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 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 been studied in mice, with severe disease reproducibly seen in C3H mice at 4 wks of infection, and mild to moderate disease found in C57BL/6 (B6) mice. Interestingly, arthritis in C3H mice is independent of effectors of the adaptive immune response. This is in contrast to numerous reports in patients identifying T cell responses in synovial fluids of arthritic joints. Interestinly, infection of B6 mice lacking IL-10 (B6 IL10-/-) have revealed a central role for CD4+ T cells in disease development, suggesting this mouse to be a useful model for study of arthritis-associated T cell responses in Lyme disease. Arthritis in B6 IL-10-/- mice is characterized by elevated production of cytokines (IFN?, IL-6 and IL1?) and chemokines (CXCL9 and CXCL10), which have also been identified in the synovial fluid of patients with chronic Lyme arthritis. The localized inflammatory response is sustained in IL-10-/- mice for at least 14 wks, when levels of B. burgdorferi are no longer detected. Arthritis development in the IL-10-/- mouse is dependent on localized production of IFN? by infiltrating NK cells and CD4+T cells, while mild arthritis in B mice reflects local production of IL-10 by CD4+ T cells and macrophages. We propose that the comparison of B6 and IL-10-/- mice will allow assessment of protective and disease potentiating T cell responses in early and chronic Lyme disease, which has not been previously exploited.
In Aim 1 we will assess functional properties of antigen-specific and bystander-activated T cells from B. burgdorferi-infected IL-10-/- and B6 mice. Cytokine production, TCR V? usage, and dependence on TLR2 will be assessed, and bystander vs. antigen specific responses tested with TCR transgenic mice.
In Aim 2 we will pursue a new direction for the Lyme disease field, the potential involvement of the NF-?B dependent microRNA, miR-146a, in the regulation of the inflammatory response to B. burgdorferi. miR-146a provides feedback of NF-?B responses by targeting key components of the signaling pathway, and is upregulated in B. burgdorferi infected mice. Previous studies with MyD88 and TLR2 deficient mice failed to reveal a role for NF-?B-dependent responses in arthritis development, however, host defense was severely compromised. Our preliminary studies suggest the miR-146a-/- mouse may provide an excellent opportunity to assess the pro-arthritic arm of NF-?B responses in the absence of its normal feedback.
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.
|Pioli, Peter D; Whiteside, Sarah K; Weis, Janis J et al. (2016) Snai2 and Snai3 transcriptionally regulate cellular fitness and functionality of T cell lineages through distinct gene programs. Immunobiology 221:618-33|
|Lochhead, Robert B; Zachary, James F; Dalla Rosa, Luciana et al. (2015) Antagonistic Interplay between MicroRNA-155 and IL-10 during Lyme Carditis and Arthritis. PLoS One 10:e0135142|
|Pioli, Peter D; Chen, Xinjian; Weis, Janis J et al. (2015) Fatal autoimmunity results from the conditional deletion of Snai2 and Snai3. Cell Immunol 295:1-18|
|Bramwell, Kenneth K C; Mock, Kelton; Ma, Ying et al. (2015) Î²-Glucuronidase, a Regulator of Lyme Arthritis Severity, Modulates Lysosomal Trafficking and MMP-9 Secretion in Response to Inflammatory Stimuli. J Immunol 195:1647-56|
|Bramwell, Kenneth K C; Ma, Ying; Weis, John H et al. (2014) Lysosomal *-glucuronidase regulates Lyme and rheumatoid arthritis severity. J Clin Invest 124:311-20|
|Lochhead, Robert B; Ma, Ying; Zachary, James F et al. (2014) MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi. PLoS Pathog 10:e1004212|
|Ma, Ying; Bramwell, Kenneth K C; Lochhead, Robert B et al. (2014) Borrelia burgdorferi arthritis-associated locus Bbaa1 regulates Lyme arthritis and K/BÃ—N serum transfer arthritis through intrinsic control of type I IFN production. J Immunol 193:6050-60|
|Donius, Luke R; Orlando, Christopher M; Weis, Janis J et al. (2014) Generation of a novel Cr2 gene allele by homologous recombination that abrogates production of Cr2 but is sufficient for expression of Cr1. Immunobiology 219:53-63|
|Bramwell, Kenneth K C; Teuscher, Cory; Weis, Janis J (2014) Forward genetic approaches for elucidation of novel regulators of Lyme arthritis severity. Front Cell Infect Microbiol 4:76|
|Donius, Luke R; Weis, Janis J; Weis, John H (2014) Murine complement receptor 1 is required for germinal center B cell maintenance but not initiation. Immunobiology 219:440-9|
Showing the most recent 10 out of 78 publications