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：
10656441
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10656441
关键词：
Aftercare Animal Model Anti-Inflammatory Agents Antibiotic Therapy Area Arthritis Bell Palsy Borrelia burgdorferi CD8-Positive T-Lymphocytes Carditis 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 Post Treatment Lyme Disease Syndrome Process Production Role Signal Transduction Site Symptoms 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 transmission process

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.

项目摘要/摘要由tick传播的病原体Borrelia burgdorferi引起的莱姆病估计是负责美国每年300,000个新案件。疾病表现包括在该部位的皮肤病变 tick咬，然后是传播症状，包括继发性皮肤病变，关节炎，贝尔的麻痹，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，尤其是在感染早期开始的情况下，多达20％的患者返回延迟正常健康。抗生素治疗后症状的这种持久性称为治疗后莱姆疾病症状，PTLD和包括传播症状，包括神经系统异常，疲劳和关节炎。尚不理解持续符号的基本机制，是积极投资。假设包括持久螺旋体的存在，促炎的存在细菌碎片，抗炎过程的失调以及自身反应性B和T的出现淋巴细胞。缺乏易于操纵的动物模型对慢性疾病的了解有限。使用IL-10缺陷小鼠作为关节疾病的模型，在免疫介导后持续存在清除伯格多菲利（B. burgdorferi），我们已经确定了驱动IFN的T淋巴细胞的旁观者激活依赖性关节炎。 T细胞的旁观者激活与经典的MHC-TCR参与无关，但取决于T细胞的固有表达TLR2。我们还发现PTLD患者升高与返回的患者相比正常健康。我们将扩大小鼠旁观者激活的T细胞的分子表征，患者以确定治疗干预的新靶标。这些将在IL-10 - / - 模型中进行测试慢性莱姆病。初步研究表明，TLR2的短期靶向是潜在的治疗莱姆关节炎。研究的总体目的是确定针对慢性莱姆病的新型治疗方法不妥善激活的T细胞而没有损害宿主防御。

项目成果

期刊论文数量（85）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fetal outcome in murine Lyme disease.

小鼠莱姆病的胎儿结局。

DOI：
10.1128/iai.63.1.66-72.1995
发表时间：
1995
期刊：
Infection and immunity
影响因子：
3.1
作者：
Silver,RM;Yang,L;Daynes,RA;Branch,DW;Salafia,CM;Weis,JJ
通讯作者：
Weis,JJ

Polymerase chain reaction detection of Lyme disease: correlation with clinical manifestations and serologic responses.

莱姆病的聚合酶链反应检测：与临床表现和血清学反应的相关性。

DOI：
10.1093/ajcp/105.5.647
发表时间：
1996
期刊：
American journal of clinical pathology
影响因子：
3.5
作者：
Mouritsen,CL;Wittwer,CT;Litwin,CM;Yang,L;Weis,JJ;Martins,TB;Jaskowski,TD;Hill,HR
通讯作者：
Hill,HR

Quantification of low-copy transcripts by continuous SYBR Green I monitoring during amplification.