156 Sex Transm Inf 2000;76:156–161 Immunological basis of chlamydia induced Sex Transm Infect: first published as 10.1136/sti.76.3.156 on 1 June 2000. Downloaded from reactive arthritis Review J S H Gaston Introduction Genitourinary infections which trigger A small proportion of patients who present reactive arthritis with clinical symptoms of urethritis or cervici- Of the sexually acquired infections, the evi- tis later develop inflammatory arthritis and, for dence implicating Chlamydia trachomatis as a an unfortunate minority, this can be the begin- cause of reactive arthritis is strongest. The ning of a persistent and disabling disease. This infection is not always symptomatic,3 and illness is now termed reactive arthritis,1 rather rheumatologists greatly value the help of than the older term, Reiter’s disease. Reiter colleagues in genitourinary medicine in track- described a triad of urethritis, conjunctivitis, ing down chlamydial infection in patients with and arthritis in first world war soldiers in the unexplained acute synovitis. There are also reports of the involvement of mycoplasmas, trenches following attacks of dysentery, and 4 mistakenly believed that it was due to infection particularly Ureaplasma urealyticum. These with a novel spirochaete. However, others had organisms are clearly capable of causing arthri- previously described the same syndrome, and tis, and a septic arthritis due to mycoplasma infection in immunodeficiencies in which the triad has no specific pathological signifi- patients lack antibody is well described.56 cance; patients can have the same arthritis Individual “reactive arthritis” cases have been whether they have conjunctivitis or not, and reported in which Mycoplasma genitalium, now urethritis is not infrequently absent, particu- thought to be a significant cause of non- larly in cases triggered by gut infection. gonococcal, non-chlamydial urethritis,7 has Because of the emphasis on urethritis in the been identified in the joint by polymerase chain definition of Reiter’s disease, it has often been reaction (PCR) or culture.89 Less clear is the assumed subsequently that Reiter’s disease is extent of mycoplasma infection in classic reac- synonymous with sexually acquired reactive tive arthritis. Problems in establishing such an arthritis (SARA),2 whereas in Reiter’s report association include the possibility of dual the index cases followed gut infection. For all infection by chlamydiae and mycoplasmas, and these reasons the term reactive arthritis is to be the carriage of mycoplasmas in the genitouri- preferred and avoids unnecessary categories nary tract of normal individuals. As discussed http://sti.bmj.com/ such as “incomplete” Reiter’s disease. in detail below, finding an organism in joint There are many advantages, from a rheuma- tissue or fluid,10 particularly when using highly tological view, in studying the pathogenesis of sensitive PCR based tests, can no longer be reactive arthritis. Unlike, for instance, rheuma- regarded as definitive proof that the organism is toid arthritis, the onset is sharply defined rather responsible for the arthritis. than insidious, and is the result of an Infection by gonococcus also gives rise to an identifiable antigenic challenge (in the form of inflammatory arthritis which is sometimes on September 25, 2021 by guest. Protected copyright. an infectious organism) to the host immune loosely referred to as “reactive,” although the system. It has also been clear for some time that occasional isolation of the organism by culture host factors influence who develops arthritis, has often led to gonococcal arthritis being HLA-B27 being the best described of these, classified with other forms of septic arthritis. and that the same factors play a part in the In any case this arthritis does not share the whole family of arthritic conditions which extra-articular features or the HLA-B27 as- make up the seronegative spondyloarthropa- sociation of classic reactive arthritis, and can- thies (table 1). There is, therefore, an expecta- not be regarded as being within the spondy- tion that exploration of the host:pathogen loarthropathy grouping. Again dual interaction in reactive arthritis may provide gonococcal and chlamydial infection can cause confusion. valuable insights into the pathogenesis of related forms of arthritis. Chlamydiae in the joint One of the major advances in reactive arthritis Table 1 Spondyloarthropathies research has been the demonstration that trig- Department of gering organisms such as chlamydiae dissemi- Medicine, University + Ankylosing spondylitis of Cambridge, + Arthritis associated with inflammatory bowel disease nate from the site of infection to the joint. Addenbrooke’s + Psoriatic arthritis Atypical elementary bodies were demonstrated Hospital, Cambridge + Reactive arthritis, secondary infections by: in reactive arthritis synovium by immunofluo- CB2 2QQ + Chlamydia trachomatis 11 + Salmonella rescence and electron microscopic studies J S H Gaston 12 + Campylobacter were also suggestive. More recently nucleic + Yersinia acid amplification techniques have confirmed Accepted for publication + Shigella 2 May 2000 the presence of organisms in synovium and Immunological basis of chlamydia induced reactive arthritis 157 13–15 synovial fluid, and indicated that they are ence between chlamydia induced and enteric Sex Transm Infect: first published as 10.1136/sti.76.3.156 on 1 June 2000. Downloaded from viable since they are transcriptionally active.16 reactive arthritis, but very recent observations Despite this evidence, the organism can rarely have shown transcriptionally active yersiniae in if ever be cultured from the joint—the precise a reactive arthritis joint.33 In the case of enteric status of early reports of cultured chlamydiae infections, there is evidence to suggest persist- remains uncertain. It is also possible to induce ence of the infection long after the sympto- a “viable but uncultivable” state in vitro by matic gut infection has resolved—yersinia anti- tryptophan deprivation17 18 or treatment with gens have been detected in arthritic joints penicillin,19 and the chlamydiae may exist in a months to years after infection. The same may similar state within macrophages which do not apply to chlamydial infection, and it will be support a productive infection.20 Indeed, mac- important to identify sites of persistence and rophages or dendritic cells would seem the the extent to which the organism is susceptible most likely carriers of organisms into the joint, to treatment with antibiotics while in a since they will be able to take up bacteria at the quiescent state. site of infection,21 enter the circulation, and be recruited to the synovial membrane. In support The immune response to chlamydiae in of this idea chlamydiae have been detected in the joint peripheral blood leucocytes of reactive arthritis T CELL MEDIATED IMMUNE RESPONSES patients22 and dendritic cells in the joint stimu- Chlamydiae are obligate intracellular patho- late chlamydia specific T cells.23 It is worth gens and as such require T cell mediated recalling that the synovial membrane is made immunity to control the infection.34 Antibody up of 50% macrophages (type A synoviocytes), may have a role in preventing reinfection, espe- and that recruitment from the blood to the cially when it is produced locally in the genital joint occurs normally. It is tempting to tract, but in most circumstances has little if any speculate that rates of recruitment are higher to role in clearing the organism.35 It is not larger joints and to those which are subject to surprising therefore that T cell mediated low level trauma through weight bearing. immune responses have been readily demon- These factors might account for the tendency strated in the joints of patients with chlamydial for reactive arthritis preferentially to aVect induced reactive arthritis.36 Indeed, character- larger joints in the lower limbs. Moreover, the ising this immune response has contributed same line of argument leads to the conclusion substantially to what is known about cell medi- that macrophages bearing chlamydiae would ated responses to C trachomatis in humans, with always be recruited to joints in infected the identification of several of the antigenic patients, and especially to inflamed joints. components of chlamydiae which elicit T cell Recent evidence supports this; one centre has mediated responses.37 38 CD4+ T cells play the studied synovial biopsies from a population major part in controlling chlamydial with a high prevalence of chlamydial infection infection,39 probably through their production and showed the presence of organisms in on interferon ã,40 but protective CD8+ T cells 41 patients with rheumatoid arthritis (RA) or have also been described in mice, and more http://sti.bmj.com/ other forms of inflammatory arthritis, where recently in humans.42 The relative importance there is a high rate of recruitment of macro- of responses by these subsets in humans has phages to a hypertrophic inflamed synovial not yet been established, and chlamydia membrane.24 25 Chlamydial DNA was even specific CD8+ T cells have not yet been detected in synovium from an asymptomatic isolated from human joints. Nevertheless, joint, although some evidence of low level CD8+ T cells are activated in the joint and also 26 inflammation was present in this case. How- produce a similar set of cytokines as CD4+ T on September 25, 2021 by guest. Protected copyright. ever, the prevalence of detection of chlamydiae cells (H Beacock-Sharp, J