Lyme Disease is caused by infection with the tick-borne spirochete Borrelia burgdorferi, and results in arthritis in up to 60% of infected individual. Arthritis is characterized by obvious edema, inflammatory cell infiltration, synovial hyperplasia, and reactive/reparative changes in joint tissue, with the knee frequently involved. Most individuals respond to antibiotic therapy, eventually resolving symptoms of arthritis. Lyme arthritis has been frequently studied in C3H mice, where it reproducibly peaks by 4 wks. post infection in the rear ankle joint. An early spike in Type I IFN, localized to joint tissue at 1 wk.of infection, is associated with the subsequent severe disease in these mice, and is absent from infected B6 mice, which display mild disease. A small number of Lyme disease patients have been characterized whose symptoms persist for months, even after a course of antibiotics. These patients have been termed Post Treatment Lyme Disease Syndrome, PTLDS. In this enigmatic group of patients, symptoms remain in the absence of detectable B. burgdorferi. We have recently proposed the B6 IL-10-/- mouse as a model for PTLDS patients: arthritis is more severe than seen in infected wild type B6 mice and the localized inflammation persists for at least 14 wks. post infection, at which time spirochetes are no longer detectable in the joints. Arthritis development in the IL-10-/- mouse is dependent on localized production of IFN? (Type II IFN) by infiltrating NK cell and CD4+T cells. Local elevation in IFN? and recruitment of CD4+ T cells is also a consistent feature of PTLDS patients. A major question regarding the PTLDS patients is the nature of the T cell response in chronically inflamed joint tissue.
In Aim 1 we propose to use the B. burgdorferi infected B6 IL-10-/- mouse to address this issue. We will determine if the CD4+T cells infiltrating the joint tissue and draining lymph nodes represent bystander activation of T cells with multiple different TCR specificities (polyclonal activation), r if the CD4+T cells sustaining the arthritis represent B. burgdorferi-specific TCRs, with possible cross reactivity with self-antigens expressed in joint tissue. In the second Aim, we will pursue a new direction for the Lyme Disease field, the potential involvement of microRNAs in the regulation of the inflammatory response to B. burgdorferi infection. A preliminary microRNA screen has identified two microRNAs upregulated in the joint tissue following B. burgdorferi infection mice: miR-146a was upregulated in C3H, B6, and B6 IL-10-/- mice suggesting a general modulatory role, while miR-155 was selectively upregulated in joints of IL-10-/- mice suggesting an IL-10 dependent effect on Lyme arthritis.
In Aim 2, we propose to define the arthritis modulatory properties of miR- 146a and miR-155 in murine models of Lyme arthritis, using miR-146a-/- mice and miR155-/- mice. Preliminary studies suggest Lyme arthritis to be a versatile model for studying the in vivo role of microRNAs in inflammatory pathologies.
Lyme Disease is caused by the tick borne spirochete Borrelia burgdorferi, and is the most common vector borne disease in the United States. Inflammatory dysregulation is a key feature of Lyme Disease in both the severe, subacute disease and in more chronic inflammatory disease. This application proposes to characterize the nature of the T cell response to B. burgdorferi and the involvement of microRNAs in regulation of disease development, using mouse models of Lyme Disease.
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