Treg cell numbers and function in patients with antibiotic-refractory or antibiotic-responsive Lyme arthritis.

Lyme arthritis, which is caused by the tick-borne spirochete Borrelia burgdorferi, is characterized by intermittent or persistent inflammation in a few large joints, especially the knee, over a period of several years (1). In most patients, the joint infection can be treated successfully with oral antibiotic therapy for 1 or 2 months, or intravenous (IV) antibiotics for 1 month, and the arthritis resolves (2). However, in about 10% of patients, particularly in those infected with highly inflammatory B. burgdorferi strains (3), the arthritis in one or both knees persists for more than 3 months after 2–3 months of oral or IV antibiotics, or both, called antibiotic-refractory Lyme arthritis. In such patients, polymerase chain reaction (PCR) results for B. burgdorferi DNA in synovial fluid (SF) are usually negative after oral and IV antibiotic therapy (3), cellular and humoral immune responses to B. burgdorferi antigens decline (4,5), and break-through cases of active infection have rarely been observed during the post-antibiotic period (2). Thus, synovitis in patients with antibiotic-refractory arthritis may persist after the near or total eradication of spirochetes from the joint with antibiotic therapy. The duration of antibiotic-refractory arthritis is variable. In a previous analysis of 67 patients, the median duration from the initiation of antibiotics to the resolution of arthritis was 11 months (range, 4–44 months) (2). In the post-antibiotic period, we usually treat with a non-steroidal anti-inflammatory agent (NSAID) and a disease modifying anti-rheumatic drug (DMARD) (2). If patients have only a minimal-to-moderate response after 12–18 months, we consider arthroscopic synovectomy. Antibiotic-refractory Lyme arthritis shares certain pathogenetic themes with other forms of chronic inflammatory arthritis, particularly rheumatoid arthritis (RA). These include similar synovial histology (6,7), HLA-DR associations with the DRB1*0401 and 0101 alleles (8–10), a dominant TH1 response in SF and synovial tissue (11,12), and high SF levels of pro-inflammatory cytokines and chemokines (13–15), especially CXCL9 and CXCL10, which are strong chemoattractants for CD4+ and CD8+ T effector cells (Teff). We have postulated that antibiotic-refractory arthritis may result from infection-induced, tissue-specific autoimmunity within affected synovia (16). The autoimmunity hypothesis has been reinforced recently by the development of a murine model (17). In this model, both the human HLA-DR4 transgene, which is associated with antibiotic-refractory arthritis, and lack of the CD28 co-receptor, which leads to dramatically reduced numbers of T regulatory cells (Treg) (18), are necessary for persistent synovitis after antibiotic therapy. Mice that lack only the CD28 co-receptor, without the HLA-DR4 transgene, do not develop persistent synovitis after treatment (19); and similarly, mice that lack the CD28 co-receptor and have the human HLA-DR11 transgene, which is associated with antibiotic-responsive arthritis, do not develop post-treatment synovitis (20). These outcomes in mice support the HLA-DR findings in human patients with Lyme arthritis (8), but Treg numbers and function have not yet been examined in human Lyme arthritis. In this study, we enumerated CD4+ T cell subsets, including Treg, in peripheral blood (PB) and SF in 18 patients with antibiotic-responsive or antibiotic-refractory Lyme arthritis. In those with antibiotic-refractory arthritis, a higher percentage of Treg correlated with a shorter duration to the resolution of arthritis. However, as in the murine model, patients with refractory arthritis and lower numbers of Treg seem unable to resolve synovial inflammation.