There is increasing evidence that chlamydial disease has an immunopathogenic basis, with both acute and chronic inflammatory responses implicated in the pathologic process leading to tubal scarring, which culminates in infertility [41
]. Other attempts to link chlamydial components (eg, heat shock proteins and homologues of human elongation factors) as provocateurs of hypersensitivity or autoimmune reactions have had inconclusive results. Moreover, polymorphisms in certain host cytokine, chemokine, and Toll-like receptor activities during chlamydial infection may underlie susceptibility to chlamydial disease [42
]. However, other than measurement of nonspecific inflammatory responses, no studies to date have investigated the role of specific immune effectors, including the Th17 pathway [44
], in the pathogenesis of the infection sequelae. Furthermore, a recent report revealed that despite microbiologic evidence that chlamydiae cured of the cryptic plasmid retained infectivity in mice, the infected animals did not develop pathologies [45
]. This observation may corroborate a testable hypothesis that the host’s specific immune responses directed against Chlamydia
-encoded components could play a key role in the development of pathologies after infection.
Other studies in animal models and supporting clinical observation in humans have established that prior infection and certain experimental vaccine regimens can produce significant levels of protective immunity against C. trachomatis
]. In this study, we confirmed that both infection-induced and vaccine-induced immunity (produced using either Fc-MOMP or Chlamydia
-pulsed IL-10KO dendritic cells) lead to enhanced clearance of a genital challenge infection, compared with nonimmune mice. The acquired immunity conferred by preinfection or vaccination, as measured by the kinetics of clearance of chlamydial shedding into the cervicovaginal vault, could suggest a functional and immunologic similarity between infection- and vaccine-induced immunity. However, because the incidence of Chlamydia
-induced tubal pathologies such as pelvic inflammatory disease increases with repeated genital Chlamydia
], we hypothesized that infection-induced immunity would not protect against the development of hydrosalpinx or infertility. The prediction is that vaccine- and infection-induced immunity may induce differential profiles of functional immune effectors, such that the profile of the latter is mostly pathogenic.
A better understanding of the functional properties of vaccine- and infection-induced immunity in relation to the key pathologic outcomes of chlamydial infection helps clarify the likely effect of an efficacious vaccine. We demonstrated in this study that vaccine-induced immunity protected against the development of infertility and hydrosalpinx, whereas infection-induced immunity did not. Unlike vaccine-induced immunity, infection-induced immunity does not prevent onset of the pathologic process leading to infertility or hydrosalpinx associated with chlamydial genital infection. In addition, the onset of pathology leading to infertility appears to be more likely after multiple live infections, including nasal infection, suggesting that pre-exposure to C. trachomatis by other routes could constitute a risk factor for developing sequelae after a genital infection. In this respect, we do not know the effects of pre-exposure to Chlamydia pneumoniae by the respiratory route or ocular infection by other C. trachomatis serovars on the severity and incidence of reproductive tract sequelae. At a minimum, our key findings provide some interesting insights into the benefit of administering a future chlamydial vaccine before exposure to genital chlamydial infection.
The inability of infection-induced immunity to protect against the development of tubal pathologies on subsequent reinfection suggested that an apparently irreversible pathologic process is initiated in the genital tract after exposure to live chlamydiae, despite the relatively rapid clearance of a reinfection. Alternatively, the initial infection induces deleterious immune responses against specific chlamydial antigens, and subsequent exposure to genital chlamydial infection leads to the expansion of disease-causing (pathogenic) memory immune effectors that aggravate disease progression. Our results favor the latter scenario, suggesting that T cell–mediated immune responses involving both CD4 and CD8 subsets are involved in Chlamydia-induced sequelae, although the CD8 T cell subset is the major contributor. We concluded that CD8 T cells play a greater role in pathology development than CD4 T cells because a predominant CD8 condition (ie, CD4KO) resulted in greater infertility than did a predominant CD4 condition (ie, CD8KO). Because the protective immunity against Chlamydia in the murine model is primarily mediated by CD4, we concluded that the protective effect of some of the CD4 T cell clonotypes may modulate the pathogenic clonotypes in predominant CD4 conditions.
The existence of protective and pathogenic immune effectors may imply that infection-induced immunity includes both pathogenic and protective components, with the latter being responsible for microbial clearance, although the extent of their involvement in pathogenesis is unclear. The activation of immunopathogenic effectors may also be a slow process, because rapid T cell response in IL-10KO mice protected them against pathologies. Furthermore, the involvement of specific T cells in protective immunity and in the pathogenesis of chlamydial disease, along with the apparent paradoxical coexistence of protective and immunopathogenic immune responses, support the suggestion that C. trachomatis
harbors protective and immunopathogenic antigens. If such antigens are identified, efforts to design a vaccine against Chlamydia
will involve distinguishing conditions for inducing protective immunity from those that help elicit deleterious effectors. In this respect, Bachmaier et al [46
] found that omcB (OMP2) of several C. trachomatis
serovars, C. pneumoniae
and Chlamydia psittaci
harbor a sequence homologous to the pathogenic epitope of the human a-myosin heavy chain, which can induce autoimmune myocarditis in mice. This sequence was not found in ompA or OMP3. Moreover, the likely pathogenic components encoded by the C. trachomatis
cryptic plasmid [47
] are unknown. The possibility that intact chlamydiae may harbor immunopathenic antigens has supported the focus on a subunit vaccine, which should be screened for toxicity as well. Finally, we have shown that specific immune effectors are involved in the pathogenesis of chlamydial disease, but their mechanism of action and the antigens they recognize are unknown. Identifying the immunopathogenic components of Chlamydia
and the deleterious immune effectors they induce, as well as the biochemical mechanisms of tissue injury, should be research priorities in efforts to develop an efficacious vaccine against Chlamydia