The primary site of chlamydial infections of the genital tract is the columnar epithelial cells of the endocervix of women and the urogenital epithelia of men.12 In men, ascending infection can cause prostatitis and epididymitis,13 this has been extensively reviewed by Cunningham and Beagley13 and will not be addressed in this review. In women, the infection can ascend the reproductive tract and cause PID and ectopic pregnancies.11 The development of disease sequelae in women following chlamydial infection is associated with ascension of Chlamydia from the lower reproductive tract into the upper reproductive tract. The mechanisms that lead to this ascension are not fully understood, neither is the rate at which this happens. It is thought that Chlamydia can gain access to the URT of women by attachment to sperm.14,15 It is also possible that movement along the reproductive tract is from general flow of fluids (Fig. 1), with studies demonstrating that particles approximately the same size of sperm,16 or radio-labeled sperm,17 deposited into the vagina of women, could be found in the uterus within 2 min, demonstrating that rapid ascension of bacteria could occur.
Figure 1. The paradigms of chlamydial pathogenesis in the female reproductive tract. Chlamydia ascends the reproductive tract either by attachment to sperm or from the general flow of fluids, infecting the upper female reproductive tract, leading to the development of pathology. Pathogenesis is thought to occur through either an innate, non-immune cellular response (Cellular paradigm), or an antigen-specific adaptive cellular response (Immunological paradigm). Green circles: Chlamydia particles; DTH: Delayed-type hypersensitivity; cHSP-60: chlamydial heat-shock protein-60; PID: Pelvic inflammatory disease; TFI: Tubal factor infertility; TLR: Toll-like receptor; IL: Interleukin; GM-CSF: Granulocyte–macrophage colony-stimulating factor.
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Murine studies using Chlamydia muridarum have greatly expanded the knowledge of infection kinetics, including the differential cell infiltration between the lower and upper genital tract, the rate at which this occurs,18–24 and also the rate of infection ascension.24–26 The infectious dose of Chlamydia is known to modulate the innate immune response, with greater inoculating doses causing a greater innate immune response.26 It has been suggested that because of the greater immune responses elicited by high infectious challenge doses, the infection does not cause as great a degree of hydrosalpinx.26 However, it has also been shown that while the infectious dose affects the degree of ascension of infection along the female reproductive tract of mice, it does not affect the pathological outcomes, such as hydrosalpinx development and cellular infiltrate.24 This suggests that, if a similar situation occurs in humans, the development of pathological sequelae may not be affected by the sexual transmission dose. Although the number of Chlamydia required to establish an infection in different strains of mice27 and the number of Chlamydia caviae transmitted by an infected male guinea pig during mating is known,28 there are no data on these parameters in human infections.
The regulation of immune responses against genital tract Chlamydia trachomatis infections in humans is largely unknown, because of the difficulty in obtaining samples and monitoring patients long term. Natural immunity to a single infection is known to be short lived and serovar specific;29 however, multiple infections with different serovars induces longer term, cross-serovar immunity.30 Immune responses to infections are linked to genetic variations, with specific polymorphisms in immune response genes influencing the magnitude of immune responses to microorganisms.31
There have been reports indicating that women have spontaneously cleared a genital infection without medical intervention; however, the exact duration of an infection cannot be determined.32 It is also believed that antibiotic intervention increases the longer term rates of re-infection because of the inability of the person to develop protective immunity against Chlamydia.33 It is widely accepted, based on animal studies, that to resolve a chlamydial genital tract infection in women, both a Th1 and Th2 response needs to be mounted. The infiltration and activation of CD4+ Th1 cells is required for the development of protective immunity and clearance of a primary infection.34 While clearance of a primary infection is dependent on the development of cell-mediated immunity, clearance of a secondary infection requires the presence and production of antibodies.12,35 Also an increase in infiltration of CD8+ T cells,36 B cells,37 neutrophils38, and dendritic cells39 (DCs) is required. This ensures effective clearance of both the intracellular reticulate bodies and extracellular elementary bodies in the genital tracts of infected individuals. Recent studies examining cytobrush samples from the endocervix demonstrated that women infected with C. trachomatis had an increase in CD3+, CD4+ and CD8+ cells, and neutrophils,40,41 and an increase in recruitment of myeloid and plasmacytoid DCs.41
The first line of defense against a Chlamydia infection within the female reproductive tract is the mucosal barrier. Initial infection of epithelial cells causes a cascade of events leading to the increased production of pro-inflammatory cytokines and chemokines including IL-1, IL-842, IL-1219, IL-6, and GM-CSF,43 which then induces an influx of innate immune cells (Fig. 1) such as natural killer (NK) cells,44 DCs,39 and neutrophils.38 These cells then produce more cytokines such as IFN-γ and TNF-α, which impede further chlamydial growth. Production of various cytokines has, however, proven to be detrimental to the mucosal barrier, with their presence linked to various tissue pathologies,12 and this has been termed the cellular paradigm45 (Fig. 1).
Tissue destruction leading to the development of tubal infertility and ectopic pregnancy is caused by the production of cytokines (Fig. 1), including IL-1 and IL-8, in response to infection.42 Fallopian tube biopsy samples infected with C. trachomatis, with or without IL-1 receptor antagonist present, revealed that the production of IL-1 leads to destruction of the ciliated epithelium.42 Toll-like receptor 2 (TLR-2) has also been implicated in the development of chronic pathology in the mouse model of genital infection,46 with TLR-2 KO mice producing lower levels of TNF-α and MIP-2, and developing significantly less oviduct pathology.46 This supports the idea that it is the host’s immune response to infection that is responsible for the damage rather than the infection itself.
It has also been suggested that the pathologies seen after an infection are linked to antigen-specific adaptive cellular responses, this is termed the immunological paradigm47 (Fig. 1). The exact mechanism or antigen behind the immunological paradigm has yet to be determined. There are conflicting reports that pathogenesis may be linked to chlamydial heat-shock protein-60 (cHSP-60) through delayed-type hypersensitivity (DTH) or molecular mimicry causing autoimmunity. Chlamydia can enter a dormant, persistent state, where, in the absence of a productive infection, there is still a low level of immune stimulation from antigen recognition. This low level stimulation is believed to cause chronic inflammatory cell infiltration.48,49 Originally, guinea pigs sensitized with Triton-X-100 soluble chlamydial elementary bodies (EBs) had greater ocular delayed hypersensitivity when re-exposed to infection at other sites, including vaginal and intestinal infections.50 Similarly, monkeys immunized against C. trachomatis developed a greater follicular response in the eye upon re-exposure than non-immune controls,51 highlighting the significance of repeated infections in terms of a delayed hypersensitivity response. T cells isolated from endometrial and salpingeal tissues, removed from patients with PID and tubal factor infertility (TFI), responded to stimulation with cHSP-60 to a greater degree than with chlamydial EBs, further supporting cHSP-60’s role in DTH52,53 (Fig. 1). The presence of cHSP-60 antibodies has also been correlated with PID severity,54–56 TFI57, and more severe salpingeal pathology.58
It has also been debated as to whether or not autoimmunity plays a role in the pathogenesis of chlamydial infections (Fig. 1), because of the high sequence homology between self and chlamydial HSP-60.48 A study where mice were immunized with either cHSP-60, mouse (self) HSP-60, or a combination of the two demonstrated that T-cell proliferation in response to self-HSP-60 was only observed after immunization with both HSP-60s. A shift in cytokine secretion following in vitro stimulation was also observed, changing from anti-inflammatory IL-10 secretion when immunized with self-HSP-60 to pro-inflammatory IFN-γ when immunized with both.59 This suggests that a chlamydial infection can induce autoimmunity, and this is supported by recent findings that human HSP-60 and cHSP-60-1 from C. trachomatis serovar D contain four potential T-cell epitopes that display 100% identity.59,60 There is still some doubt over how involved cHSP-60 is in the development of autoimmunity, as, in these same experiments, immunization of mice with cHSP-60 alone did not induce cross-reactive autoimmune T cells;59 however, during an actual chlamydial infection, it is highly likely that both host and chlamydial HSP-60 are produced.
The earlier studies highlights that it is not necessarily the damage caused by the infection itself that leads to the development of reproductive sequelae such as PID, but rather the host’s immune response to infection that may actually cause the damage.