Fc receptor regulation of protective immunity against Chlamydia trachomatis

Abstract

SUMMARYThe prevailing paradigm for designing potentially ef®cacious vaccines against the obligate intracellular bacterium, Chlamydia trachomatis, advocates regimens capable of inducing a mucosal antigen-speci®c T helper type 1 (Th1) response. However, recent reports indicate that rapid and ef®cient clearance of a secondary infection also requires certain B-cell functions. We investigated the hypothesis that Fc receptor (FcR)-mediated antibody effector mechanisms are important B-cell-related functions involved in controlling a chlamydial genital reinfection. Microbiological analysis of genital chlamydial infection in FcR knockout (FcRKO) mice lacking the activatory FccRI (CD64) and FcRcIII (CD16), as well as the inhibitory FccRIIB1 (CD32), revealed a greater intensity of secondary infection (i.e. bacterial shedding) in FcRx/x as compared to FcR +/+ mice; however, the course of the primary infection was indistinguishable in both animals. Pathologically, FcRKO mice suffered greater ascending infection than immunocompetent wild-type (WT) mice after a secondary infection. Immunological evaluation indicated that the presence of speci®c anti-chlamydial antibodies enhanced chlamydial antigen presentation for induction of a Th1 response by FcRx/x , antigen-presenting cells. In addition, speci®c anti-chlamydial antibodies augmented both macrophage killing of infected epithelial cells by antibody-dependent cellular cytotoxicity (ADCC) and macrophage inhibition of productive growth of chlamydiae in co-cultures. These results indicate that B cells participate in anti-chlamydial immunity via FcR-mediated effector functions of antibodies, which are operative during reinfections. Such effector functions include ADCC, and possibly enhanced uptake, processing and presentation of chlamydial antigens for rapid induction of a Th1 response, all facilitating the early clearance of an infection. These ®ndings suggest that a future anti-chlamydial vaccine should elicit both humoral and T-cell-mediated immune responses for optimal memory response and vaccine ef®cacy.

Fcγ Receptors Regulate Immune Activation and Susceptibility during Mycobacterium tuberculosis Infection

“…Deficiency of the Fc␥-chain was previously reported to affect the progression of infection with other intracellular pathogens, including influenza and Leishmania species (17)(18)(19)(20)(21)(22). Diminished survival was associated with statistically significantly elevated bacterial burden in the lungs and spleens 15 wk, but not 3 wk, after infection.…”

“…Other reports have previously implicated Fc␥R as affecting host defense in infectious disease models (17)(18)(19)(20)(21)(22)47). Interestingly, lupus-associated polymorphisms in Fc␥RIIB have been correlated with reduced susceptibility to malaria in humans (21), suggesting that infectious diseases may provide selective pressure for autoimmunity.…”

“…Separated into activating and inhibiting types, Fc␥R mediate immune activation or suppression based upon a threshold determined by the summation of their reciprocal signals (16). Murine models of Fc␥R deficiency have been useful in assessing the relevance of these receptors against intracellular pathogens, including Chlamydia trachomatis, influenza virus, Leishmania species, Plasmodium, and Salmonella enterica (17)(18)(19)(20)(21)(22). However, no such study had yet been conducted with M. tuberculosis, possibly because of the prevailing view that humoral immunity has little or no role in host defense against this pathogen.…”

Immune-mediated control of Chlamydia infection

“…Subsequently, it was demonstrated that monoclonal antibodies against Chlamydia MOMP could neutralize Chlamydia infection in vitro (Peeling et al, 1984;Peterson et al, 1991) and provide a modest level of protection against infection when passively administered to mice (Cotter et al, 1995). In addition to neutralization, there is also evidence that Fc receptor mediated activities of antibodies also play an important role in combating infection (Moore et al, 2002;.…”

Chlamydial vaccine development

“…Studies in the guinea pig model for human genital tract infections have demonstrated a role for antibody in limiting primary infection (Rank et al, 1979;Rank & Batteiger, 1989), whereas B cell-deficient gene-knockout studies have shown that there appears to be no requirement for antibody in the murine model, although these mice are more susceptible to reinfection than are immunocompetent mice (Su et al, 1997). Studies in Fc receptorknockout mice (Moore et al, 2002) suggest that the predominant role of antibodies is in resistance to re-infection, by enhancing the uptake, processing and presentation of chlamydial antigens by antigen-presenting cells for rapid Th1 activation and clearance of infection.…”