Decline in the Frequencies of Borrelia burgdorferi OspA161–175-Specific T Cells after Antibiotic Therapy in HLA-DRB1*0401-Positive Patients with Antibiotic-Responsive or Antibiotic-Refractory Lyme Arthritis

Abstract

Synovitis in patients with antibiotic-refractory Lyme arthritis persists for months to several years after antibiotic therapy. This course, which may result from infection-induced autoimmunity, is associated with T cell recognition of Borrelia burgdorferi outer surface protein A (OspA161–175) and with HLA-DR molecules that bind this epitope, including the DRB1*0401 molecule. In this study, we used tetramer reagents to determine the frequencies of OspA161–175-specific T cells in samples of PBMC and synovial fluid mononuclear cells (SFMC) from 13 DRB1*0401-positive patients with antibiotic-responsive or antibiotic-refractory arthritis. Initially, three of the six patients (50%) with antibiotic-responsive arthritis and four of the seven patients (57%) with antibiotic-refractory arthritis had frequencies of OspA161–175-specific CD4+ T cells in peripheral blood above the cutoff value of 4 per 105 cells. Among the five patients with concomitant PBMC and SFMC, four (80%) had OspA tetramer-positive cells at both sites, but the mean frequency of such cells was 16 times higher in SFMC, reaching levels as high as 1,177 per 105 cells. In the two patients in each patient group in whom serial samples were available, the frequencies of OspA161–175-specific T cells declined to low or undetectable levels during or soon after antibiotic therapy, months before the resolution of synovitis in the two patients with antibiotic-refractory arthritis. Thus, the majority of patients with Lyme arthritis initially have increased frequencies of OspA161–175-specific T cells. However, the marked decline in the frequency of such cells with antibiotic therapy suggests that persistent synovitis in the refractory group is not perpetuated by these cells.

HLA type and immune response to Borrelia burgdorferi outer surface protein a in people in whom arthritis developed after Lyme disease vaccination

“…Although previous findings suggesting possible molecular mimicry between OspA 165–173 and hLFA1 αL332–340 were the impetus for this study, our results are consistent with more recent findings showing minimal T cell responses to hLFA1 αL332–340 in patients with treatment-resistant Lyme arthritis (19–21). These latter findings have cast doubt on the earlier hypothesis and raised other possibilities.…”

A novel human autoantigen, endothelial cell growth factor, is a target of T and B cell responses in patients with Lyme disease

“…As evidence against the persistent infection hypothesis, polymerase chain reaction and culture results of synovectomy specimens obtained in the postantibiotic period have been uniformly negative (11), and relapse of infection has not been observed with the use of diseasemodifying antirheumatic drugs (DMARDs) after antibiotic therapy (8). Contrary to what might be expected with retained spirochetal antigens, T and B cell responses to Bb decline similarly in patients with refractory arthritis and those with responsive arthritis (12,13), whereas levels of inflammatory mediators in synovial fluid (SF), particularly interferon-␥ (IFN␥), remain high or even increase in patients with refractory arthritis during the postantibiotic period (14). In support of the autoimmunity hypothesis, specific HLA-DR alleles, particularly the DRB1*0101 or 0401 alleles, are the greatest known genetic risk factor for antibioticrefractory arthritis (15).…”

Searching for borrelial T cell epitopes associated with antibiotic-refractory Lyme arthritis

“…(Dattwyler et al, 1988;Steere et al, 1994) In rare cases however, synovitis persists for months or even several years despite treatment with ≥2 months of oral antibiotics, ≥1 months of IV antibiotics, or usually both. (Steere and Angelis, 2006;Steere et al, 1994) Since PCR results for Bb DNA in joint fluid are almost always negative in the post-antibiotic period (Carlson et al, 1999;Nocton et al, 1994;Steere and Angelis, 2006) and since cellular and humoral immune responses to Bb antigens begin to decline soon after antibiotic treatment (Kannian et al, 2007a;Kannian et al, 2007b), antibiotic therapy appears to result in the nearly complete or total eradication of spirochetes from the joint, yet synovial inflammation still persists. This disease course, which has been termed antibiotic-refractory Lyme arthritis, is thought to be the result of an infection-induced autoimmune response.…”