Immunology of chlamydial infections:
Contemporary immunological paradigms
Anti-chlamydial mechanisms of immune effectors
In vitro experimental systems for mechanistic analysis and corroborative in vivo studies have revealed that T cell-derived cytokines, especially IFN-g
and TNF-a
, are crucial for chlamydial clearance in humans and in experimental animals [Byrne et al.,
1986]. The biochemical basis of the antimicrobial action of these cytokines include: (i) the activation of phagocytes (e.g. macrophages) to rapidly take up and degrade chlamydiae or infected cells
[Zhong & de La Maza, 1988]; (ii) the induction of indoleamine 2, 3-dioxygenase, an enzyme that catalyzes the decyclization of L-tryptophan into
N-formylkynurenine [Byrne et al.,
1986], thereby limiting the availability of the essential amino acid, and consequently inhibiting chlamydial
growth [see: role of IFN-g]; (iii) the activation of the inducible nitric oxide synthase
(iNOS), which catalyzes the production of various antimicrobial reactive nitrogen intermediates, most notably nitric oxide (NO) from
L-arginine [Chen et al., 1996]; and (iv) the induction of intracellular iron deficiency, involving the down-regulation of transferrin receptors
[Byrd & Horwitz, 1993]. There is evidence for the involvement of all three mechanisms in the antichlamydial action of T cell-derived cytokines
[Igietseme et al., 1998]. Iron deprivation influences the growth of different species of Chlamydia
[Raulston, 1997; Freidank et al.,
2001; see: Figures 3 and 4].
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Figure 3. Highly protective Th1 cells from
mice immunised with chlamydia-pulsed dendritic cells from IL10-deficient
mice (see Figure 2) do not confer protection when transferred to
IFN-g-receptor deficient mice, as opposed to IFN-g-receptor competent
mice. Here immunocompetence is shown by the ability to eradicate inclusion
forming units of chlamydial elementary bodies.
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Figure 4. Three main types of
anti-chlamydial biochemical response may be induced in the human
epithelial cell line RT4 by cytokines and / or bacterial
lipopolysaccharide (LPS). These are the production of inducible nitric
oxide synthase (iNOS) which is inhibited by methyl arginine (NAME); the
IFN-g stimulated induction of indoleamine dioxygenase (IDO) which is
affected by tryptophan; and the sequestration of iron (FeCl3), an
essential requirement for chlamydiae. The figure shows that these 3
mechanisms can operate together against chlamydiae. |
Beside neutralization of extracellular infectious elementary bodies and antibody dependent cellular cytotoxicity
(ADCC) by macrophages and NK cells, a major function of antibodies is the enhancement of
the Th1 response during re-infections [Moore et al.,
2002]. The significance of the Th1-enhancing function of antibodies is underscored by the failure of in vitro neutralizing antibodies to transfer protective passive immunity in vivo in mice
[Igietseme et al., 1998], and the inability of local IgG to prevent ocular chlamydial infection and trachoma development in humans
[Bailey et al., 1993]. Perhaps more persuasive are the findings that chlamydial clearance has an obligatory requirement for Th1 effectors even in the presence
of high levels of secretory and systemic antibodies [Cotter et al.,
1997;
Johansson et al., 1997a; Johansson et al.,
1997b; Stagg, 1998]. Thus, FcR-dependent antibody-mediated enhancement of T cell activation appears to
be an integral component of the adaptive anamnestic cell mediated immune (CMI)
response, and its physiologic relevance includes the boosting of Th1 response against certain intracellular pathogens and possibly tumors that are controlled primarily by CMI effectors
(Figure 5). A simplified model for the induction of protective immunity against
chlamydial infection is presented in Figure 6.
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Figure 5. Antibody enhancement of TH1 cell
activity (measured by production of IFN-g) against chlamydiae. The presence
of specific anti-chlamydial antibodies (α-MOPN) but not
anti mycobacterial antibody (α-TB) enhances TH1 activation (IFN-g
production) by antigen presenting cells expressing the FcR receptor for
antibody (FcR+/+ APCs) but not those lacking the receptor (FcR-/- APCs).
Antibody to IgG2a blocks antibody mediated enhancement of Th1 activation,
demonstrating that this antibody isotype plays a crucial role.
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Figure 6. A unified
model for the induction of protective immunity against chlamydial infection.
In the presence of specific IgG2a antibody, chlamydial elementary bodies (EBs)
(1) are opsonized by dendritic cells (2) bearing an FcR receptor. After
migration to the regional lymph node for Th1 activation (3) there is rapid
production and activation of Th1 cells (4). Chlamydial infected epithelial
cells also secrete various cytokines (5). Recruitment of Th1 cells into the
genital mucosae leads to in situ production of cytokines (IFN-g and
TNF-a) (6) and the induction of the three antichlamydial mechanisms of iNOS,
IDO and Fe binding (7). After elimination of chlamydiae retention of T cells
in the mucosa (8) leads to a local memory effect if the antigen is seen
again, shortening the duration of subsequent infection. |
The CD8+ cytotoxic T cells exert anti-chlamydial action via cytokine-mediated anti-microbial effects rather than their cytolytic function
[Lampe et al., 1998]. In fact,
apoptosis via Fas/Fas ligand, or both perforin and Fas ligand were irrelevant to the antichlamydial action of T cells in mice
[Perry et al., 1999]. However, Chlamydia could inhibit apoptosis of infected cells
[Fan et al., 1998] and a chlamydial protease down-regulated MHC class I and II expression by degrading critical transcription factors
[Zhong et al., 2000]. These findings may have significance in chlamydial-induced immunosupression, evasion of immune effectors, persistent infection and potential targets for intervention or strategies to boost host immune effectors against Chlamydia. Nevertheless, the operational model guiding vaccine research is that protective immune effectors control chlamydia principally via Th1 cytokine-induced anti-microbial processes, which are augmented by certain antibody-dependent functions.
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Protection versus immunopathology
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