Borrelia burgdorferi-Induced Autoimmunity in Lyme Disease

伯氏疏螺旋体诱导的莱姆病自身免疫

基本信息

批准号：
9757687
负责人：
ALLEN C STEERE
金额：
$ 50.39万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757687
关键词：
Aftercare Alleles Annexins Anti-inflammatory Antibiotic Therapy Antibiotics Antibodies Antigen Presentation Antigen Presentation Pathway Antigen-Presenting Cells Antigens Autoantibodies Autoantigens Autoimmune Process Autoimmunity B-Lymphocytes Binding Blood Vessels Borrelia burgdorferi CD4 Positive T Lymphocytes Cell Culture Techniques Cell Proliferation Cell-Mediated Cytolysis Cells Characteristics Clinical Cytotoxic T-Lymphocytes Data Data Reporting Diagnostic Disease Early identification Early treatment Endothelial Cells Environment Eragrostis Fibroblast Growth Factor Fibroblasts Fibrosis Gene Expression Profile Gene Expression Regulation Goals Grant Granzyme HLA-DR Antigens Histocompatibility Antigens Class II IgG4 Immune Immune response Immunoglobulin G Infection Inflammation Inflammatory Interferons Interleukin-10 Lesion Link Lyme Arthritis Lyme Disease MicroRNAs Outcome Pathogenesis Pathology Patients Peptides Peripheral Blood Mononuclear Cell Phenotype Polysaccharides Population Process Proliferating Proteins Refractory Regulatory T-Lymphocyte Reporting Shapes Signs and Symptoms Source Specificity Syndrome Synovitis T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Th1 Cells Tissue Sample Tissues To autoantigen Translational Research Up-Regulation apolipoprotein B-100 base cytokine cytotoxic effective therapy erythema migrans genetic risk factor immunogenic immunogenicity innovation maltreatment novel overtreatment patient subsets prevent response single-cell RNA sequencing stromelysin 2 transcriptome sequencing tumor

项目摘要

This grant seeks to characterize autoimmune features of a post-infectious Lyme disease (LD) syndrome called antibiotic-refractory Lyme arthritis (LA), the only post-treatment LD syndrome for which a specific pathology has been defined. We have previously reported that excessive inflammation, immune dysregulation of the Teff/Treg cell ratio, up-regulation of certain microRNAs, and infection-induced autoimmunity are features of this untoward outcome. Moreover, the greatest genetic risk factor for refractory LA is certain HLA-DR alleles, and we have identified immunogenic HLA-DR-presented peptides directly from synovial tissue in these patients. In this way, we have shown that 4 autoantigens, endothelial cell growth factor (ECGF), MMP-10, apoB-100, and annexin A2, are targets of T and B cell responses in subsets of patients with each of the manifestations of LD; and nearly half of patients with antibiotic- refractory LA have autoantibody responses to 1 or more of these autoantigens. Based on RA- seq data, we report in this grant that the synovial lesion in refractory LA has a highly inflammatory expression signature, which includes up-regulation of genes associated with IFN- -responses, MHC class II antigen processing and presentation, cell-mediated cytotoxicity, and cell proliferation. We now propose that synovial fibroblast-like synoviocytes (FLS), the most common cell in the lesion, become unconventional antigen presenting cells (uAPC), and CD4+ T cells with cytotoxic potential may be directed against FLS. As detailed in Aim 1, we have identified two types of CD4+ SLAMF7+ T cells with cytotoxic potential in LA patients, and we will further determine their phenotype using single-cell RNA-seq. In Aim 2, we will identify a greater range of HLA-DR-peptides presented to CD4+ T cells by professional APCs or uAPC (FLS), and we will delineate molecular interactions between CD4+SLAMF7+T cells and FLS in cell cultures. In Aim 3, we present preliminary data that autoantibodies in refractory LA may participate in this disease process. In these patients, high levels of IgG4 autoantibodies to ECGF, MMP-10 and apoB-100 each correlate with marked fibrosis and obliterative microvasular lesions in synovial tissue. We will assess whether the binding characteristics and glycan composition of these autoantibodies shift from an anti-inflammatory to a pro-inflammatory phenotype in refractory patients. Finally, we will determine the utility of autoantibody determinations as part of a diagnostic platform for early identification of patients with maladaptive immune responses, which may allow earlier therapy to ameliorate or prevent this post-infectious syndrome.

这笔赠款旨在描述感染后莱姆病（LD）的自身免疫特征称为抗生素难治性莱姆关节炎 (LA) 的综合征，是唯一的治疗后 LD 综合征我们之前已经报道过这种过度的特定病理学。炎症、Teff/Treg 细胞比例的免疫失调、某些细胞因子的上调 microRNA 和感染引起的自身免疫是这种不良结果的特征。此外，难治性 LA 的最大遗传风险因素是某些 HLA-DR 等位基因，我们已经鉴定出直接来自这些滑膜组织的免疫原性 HLA-DR 呈递肽通过这种方式，我们已经证明了4种自身抗原，内皮细胞生长因子（ECGF）， MMP-10、apoB-100 和膜联蛋白 A2 是 T 细胞和 B 细胞亚群反应的靶标具有每种 LD 表现的患者；并且近一半的患者使用抗生素基于RA-，难治性LA对这些自身抗原中的一种或多种具有自身抗体反应。 seq 数据，我们在本次资助中报告说，难治性 LA 中的滑膜病变具有高度炎症表达特征，包括与 IFN-相关基因的上调 γ-反应、MHC II 类抗原加工和呈递、细胞介导的细胞毒性以及我们现在提出滑膜成纤维细胞样滑膜细胞（FLS）是最重要的。病变中的常见细胞，成为非常规抗原呈递细胞（uAPC）和CD4+ 具有细胞毒性潜力的 T 细胞可能针对 FLS，如目标 1 中详述，我们有。在洛杉矶患者中鉴定出两种具有细胞毒性潜力的 CD4+ SLAMF7+ T 细胞，我们将使用单细胞 RNA 测序进一步确定它们的表型在目标 2 中，我们将鉴定出更大的表型。由专业 APC 或 uAPC (FLS) 呈递给 CD4+ T 细胞的一系列 HLA-DR 肽，我们将描述细胞中 CD4+SLAMF7+T 细胞与 FLS 之间的分子相互作用在目标 3 中，我们提供了难治性 LA 中自身抗体可能的初步数据。在这些患者中，高水平的 IgG4 自身抗体参与了这一疾病过程。 ECGF、MMP-10 和 apoB-100 均与明显的纤维化和闭塞性微血管相关我们将评估滑膜组织中的病变是否与聚糖结合。这些自身抗体的组成从抗炎性转变为促炎性最后，我们将确定自身抗体的效用。测定作为诊断平台的一部分，用于早期识别患者适应不良的免疫反应，这可能允许早期治疗改善或预防这种情况感染后综合症。