Molecular Biology of Infectious Agents in Chronic Arthritis
Section snippets
Epidemiology and disease characteristics
Detailed discussion of the clinical characteristics of reactive arthritis induced by gastrointestinal pathogens and by chlamydiae, and discussion of management and therapy of patients with the disease, will be found in another article in this issue. It will be useful, though, to include a brief summary of those and other disease aspects to provide a context for what follows. Current criteria specified by the American College of Rheumatology (ACR) for diagnosis of reactive arthritis require
Reactive arthritis induced by gastrointestinal pathogens
Reactive arthritis can follow infection by any of several species of gram-negative enteric pathogens, including those subsumed under the genera Yersinia, Campylobacter, Shigella, Salmonella, and others. Arthritis attributed to Klebsiella spp, E coli, and other normal gut bacterial species is rarer, as is synovial disease subsequent to infections with Neisseria gonorrhea, various Mycoplasma spp, Ureaplasma urealyticum, and others.2, 14, 19 The official ACR clinical definition of reactive
Chlamydial biology
Nine species are currently recognized in the order Chlamydiales. All species are obligate intracellular parasites of eukaryotic cells, and all are pathogenic to their various hosts. C trachomatis is the etiologic agent for trachoma, a disease that remains the leading cause of preventable or treatable blindness worldwide.29 This organism also is the most prevalent sexually-transmitted bacterial pathogen in the United States and other developed nations. C pneumoniae is a respiratory pathogen30
Initial studies of Chlamydia-induced arthritis
Early studies relating genital infection by C trachomatis with subsequent development of inflammatory arthritis were primarily correlational in nature. For example, one electron microscopic study of patients with early reactive arthritis provided evidence for Chlamydia in synovial mononuclear cells;34 another report demonstrated elementary and reticulate bodies within synovial macrophages, also in a patient diagnosed with reactive arthritis.35 A group in the UK identified elementary bodies in
Dissemination of chlamydiae, synovial host cells in reactive arthritis
Whereas Campylobacter is the most common cause of bacterial enteritis, C trachomatis is by far the most prevalent sexually-transmitted bacterial pathogen in the United States and in most other developed nations.45 Recent data from the Centers for Disease Control and Prevention indicate more than 3 million new cases are reported each year, with a stable population of Chlamydia-infected individuals in excess of 6 million.45C trachomatis and C pneumoniae have been detected in synovial tissues by
Chlamydophila pneumonia in the joint
While enteric pathogens and C trachomatis have long been associated with genesis of reactive arthritis, many groups have reported DNA from C pneumoniae in synovial tissues from a small but significant number of patients with various arthritides.49, 56, 57 PCR-based screening showed that about 13% of synovial biopsies from nearly 200 patients with various arthritides were positive for C pneumoniae DNA.50 No samples from control individuals were positive in parallel assays. Reverse
Chlamydial persistence
Under some circumstances, including those relevant to synovial infections, the chlamydial developmental cycle can be arrested, obviating production and release of new elementary bodies. This state of arrested development under certain growth conditions or within certain host cell types has been designated “persistence.”33 The arrest in the cycle which engenders this state is transcriptionally governed. Much of the initial study of chlamydial persistence was done by the Byrne laboratory, based
Molecular biology and genetics of chlamydial persistence in inflammatory arthritis
Transcriptional analyses of persistent C trachomatis in the in vitro monocyte model, and in synovial samples from patients with Chlamydia-induced arthritis, have revealed unusual biochemical and molecular genetic characteristics that distinguish this state from that characterizing normal passage through the developmental cycle. PCR-based studies indicated that synovial tissue, rather than synovial fluid, is the primary site of residence for the organism in chronic Chlamydia-induced arthritis.48
Other molecular genetic studies concerning chlamydial persistence
Pathogens other than chlamydiae undergo persistent infection.87 For example, Mycobacterium tuberculosis undergoes persistent infection, and its primary host cell type, like that of persistent chlamydiae in the joint, is the monocytic cell. One report identified nearly 200 genes whose expression is required for M tuberculosis growth and persistence in an animal model, and most of these are not expressed, or are expressed at only a low level, during normal growth of the organism.88 More than half
Relevant aspects of host-pathogen interaction
Establishment and maintenance of the persistent state for chlamydiae, and thus aspects of immunopathogenesis, must result from interaction between bacterium and host cell. Several host-directed microarray-based studies relevant to chlamydial infection have appeared over the last few years. One analyzed expression of some 1200 host genes on an array using RNA from C trachomatis and mock-infected HeLa cells.96 Transcription of only 18 genes was up-regulated by chlamydial infection, including
Summary
The observations outlined briefly demonstrate that some understanding of meaningful details concerning the Chlamydia-induced synovial pathogenesis process in reactive arthritis has emerged from research efforts over the last 20 years. However, many important questions remain, several of which center on issues of host-pathogen interaction. It has never been clear why only a subset of the many individuals who acquire a genital infection by C trachomatis, or the minority of individuals who are C
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Cited by (0)
This work was supported by grants AR-42541 (APH), AR-47186 (HCG), AR-48331 (JAW-H), and AR-53646 (JDC) from the US National Institutes of Health. APH has also been supported in part by grants from the Department of Veterans Affairs Medical Research Service.