Chlamydia Pneumoniae And Rhematoid Arthritis

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Expression at 48 h Postinfection

Expression at 48 h Postinfection

Gene no IFN-y 0,15 ng/ml rIFN-y 0.50 ng/ml rIFN-y rffwA* polA"

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"Determinations done by standard RT-PGR; see ref. 33 for details and all

^Representative genes encoding products required for DNA replication. ' Representative genes encoding products required for cytokinesis.

5. Chlamydia pneumoniae AND CYTOKINES

The cytokine balance elicited during a host immune response to any infectious agent strongly influences whether that pathogen is eliminated with minimal damage to the host, or whether pathogen- or immune-mediated damage ensues.(36) The predominance ofThl-orTh2-associated cytokines, i.e., IL-2, IFNy, TNFa versus IL-4, IL-6, IL-10, produced by lymphocytes at sites of inflammation is often used as a general indicator ofwhich CD4+ population is involved at that site, but macrophages/monocytes produce some T cell-associated cytokines, including IL-10, TNFa, IL-6. Th1 CD4+ cells drive delayed-type hypersensitivity responses, whereas Th2 CD4+ cells are associated with T-dependent antibody responses.(37) CD8+ T cells have other effector functions, including cytotoxicity for infected cells; they produce some of the same Thl- and Th2-like cytokines (e.g., IFNy, TNFa, IL-5). Studies have shown a shift over the course of chronic disease from a Thl- to a Th2-dominant cytokine pattern.(38) In addition to proinflammatory mediators such as IL-1 and TNFa, monocytes/macrophages produce a varied repertoire of cytokines, including IL-12 and TGF(5, some ofwhich are upregulated in experimental or clinical Chlamydia infection.(39-40)

Many studies have indicated roles for cytokines in the growth, differentiation, and persistence ol'Cli lam\dia e. '1 '' ' '1A s mentioned, if cultured in the presence of low levels of IFNy, growth of both C. trachomatis and C. pneumoniae is inhibited in vitro, aberrant forms of intracellular organisms develop, and the profile of bacterial genes expressed becomes unusual.(19'33) The growth inhibition results from induction of indoleamine-2,3-dioxygenase, which deprives the pathogen of tryptophan by degrading it.(41) Moreover, IFNy causes a selective transcriptional downregulation of several chlamydial genes, including ompl; LPS production is also attenuated, and other chlamydial genes, including groEL, are upregulated.(5'7) When IFNy is removed from the growth medium, infectious organisms are again produced, LPS and major outer membrane protein levels return to normal, and the groEL gene product is decreased. TNFa, a proinflammatory cytokine produced by both T cells and macrophages, has similar, synergistic effects to those of IFNy in this system.(41) Studies have shown that IFNai/p and NO also are induced during in vitro chlamydial infection of host cells. Interestingly, a recent report indicated that the amount of NO released by macrophages has important regulatory effects on chlamydial pathogenesis.*42' can modulate inflammation and immune responses and have been associated with some forms of arthritis. The presence of NO is consistent with recent experimental results showing that activated NO synthetase correlates with clearance of infection. In vivo sites of chlamydial infection show chronic inflammation and generally contain T cells, monocytes/macrophages, and at some sites B lymphocytes.(43)

It is not clear whether chlamydial infection elicits an inflammatory response because of upregulated cytokine production in infected or neighboring cells, or if the immune response to infected cells drives the inflammatory response via influx of cytokine-producing lymphocytes and macrophages. Nonetheless, synovial materials have been studied for the panel of cytokines present in C. trachomatis- and C. pneumoniae-induced inflammatory arthritis. After development of inflammation, Th1/Th2 CD4+ cells, as well as CD8+ cells and macrophages, have been detected in synovial fluid.(44) Many studies have indicated that, in patient materials from individuals with early disease, proinflammatory cytokines such as IL-12 and IFNy are prominent.(39 44) However, in a large-scale study of the steady-state pattern of cytokine and chemokine mRNA production elicited by C. trachomatis during chronic synovial infection, a significant difference in the pattern of inflammatory mediators was identified compared with that of early disease. That is, in C. trachomatis-infected joint tissues from chronic reactive arthritis patients, IL-10 and IL-8 messengers strongly predominated, although low levels of mRNA encoding IFNy, TNFa, and IL-15 were also identified; transcripts for the MCP-1, but not the RANTES, chemokine were present.(45) In the same study, it was shown that in synovial tissue samples from arthritis patients chronically infected at that site with C. pneumoniae, essentially only mRNA encoding IL-8, IHp, and RANTES were present (Fig. 1).

Thus, chronic synovial infection with C. pneumoniae shows important differences in host attributes and host response than does chronic infection at that site with C. trachomatis. Such differences almost certainly account for the observed differences in extra-articular features noted above for C. trachomatis-vs. C. pneumoniae-induced arthritis. Regardless, all available data indicate that joint infection with C. pneumoniae does engender a form of inflammatory, reactive arthritis.

Chlamydia Arthritis

FIGURE 1. Relative levels of cytokine-encoding mRNA in synovial tissue chronically infected with C. trachomatis (panel A) or C. pneumoniae (panel B). Similar assays using RNA/cDNA from a patient with undifferentiated oligoarthritis but who was PCR-negative for all organisms examined showed no induction of cytokine transcripts (not shown). Assays were done by real time RT-PCR; see ref. 45 for all experimental details and complete data and discussion. C1, C2, control patients. Figure adapted with permission from ref. 45.

FIGURE 1. Relative levels of cytokine-encoding mRNA in synovial tissue chronically infected with C. trachomatis (panel A) or C. pneumoniae (panel B). Similar assays using RNA/cDNA from a patient with undifferentiated oligoarthritis but who was PCR-negative for all organisms examined showed no induction of cytokine transcripts (not shown). Assays were done by real time RT-PCR; see ref. 45 for all experimental details and complete data and discussion. C1, C2, control patients. Figure adapted with permission from ref. 45.

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