Borrelia burgdorferi-Induced Autoimmunity in Lyme Disease

这项资助旨在描述感染后莱姆病（LD）的自身免疫特征 综合征称为难治性莱姆病关节炎（LA），唯一的治疗后LD综合征 已经定义了特定的病理学。我们之前报道过， 炎症，Teff/Treg细胞比率的免疫失调，某些细胞因子的上调， microRNA和感染诱导的自身免疫是这种不良结果的特征。 此外，难治性LA的最大遗传危险因素是某些HLA-DR等位基因，我们认为， 已经鉴定出免疫原性HLA-DR呈递肽直接来自这些关节炎的滑膜组织， 患者以这种方式，我们已经证明了4种自身抗原，内皮细胞生长因子（ECGF）， MMP-10、apo B-100和膜联蛋白A2是T和B细胞应答的靶点， 有各种LD表现的患者;近一半的抗生素患者- 难治性LA具有对这些自身抗原中的一种或多种的自身抗体应答。基于RA- 在本研究中，我们报告了以下数据：难治性LA的滑膜病变具有高度的 炎症表达特征，包括与IFN-γ相关的基因的上调。 免疫应答，MHC II类抗原加工和呈递，细胞介导的细胞毒性，以及 细胞增殖我们现在提出，滑液成纤维细胞样滑液细胞（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），并且CD 4 + 具有细胞毒性潜能的T细胞可针对FLS。如目标1所述，我们有 在LA患者中鉴定了两种具有细胞毒性潜力的CD 4 + SLAMF 7 + T细胞，我们将 使用单细胞RNA-seq进一步确定它们的表型。在目标2中，我们将确定一个更大的 由专职APC或uAPC（FLS）呈递给CD 4 + T细胞的一系列HLA-DR肽， 我们将描述CD 4 + SLAMF 7 +T细胞与FLS在细胞内的分子相互作用， cultures.在目标3中，我们提出了初步数据，难治性LA中的自身抗体可能 参与了这个疾病的过程。在这些患者中，高水平的IgG 4自身抗体， ECGF、MMP-10和apoB-100均与显著的纤维化和闭塞性微血管相关。 滑膜组织损伤。我们将评估结合特征和聚糖 这些自身抗体的组成从抗炎转变为促炎 难治性患者的表型。最后，我们将确定自身抗体的效用 作为诊断平台的一部分，用于早期识别患有 适应不良的免疫反应，这可能允许早期治疗，以改善或预防这一点。 感染后综合症

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.