权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cellular and humoral immunity in Lyme arthritis

莱姆关节炎的细胞和体液免疫

基本信息

批准号：
10317057
负责人：
ALLEN C STEERE
金额：
$ 58.28万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-08 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317057
关键词：
Affinity Annexins Anti-Inflammatory Agents Antibiotic Therapy Antibiotics Antibodies Antibody Response Arthritis Autoantibodies Autoantigens Autoimmune Autoimmune Diseases B-Lymphocytes Binding Biological Assay Blood Vessels Borrelia burgdorferi CD8-Positive T-Lymphocytes Cells Cellular Immunity Chronic Cytotoxic T-Lymphocytes Data Diagnosis Disease Endothelial Growth Factors Fc Receptor Fibroblasts Fibronectins Fibrosis Flow Cytometry Frequencies Grant Granzyme Humoral Immunities Hyperplasia IgG1 IgG2 IgG3 IgG4 Immune response Immunity Infection Inflammation Inflammatory Inflammatory Arthritis Inflammatory Response Innate Immune Response Interferons Interleukin-10 Interleukin-17 Laminin Lesion Lyme Arthritis Lyme Disease Lymphocyte Malignant Neoplasms Measures Mononuclear Natural Killer Cells Order Spirochaetales Pathogenesis Pathogenicity Pathology Patients Peripheral Blood Mononuclear Cell Phagocytosis Phenotype Play Polysaccharides Population Property Proteins Refractory Regulatory T-Lymphocyte Research Resolution Rheumatoid Arthritis Role Serology Serum Synovial Fluid Synovitis System T-Lymphocyte Th1 Cells Tissues Vascular Proliferation antibody-dependent cell cytotoxicity apolipoprotein B-100 cytokine cytotoxic cytotoxicity extracellular genetic signature human model in vivo insight joint infection neoplastic cell neutrophil novel perforin peripheral blood receptor binding repaired response single-cell RNA sequencing stromelysin 2 tissue repair transcriptomics

项目摘要

In most patients, antibiotic treatment of Lyme arthritis (LA) combined with host immunity results in spirochetal elimination, tissue repair and resolution of arthritis, called antibiotic-responsive LA. However, despite spirochetal killing, some patients develop an inflammatory, proliferative synovitis lasting months to several years after antibiotic therapy, called post-infectious (antibiotic- refractory) LA. The synovial lesion in these patients is similar with that in other forms of chronic inflammatory arthritis, including rheumatoid arthritis. The central feature in setting the stage for post-infectious LA seems to be a sustained, excessive pro-inflammatory response, with exceptionally high levels of IFN-, which overwhelms regulatory control mechanisms. In these patients, persistent inflammation leads to further vascular damage, fibrosis, and autoimmune phenomena in synovia, as seen in other forms of chronic inflammatory arthritis. We have shown that this response may be accompanied by Lyme disease (LD)-associated autoantibodies, a response that becomes T cell dependent and potentially pathogenic. In these patients, IgG4 autoantibodies in synovial fluid, but not antibodies of other subclasses, correlate with specific synovial pathology – obliterative microvascular lesions and fibrosis. Moreover, obliteration of blood vessels suggests cytotoxic immune responses, and our recent transcriptomic studies of post-infectious LA synovial tissue show a strong cytotoxic gene signature, similar with that in RA. In this grant, we will use a “systems serology” approach to understand functions of Borrelia burgdorferi (Bb) antibodies and LD autoantibodies by delineating Fc receptor binding, binding affinity, Fc glycans, antibody-dependent phagocytosis and antibody-dependent cytotoxicity in antibiotic-responsive vs. post-infectious LA patients. In addition, we will define the types and frequencies of lymphocytes with cytotoxic and inflammatory potential in peripheral blood and synovial fluid in these two patient groups using flow cytometry, and will further delineate the complete phenotype of implicated cytotoxic cells by single-cell RNA-sequencing. We will correlate these data with determinations of cytokine, granzyme, and perforin levels in vivo in serum and synovial fluid of these patients, as measured by Luminex. Finally, we will examine the cytotoxic potential of implicated T cells in directly killing target cells, and indirectly by asessing the effects of extracellular cytotoxic effector molecules on cells. This research has significant implications for understanding pathogenesis and aiding in diagnosis and treatment of LA, and more generally, as a human model of infection-induced chronic inflammatory arthritis.

在大多数患者中，抗生素治疗莱姆病（LA）结合宿主免疫效果