| Description |
Lyme disease is a tick borne spirochetosis with arthritis being the most common and characteristic clinical feature. Lyme arthritis in humans includes two subtypes: subacute, antibiotic-treatable arthritis, and chronic, antibiotic-resistant arthritis. Lipoproteins are abundantly expressed on the outer surface membrane of Borrelia burgdorferi, the agent of Lyme disease, and provide the major antigens for this bacterium. Toll-like receptor 2 (TLR2) and its adaptor molecule, myeloid differentiate factor 88 (MyD88), are the major receptor and signaling pathway, respectively, for lipoproteins. As expected, TLR2- or MyD88- deficient mice have defects in Borrelia clearance. Surprisingly, a more severe arthritis with relatively normal humoral responses was observed in these mutant mice. In this dissertation, the importance of TLR2 in the humoral response to lipoproteins, such as outer surface protein A (OspA), was investigated. Compared with wild-type mice, TLR2¯/¯ mice produced less antibodies, having a skewed isotype distribution. However, the protective properties of these antibodies were not altered. The adjuvant properties of Pam3Cys modification of bacterial lipoprotein were demonstrated to induce antibody responses independent of TLR2 signaling. The relative contributions of innate and adaptive host defense mechanisms to Lyme disease were also investigated using TLR2¯/¯/scid double-mutant mice. The innate immune response has the major responsibility for controlling B. burgdorferi in tissues at early time points after infection, while the importance of the adaptive immune response is greater later during infection, at 8 weeks. Interestingly, the increased arthritis severity of TLR2¯/¯ mice was found to be reduced by the presence of the scid mutation. In the final study, the enhanced arthritis in TLR2¯/¯ mice was found to be due to increased T cell infiltration in ankle tissues. The enhanced T cell response was not due to dysfunctional regulatory T (Treg) cells. Interestingly, IFN dependent T cell chemokines were increased in TLR2¯/¯ mice prior to T cell migration, suggesting an earlier and a more important role of IFNs than TLR2 signals in the pathogenesis of Lyme arthri |
