R131 with FcgRIIIb-NA2/NA2 allotypes 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-deficient patients. The importance of FcgRIIa allotypes was also demonstrated using in vitro phagocytosis assays. PMN from Fcg RIIa-R/ R131 homozygous donors internalized IgG2 opsonized meningococci W135 significantly (P , 0´05) less than PMN from FcgRIIa-H/H131 donors. When properdin-deficient serum was tested, it was observed that reconstitution with properdin resulted in enhanced PMN phagocytosis of the W135 meningococci (P 0´001). This enhanced phagocytosis was parallelled by an increase in C3 deposition onto the opsonized meningococci W135 (r 0´6568, P 0´01). We conclude that the occurrence of meningococcal disease in LCCD patients is associated with certain FcgR allotypes. Properdin-deficient individuals are susceptible to meningococcal disease because of an insufficient C3 deposition on the surface of meningococci, resulting in insufficient phagocytosis.

Genetic risk factors for infection in patients with early rheumatoid arthritis

“…The FCGR3B NA2 allele may play a role in susceptibility to other infections, as the combination of FCGR2A 131 R/R and FCGR3B NA2/ NA2 genotypes is associated with meningococcal disease in subjects with late complement component (C5-C9) deficiency. 21 The current study is the first to demonstrate a role for the FCGR3B NA2 allele in a common form of infection, URI.…”

Functions of Antibodies

“…In the case of N. meningitidis, complement-mediated clearance or bactericidal activity appears to be more important than FcγR-mediated phagocytosis (see above). However, FcγR-mediated phagocytosis can be demonstrated in vitro (232,233). Furthermore, some studies, but not all, have found associations between FcγRIIa genotypes and susceptibility to or severity of meningococcal infection (233,234,235,236,237,238).…”

“…However, FcγR-mediated phagocytosis can be demonstrated in vitro (232,233). Furthermore, some studies, but not all, have found associations between FcγRIIa genotypes and susceptibility to or severity of meningococcal infection (233,234,235,236,237,238). Finally, γδT cells capable of phagocytosing antibody-opsonized E. coli via FcγRIIIa have been described (239).…”

Prognostic Factors in Follicular Lymphoma in the Rituximab Era: How to Identify a High-Risk Patient?

“…Genes encoding Fc receptors are located on the first chromosome and show functional allelic polymorphism leading to structural and thus functional diversity of the encoded proteins (receptors). Certain polymorphisms have been identi-fied as genetic predispositions leading to a higher risk of autoimmune or infectious diseases 79,80 . The most studied allelic variation is FCGR3A gene dimorphism, encoding the amino acids phenylalanine (FcγRIIIa-158F) or valine (FcγRIIIa-158V) at position 158.…”