T cells predominate the immune responses in the synovial fluid of patients with persistent Lyme arthritis; however, their role in Lyme disease remains poorly defined. Using a murine model of persistent Lyme arthritis, we observed that bystander activation of CD4 and CD8 T cells leads to arthritis-promoting IFN-γ, similar to the inflammatory environment seen in the synovial tissue of patients with posttreatment Lyme disease. TCR transgenic mice containing monoclonal specificity toward non- epitopes confirmed that bystander T cell activation was responsible for disease development. The microbial pattern recognition receptor TLR2 was upregulated on T cells following infection, implicating it as marker of bystander T cell activation. In fact, T cell-intrinsic expression of TLR2 contributed to IFN-γ production and arthritis, providing a mechanism for microbial-induced bystander T cell activation during infection. The IL-10-deficient mouse reveals a novel TLR2-intrinsic role for T cells in Lyme arthritis, with potentially broad application to immune pathogenesis.

Previously, using a forward genetic approach we identified differential expression of type I IFN as a positional candidate for an expression quantitative trait locus (eQTL) underlying B. burgdorferi arthritis-associated locus 1 (Bbaa1). In this study, we show that mAb blockade revealed a unique role for IFN-β in Lyme arthritis development in B6.C3-Bbaa1 mice. Genetic control of IFN-β expression was also identified in bone marrow-derived macrophages stimulated with B. burgdorferi, and was responsible for feed-forward amplification of interferon-stimulated genes. Reciprocal radiation chimeras between B6.C3-Bbaa1 and B6 mice revealed that arthritis is initiated by radiation-sensitive cells, but orchestrated by radiation-resistant components of joint tissue. Advanced congenic lines were developed to reduce the physical size of the Bbaa1 interval, and confirmed the contribution of type I IFN genes to Lyme arthritis. RNA-seq of resident CD45− joint cells from advanced interval specific recombinant congenic lines identified myostatin as uniquely upregulated in association with Bbaa1 arthritis development, and myostatin expression was linked to IFN-β production. Inhibition of myostatin in vivo suppressed Lyme arthritis in the reduced interval Bbaa1 congenic mice, formally implicating myostatin as a novel downstream mediator of joint-specific inflammatory response to B. burgdorferi.

Anticoagulation therapy is widely used to reduce clotting during hemodialysis (HD), but may cause adverse effects in end‐stage kidney disease patients. A new hemodialyzer with a membrane modified by surface modifying molecule was developed to improve hemocompatibility that aimed to reduce the need for anticoagulation during dialysis treatments. We compared membrane surface characteristics and in vitro hemocompatibility of the new hemodialyzer to the standard polysulfone (PSF) hemodialyzer membrane. Scanning electron microscopy, contact angle measurement (68° ± 3° test vs. 41.6° ± 6° control), and X‐ray photoelectron spectrometry measurement for fluorine atomic % (7.4% ± 0.4% test vs. not detectable control), showed that the membrane surface was modified with surface modifying macromolecule (SMM1) but maintained membrane structure and surface hydrophilicity. Zeta potential of the blood‐contacting surface showed that the absolute surface charge was reduced at neutral pH (−3.3 mV ± 1.1 mV test vs. −15.6 mV ± 1.0 mV control). Platelet count reduction was significantly less for the SMM1‐modified dialyzer (40.88% ± 21.89%) compared to the standard PSF dialyzer (62.62% ± 34.13%), along with Platelet Factor 4 (1824.10 ng/ml ± 436.26 ng/ml test vs. 2479.00 ng/ml ± 852.96 ng/ml control). These studies demonstrate the successful incorporation of SMM1 into the new hemodialyzer with the expected results. Our in vitro experiments indicate that the SMM1‐modified hemodialyzers could improve hemocompatibility compared to standard PSF hemodialyzers and have the potential to minimize the patient's anticoagulant requirements during HD. Additional research with SMM1 additives incorporated into the entire dialysis circuit and use in a clinical settings are required to confirm these promising findings.

Infection with the bacteria Borrelia burgdorferi results in a multidimensional disease including, fever, headache, arthritis, and a characteristic skin rash. When left untreated, bacteria can disseminate to multiple parts of the body including joints, heart, and nervous system. Approximately 10–20% of patients treated with antibiotic therapy for Lyme disease will continue to have persistent symptoms for months or years. T cells predominate the immune response in the synovial fluid of these patients; however, their role in Lyme disease remains poorly defined. Using a murine model of persistent Lyme arthritis, we observed that bystander activation of CD4+ and CD8+ T cells leads to the secretion of arthritis-promoting IFN-γ, similar to the inflammatory environment seen in the synovial tissue of patients with post-treatment Lyme disease (PTLD). T cell receptor (TCR) transgenic mice containing monoclonal specificity towards non-Borrelia epitopes confirmed that bystander T cell activation was responsible for disease development. RNA-sequencing of bystander activated T cells provided insight into the molecular characteristics of non-classical T cell activation. The microbial pattern recognition receptor Toll-like receptor 2 (TLR2) was upregulated on T cells following infection, implicating it as marker of bystander T cell activation. In fact, T cell intrinsic expression of TLR2 contributed to IFN-γ production and arthritis, providing a mechanism for microbial-induced bystander T cell activation during infection. These results reveal a novel TLR2-intrinsic role for T cells in Lyme arthritis, with potentially broader application to bystander T cell activation and immune pathogenesis.