Cellular and humoral immunity in Lyme arthritis

在大多数患者中，莱姆关节炎(LA)的抗生素治疗与宿主免疫结果相结合 在消除螺旋体、组织修复和解决关节炎方面，称为抗生素反应性LA。 然而，尽管螺旋体被杀死，但一些患者发展为炎症性、增殖性 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- 耐火材料)洛杉矶。这些患者的滑膜损害与其他形式的慢性滑膜病变相似。 炎性关节炎，包括类风湿性关节炎。设置舞台的主要特点是 感染后LA似乎是一种持续的、过度的促炎反应， 异常高的干扰素-水平，压倒了监管机制。在这些 患者持续的炎症导致进一步的血管损伤、纤维化和自身免疫。 滑液中的现象，如在其他形式的慢性炎症性关节炎中所见。我们已经展示了 这种反应可能伴随着莱姆病(LD)相关的自身抗体， 依赖T细胞并可能致病的反应。在这些患者中，IgG4 滑液中的自身抗体，而不是其他亚类的抗体，与特异性 滑膜病理学：闭塞性微血管病变和纤维化。此外，抹去 血管提示细胞毒性免疫反应，我们最近的转录转录研究 感染后的LA滑膜组织表现出强烈的细胞毒基因特征，与RA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。 伯氏杆菌(BB)抗体和LD自身抗体通过Fc受体结合、结合 亲和力、Fc葡聚糖、抗体依赖的吞噬作用和抗体依赖的细胞毒作用 抗生素反应与感染后LA患者的对比。此外，我们将定义类型和 外周血和外周血中具有细胞毒性和炎症潜能的淋巴细胞频率 在这两组患者的滑液中进行流式细胞术，并将进一步描绘出 通过单细胞RNA测序获得相关细胞毒细胞的完整表型。我们将相互关联 这些数据与体内细胞因子、颗粒酶和穿孔素水平的测定有关 这些患者的滑液，用Luminex测量。最后，我们将检测细胞毒性 相关T细胞直接杀伤靶细胞的潜力，以及通过评估其效应间接杀伤靶细胞的潜力 细胞外细胞毒效应分子在细胞上的作用。这项研究对 了解LA的发病机制，有助于LA的诊断和治疗，更广泛地说，AS 感染诱导的慢性炎症性关节炎的人体模型。

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.