Abstract
OBJECTIVE: Persistence of intracellular organisms may play a critical role in the initiation and perpetuation of synovitis in reactive arthritis (ReA). We investigated factors that may influence local clearance of arthritogenic pathogens in ReA. METHODS: We studied 11 HLA-B27 positive patients with spondyloarthropathies and contrasted these patients with 6 HLA-B27 negative control patients with rheumatoid arthritis or osteoarthritis. We employed an ex vivo system in which human synoviocytes derived from patients with ReA are cocultured with arthritogenic pathogens, and intracellular clearance is measured by quantitating colony-forming units over time. RESULTS: The clearance kinetics of the organisms bore no relationship to the HLA-B27 status of the patient. Clearance of S. typhimurium over a 10 day period was accompanied by a progressive rise in nitric oxide (NO) production, but this appeared not to be rate-limiting, since (1) clearance kinetics were comparable between high versus low NO-producing synoviocytes; and (2) L-NMMA inhibition of NO production did not alter clearance kinetics of S. typhimurium. Interferon-g (IFN-g) was observed to have a small but measurable effect on bacterial clearance. In certain patients with ReA there was a paradoxical stimulatory response to IFN-g, in which the addition of IFN-g was accompanied by an increase in intracellular bacteria. This effect was found to be attributable to IFN-g mediated suppression of NO production in these cells. This pattern was not observed in B27 negative synoviocytes. CONCLUSION: Intracellular persistence of arthritogenic organisms may contribute to the cellular basis of ReA, but the molecular basis of the bacteriocidal pathways in synoviocytes has not been fully resolved. Our findings indicate that a direct effect of HLA-B27 on these events is unlikely, but that alterations in cytokine response profiles may play a contributory role. Characterizing these mechanisms holds the promise of more specific therapeutic interventions in this disease.
