Presence of bacterial DNA and bacterial peptidoglycans in joints of patients with rheumatoid arthritis and other arthritides

Abstract

Objective. The continuous presence of bacteria or their degraded antigens in the synovium may be involved in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to determine the presence of bacterial nucleic acids and bacterial cell wall constituents in the joints of patients with RA and other forms of arthritis.Methods. Joint samples were obtained from patients with RA (n ‫؍‬ 26), septic arthritis (n ‫؍‬ 2), inflammatory osteoarthritis (n ‫؍‬ 5), and gout (n ‫؍‬ 6), and joint trauma (n ‫؍‬ 1). Universal 16S-ribosomal RNA primers were used to detect the presence of bacterial DNA in these samples, using stringent regimens for sample collection and molecular microbiologic analysis. Automated sequencing and comparative data analysis were performed to identify the species. The presence of bacterial peptidoglycan-polysaccharide complexes in synovial tissue was detected by immunohistologic analysis with a specific antibody.Results. The bacterial species cultured from the synovium could be identified in both of the patients with septic arthritis. DNA amplicons were also detected in the synovial fluid and/or tissue samples from 5 patients with RA and 2 patients with crystal-induced arthritis; these originated from multiple bacterial species. Staining for peptidoglycan-polysaccharide complexes was positive in the synovial tissue of both patients with septic arthritis, 16 with RA, 4 with inflammatory osteoarthritis, 4 with crystal-induced arthropathy, and 1 with joint trauma. The staining was mainly found in cells in the synovial sublining, including macrophages.Conclusion. The results indicate that bacterial DNA and bacterial cell wall constituents are retained in the joints of some patients with arthritis, where they might enhance synovial inflammation.

Inhibition of toll‐like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis

“…Indeed, TLR ligands of exogenous origin such as bacterial peptidoglycans and CpG-containing DNA, activating TLR-2 and TLR-9, respectively, have been found in the synovial fluid of patients with RA (5,6). In experimental models of arthritis, TLR ligands have repeatedly been used to induce the disease in susceptible animals; for instance, intraarticular injection of streptococcal cell wall fragments, double-stranded RNA, or CpGcontaining DNA, which mainly signal through TLR-2, TLR-3, and TLR-9, respectively, can induce arthritis (7)(8)(9).…”

Increased macrophage activation mediated through toll‐like receptors in rheumatoid arthritis

“…These studies are important, because ligands for TLR-2 and TLR-4 have been identified in the rheumatoid joint. Bacterial PG was identified in RA synovial tissue by a monoclonal antibody, particularly in macrophages and antigen-presenting cells (20,21). Additionally, endogenous mammalian TLR agonists, including fibrinogen, extra domain A (ED-A) of fibronectin, Hsp60 and Hsp70, low molecular weight fragments of hyaluronic acid, and high mobility group box chromosomal protein 1 (HMGB-1), a highly conserved nuclear protein that stabilizes nucleosome formation, are expressed in the RA joint, and each has been shown to activate NF-B through TLR-4 and/or TLR-2 (22)(23)(24)(25)(26)(27)(28)(29).…”

Toll‐like receptors and chondrocytes: The lipopolysaccharide‐induced decrease in cartilage matrix synthesis is dependent on the presence of toll‐like receptor 4 and antagonized by bone morphogenetic protein 7

“…Interestingly, several pathogen-associated structures, such as peptidoglycans and bacterial DNA and RNA, have been found in the joint tissue or synovial fluid of patients with RA and in those with other sterile forms of arthritides (6,7), suggesting that infectious agents may be involved in the initiation and/or perpetuation of these arthritides. A pathogenic role of such agents is supported not only by epidemiologic evidence (8), but also by the capacity of streptococcal cell walls or material contained in Freund's adjuvant (9,10) to induce severe chronic arthritis.…”