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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：
10541106
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541106
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 Cell secretion Cells Cellular Immunity Chronic Data Correlations Diagnosis Disease Endothelial Growth Factors Fc Receptor Fibroblasts Fibronectins Fibrosis Flow Cytometry Frequencies Grant Granzyme Humoral Immunities Hyperplasia IL17 gene IgG1 IgG2 IgG3 IgG4 Immune response Immunity Infection Infiltration Inflammation Inflammatory Inflammatory Arthritis Inflammatory Response Innate Immune Response Interferons Interleukin-10 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 Proliferating 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，莱姆关节炎 (LA) 的抗生素治疗结合宿主免疫结果螺旋体消除、组织修复和关节炎消退，称为抗生素反应性 LA。然而，尽管螺旋体被杀死，一些患者仍会出现炎症、增殖性疾病。抗生素治疗后持续数月至数年的滑膜炎，称为感染后（抗生素- 耐火）洛杉矶。这些患者的滑膜病变与其他形式的慢性病相似。炎症性关节炎，包括类风湿性关节炎。其核心特征是为感染后 LA 似乎是一种持续的、过度的促炎症反应， IFN-γ 水平异常高，超出了监管控制机制。在这些对于患者来说，持续的炎症会导致进一步的血管损伤、纤维化和自身免疫滑膜中的现象，如其他形式的慢性炎症关节炎中所见。我们已经展示了这种反应可能伴随着莱姆病（LD）相关的自身抗体，反应变得依赖于 T 细胞并具有潜在的致病性。在这些患者中，IgG4 滑液中的自身抗体，但不包括其他亚类的抗体，与特定的抗体相关滑膜病理学——闭塞性微血管病变和纤维化。此外，抹除血管表明细胞毒性免疫反应，我们最近的转录组学研究感染后的 LA 滑膜组织表现出强烈的细胞毒性基因特征，与 RA 相似。在这笔资助中，我们将使用“系统血清学”方法来了解疏螺旋体的功能伯氏 (Bb) 抗体和 LD 自身抗体通过描绘 Fc 受体结合、结合亲和力、Fc 聚糖、抗体依赖性吞噬作用和抗体依赖性细胞毒性对抗生素有反应的洛杉矶患者与感染后的洛杉矶患者。此外，我们将定义类型和外周血中具有细胞毒性和炎症潜力的淋巴细胞的频率使用流式细胞术对这两个患者组的滑液进行分析，并将进一步描绘通过单细胞 RNA 测序获得相关细胞毒性细胞的完整表型。我们将关联这些数据与血清和体内细胞因子、颗粒酶和穿孔素水平的测定有关通过 Luminex 测量这些患者的滑液。最后，我们将检查细胞毒性相关 T 细胞直接杀死靶细胞的潜力，以及通过评估效果间接杀死靶细胞的潜力细胞外细胞毒效应分子的作用。这项研究具有重大意义了解 LA 的发病机制并帮助诊断和治疗，更一般地说，如感染引起的慢性炎症关节炎的人类模型。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lyme Arthritis.

DOI：
10.1016/j.idc.2022.03.006
发表时间：
2022-09
期刊：
INFECTIOUS DISEASE CLINICS OF NORTH AMERICA
影响因子：
4.4
作者：
Arvikar, Sheila L.;Steere, Allen C.
通讯作者：
Steere, Allen C.

Heightened Proinflammatory Glycosylation of Borrelia burgdorferi IgG Antibodies in Synovial Fluid in Patients With Antibiotic-Refractory Lyme Arthritis.

抗生素难治性莱姆关节炎患者滑液中伯氏疏螺旋体 IgG 抗体的促炎糖基化增强。

DOI：
10.1002/art.42465
发表时间：
2023
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
0
作者：
Sanes,JurgenT;Costello,CatherineE;Steere,AllenC
通讯作者：
Steere,AllenC

Lyme arthritis: linking infection, inflammation and autoimmunity.

DOI：
10.1038/s41584-021-00648-5
发表时间：
2021-08
期刊：
Nature reviews. Rheumatology
影响因子：
0
作者：
通讯作者：

Identification of Novel, Immunogenic HLA-DR-Presented Prevotella copri Peptides in Patients With Rheumatoid Arthritis.

DOI：
10.1002/art.41807
发表时间：
2021-12
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
0
作者：
Pianta A;Chiumento G;Ramsden K;Wang Q;Strle K;Arvikar S;Costello CE;Steere AC
通讯作者：
Steere AC

Cell-Mediated Cytotoxicity in Lyme Arthritis.

莱姆关节炎中细胞介导的细胞毒性。

DOI：
10.1002/art.42408
发表时间：
2023
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
0
作者：
Ordóñez,David;Lochhead,RobertB;Strle,Klemen;Pianta,Annalisa;Arvikar,Sheila;VanRhijn,Ildiko;Stemmer-Rachamimov,Anat;Steere,AllenC
通讯作者：
Steere,AllenC