(Verbatim) - About 10 percent of patients with Lyme arthritis have persistent knee swelling for months or even several years after oral and intravenous antibiotic therapy. After treatment, such patients, in our experience, have no remaining spirochetal DNA in synovial tissue or joint fluid, suggesting that live spirochetes have been eliminated from the joint. During the past grant cycle, we identified a possible autoimmune mechanism that may partially explain the persistence of Lyme arthritis after antibiotic therapy. The mechanism in DRB1*0401-positive individuals involves molecular mimicry between the dominant T cell epitope of B. burgdorferi outer-surface protein A (OspA165-173) and a homologous sequence of human lymphocyte function associated antigen-1 (hLFA-1alpha332-340). In this proposal, we test the hypothesis that synovial inflammation may persist in treatment-resistant arthritis patients with a range of MHC alleles because of molecular mimicry between this dominant T cell epitope of OspA and hLFA-1. Our plan is to determine the frequencies of various MHC alleles in patients with treatment-resistant arthritis compared with those in treatment-responsive patients and those in a control population. PBL and synovial fluid lymphocytes (SFL) from treatment-responsive and treatment-resistant patients will be screened for reactivity with OspA165-173 and LFA-1alpha332-340, and cloned OspA165-173-reactive T cells from selected patients with a range of MHC alleles will be tested for reactivity with hLFA-1alpha332-340. Using an in vitro peptide binding assay, DR or DQ molecules obtained from selected patients' EBV-transformed B cells will be tested for their ability to bind the OspA and hLFA-1 peptides. Finally, after appropriate antibiotic treatment, the efficacy and safety of DMARD therapy will be observed in treatment-resistant patients. Lyme arthritis is the only human form of chronic inflammatory arthritis in which the triggering agent, immunogenetic susceptibility, and a candidate autoantigen are known. Thus, it is currently the only human system in which it is possible to explore specific infectious and autoimmune mechanisms that may lead to chronic inflammatory arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR020358-30S1
Application #
6914805
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Serrate-Sztein, Susana
Project Start
1987-07-01
Project End
2006-02-28
Budget Start
2004-07-01
Budget End
2005-02-28
Support Year
30
Fiscal Year
2004
Total Cost
$60,373
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Vudattu, Nalini K; Strle, Klemen; Steere, Allen C et al. (2013) Dysregulation of CD4+CD25(high) T cells in the synovial fluid of patients with antibiotic-refractory Lyme arthritis. Arthritis Rheum 65:1643-53
Drouin, Elise E; Seward, Robert J; Strle, Klemen et al. (2013) A novel human autoantigen, endothelial cell growth factor, is a target of T and B cell responses in patients with Lyme disease. Arthritis Rheum 65:186-96
Katchar, Kia; Drouin, Elise E; Steere, Allen C (2013) Natural killer cells and natural killer T cells in Lyme arthritis. Arthritis Res Ther 15:R183
Li, Xin; Strle, Klemen; Wang, Peng et al. (2013) Tick-specific borrelial antigens appear to be upregulated in American but not European patients with Lyme arthritis, a late manifestation of Lyme borreliosis. J Infect Dis 208:934-41
Strle, Klemen; Shin, Junghee J; Glickstein, Lisa J et al. (2012) Association of a Toll-like receptor 1 polymorphism with heightened Th1 inflammatory responses and antibiotic-refractory Lyme arthritis. Arthritis Rheum 64:1497-507
Seward, Robert J; Drouin, Elise E; Steere, Allen C et al. (2011) Peptides presented by HLA-DR molecules in synovia of patients with rheumatoid arthritis or antibiotic-refractory Lyme arthritis. Mol Cell Proteomics 10:M110.002477
Li, Xin; McHugh, Gail A; Damle, Nitin et al. (2011) Burden and viability of Borrelia burgdorferi in skin and joints of patients with erythema migrans or lyme arthritis. Arthritis Rheum 63:2238-47
Steere, Allen C; Drouin, Elise E; Glickstein, Lisa J (2011) Relationship between immunity to Borrelia burgdorferi outer-surface protein A (OspA) and Lyme arthritis. Clin Infect Dis 52 Suppl 3:s259-65
Strle, Klemen; Jones, Kathryn L; Drouin, Elise E et al. (2011) Borrelia burgdorferi RST1 (OspC type A) genotype is associated with greater inflammation and more severe Lyme disease. Am J Pathol 178:2726-39
Yakimchuk, Konstantin; Roura-Mir, Carme; Magalhaes, Kelly G et al. (2011) Borrelia burgdorferi infection regulates CD1 expression in human cells and tissues via IL1-?. Eur J Immunol 41:694-705

Showing the most recent 10 out of 88 publications