Borrelia burgdorferi mitogen in development of arthritis

伯氏疏螺旋体丝裂原在关节炎发展中的作用

基本信息

批准号：
10439655
负责人：
Janis J. Weis
金额：
$ 45.75万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-04-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439655
关键词：
Aftercare Animal Model Anti-Inflammatory Agents Antibiotic Therapy Area Arthritis B-Lymphocytes Bell Palsy Borrelia burgdorferi CD8-Positive T-Lymphocytes Carditis Centers for Disease Control and Prevention (U.S.)Chronic Chronic Disease Development Disease Encephalitis Fatigue Gene Expression Profile Genes Goals Health Host Defense Human Immune Individual Infection Inflammatory Interferons Interleukin-10 Investigation Ixodes Joints Lyme Arthritis Lyme Disease MHC Class I Genes Maintenance Mediating Meningitis Mitogens Modeling Molecular Mus Neurologic Order Spirochaetales Pathogenicity Pathway interactions Patients Peptides Peripheral Nervous System Diseases Process Production Role Signal Transduction Site Symptoms Syndrome T-Cell Activation T-Lymphocyte TLR2 gene Testing Therapeutic Therapeutic Intervention Ticks Tissues Transgenic Mice United States arthropathies autoreactivity cytokine experience extracellular in vitro Assay inhibitor mouse model new therapeutic target novel pathogen pathogenic bacteria peripheral blood response skin lesion targeted treatment therapeutic target tick bite tick transmission transcriptome transcriptome sequencing

项目摘要

Project Summary/Abstract Lyme disease, caused by the tick transmitted pathogen Borrelia burgdorferi, is estimated to be responsible for 300,000 new cases per year in the United States. Disease manifestations include a skin lesion at the site of the tick bite, followed by disseminated symptoms including secondary skin lesions, arthritis, Bell’s palsy, peripheral neuropathies, meningitis/encephalitis, and carditis. Most individuals respond to antibiotic treatment, particularly if started early in infection, however, up to 20% of patients experience a delay in the return to normal health. This persistence of symptoms following antibiotic treatment is termed post treatment Lyme disease symptoms, PTLDS, and encompasses disseminated symptoms including neurological abnormalities, fatigue, and arthritis. The underlying mechanism of sustained symptoms is not understood and is an area of active investigation. Hypotheses include presence of persister spirochetes, presence of pro-inflammatory bacterial fragments, dysregulation of anti-inflammatory processes, and emergence of auto-reactive B and T lymphocytes. The lack of easily manipulated animal model has limited understanding of chronic disease. Using the IL-10 deficient mouse as a model for joint disease that persists following immune-mediated clearance of B. burgdorferi, we have identified bystander activation of T lymphocytes that drive IFN dependent arthritis. Bystander activation of T cells is independent of classic MHC-TCR engagement, but dependent on T cell intrinsic expression of TLR2. We have also found that patients with PTLDS have elevated numbers of activated CD4+ and CD8+ T cells in their peripheral blood, when compared with patients who return to normal health. We will expand molecular characterization of bystander-activated T cells in mice and patients in order to identify novel targets for therapeutic intervention. These will be tested in the IL-10-/- model of chronic Lyme disease. Preliminary studies indicate short-term targeting of TLR2 is potential therapeutic for Lyme arthritis. The overall goal of study is to identify novel treatments for chronic Lyme disease that target inappropriately activated T cells without compromising host defense.

项目概要/摘要莱姆病是由蜱传播的病原体伯氏疏螺旋体引起的，估计是造成美国每年有 300,000 例新病例疾病表现包括局部皮肤病变。蜱虫叮咬后出现播散性症状，包括继发性皮肤损伤、关节炎、贝尔氏麻痹症、周围神经病、脑膜炎/脑炎和心脏炎大多数人对抗生素治疗有反应。然而，特别是如果在感染早期就开始治疗，多达 20% 的患者会出现恢复延迟的情况抗生素治疗后症状持续存在被称为治疗后莱姆病。疾病症状、PTLDS，并涵盖播散性症状，包括神经系统异常、持续症状的潜在机制尚不清楚，并且是一个领域。积极的研究包括存在持续性螺旋体、存在促炎性螺旋体。细菌碎片、抗炎过程失调以及自身反应性 B 和 T 的出现缺乏易于操作的动物模型限制了对慢性疾病的了解。使用 IL-10 缺陷小鼠作为免疫介导后持续存在的关节疾病模型为了清除伯氏疏螺旋体，我们发现了驱动 IFN 的 T 淋巴细胞的旁观者激活 T 细胞的旁观者激活独立于经典的 MHC-TCR 参与，但是依赖于 TLR2 的 T 细胞内在表达我们还发现 PTLDS 患者的 TLR2 表达升高。与返回的患者相比，外周血中活化的 CD4+ 和 CD8+ T 细胞数量我们将扩大小鼠中旁观者激活的 T 细胞的分子特征患者，以确定治疗干预的新靶标，这些将在 IL-10-/- 模型中进行测试。初步研究表明，短期靶向 TLR2 是治疗慢性莱姆病的潜在方法。莱姆关节炎研究的总体目标是寻找针对慢性莱姆病的新疗法。不当激活 T 细胞而不损害宿主防御。