Cellular and humoral immunity in Lyme arthritis

莱姆关节炎的细胞和体液免疫

• 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
• 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

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，莱姆病关节炎（LA）的抗生素治疗结合宿主免疫结果 在螺旋体消除、组织修复和关节炎消退中，称为抗血小板反应性LA。 然而，尽管螺旋体杀死，一些患者发展成炎性、增殖性和/或炎症性疾病。 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- 难治性）LA。这些患者的滑膜病变与其他形式的慢性滑膜炎相似， 炎症性关节炎，包括类风湿性关节炎。在设置舞台的中心特征， 感染后LA似乎是一种持续的、过度的促炎反应， 异常高水平的IFN-γ，这干扰了调节控制机制。在这些 在患者中，持续的炎症导致进一步的血管损伤、纤维化和自身免疫性疾病。 滑膜中的现象，如在其他形式的慢性炎症性关节炎中所见。我们已经表明 这种反应可能伴随着莱姆病（LD）相关的自身抗体， 这种反应变得依赖于T细胞并具有潜在的致病性。在这些患者中，IgG 4 滑液中的自身抗体，而不是其他亚型的抗体，与特异性 滑膜病理学-闭塞性微血管病变和纤维化。此外， 血管提示细胞毒性免疫反应，我们最近的转录组学研究表明， 感染后的LA滑膜组织显示出强的细胞毒性基因特征，与RA中的相似。 在这项资助中，我们将使用“系统血清学”的方法来了解疏螺旋体的功能 通过描述Fc受体结合、结合抗体和LD自身抗体， 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， 免疫应答vs.感染后LA患者。此外，我们将定义类型， 外周血中具有细胞毒性和炎症潜能的淋巴细胞的频率， 使用流式细胞术检测这两个患者组中的滑液，并将进一步描述 通过单细胞RNA测序确定涉及的细胞毒性细胞的完整表型。我们将把 这些数据与体内血清中细胞因子、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 直接杀伤靶细胞和通过评估效应间接杀伤靶细胞的潜能 细胞外的细胞毒性效应分子。这项研究对以下方面具有重要意义： 了解LA的发病机制并帮助诊断和治疗，更一般地说， 感染诱导的慢性炎性关节炎的人类模型。

项目成果

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.)
• 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

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.)
• 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

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.)
• 作者: Pianta A;Chiumento G;Ramsden K;Wang Q;Strle K;Arvikar S;Costello CE;Steere AC
• 通讯作者: Steere AC