Auto-antibodies as predictive markers for Post treatment Lyme Disease Syndrome

摘要 伯氏疏螺旋体作为一种长期存在于其自然宿主中的生物体，其病原菌 莱姆病的代理人，已经采取了许多策略来生存和逃避宿主的免疫反应。它 基因组非常小，不能为自己产生许多必要的营养物质，相反，依赖于 从它的环境中利用它们。我们最近发现伯氏杆菌能够获得宿主 磷脂，并将它们完整地部署在其膜中。利用宿主磷脂的成本是它可以 导致产生或抑制针对宿主磷脂靶标的自身抗体。事实上，在我们的初选中 研究发现，感染伯氏杆菌的小鼠和人类会产生针对宿主磷脂的抗体。 生物体本身不会产生。抗磷脂抗体比其他抗B组抗体出现得快。 Burgdorferi和似乎也更快地解决，正如可能预期的那样，因为自身抗体的产生 通常受到严格的监管。然而，在PTLDS患者中，与解决了他们的 症状治疗莱姆病后，抗磷脂抗体水平似乎有所上升。它是 目前尚不清楚这些抗体可能是致病的，还是只是PTLDS的一个标志。 在这项建议中，我们将探讨抗脂/磷脂抗体在莱姆病和 它们在PTLDS中的潜在作用。在目标1中，我们将确定抗脂/磷脂的发展程度 疾病的不同阶段，并确定它们与疾病解决/持续症状的关系 莱姆病患者。在目标2中，我们将检查这些抗体与人类细胞和组织的结合。 并寻找免疫复合体的存在，这些免疫复合体通常在自身免疫性疾病中沉积。最后， 在目标3中，我们将探索一种新的PTLDS动物模型。最近的一项研究表明，注射抗体 从纤维肌痛患者，一种在症状上与PTLDS有显著相似之处的疾病，进入老鼠体内，结果是 对疼痛和寒冷以及运动能力的改变过敏。组织学研究表明， 人类对神经组织和巨噬细胞的抗体。我们将测试一个类似的模型，使用来自 PTLDS患者恢复莱姆病和纤维肌痛。在我们的初步研究中，我们发现 PTLDS患者的抗体与小鼠脑组织的结合比来自PTLDS患者的抗体更强 健康对照抗体。抗脂/磷脂自身抗体的发现开辟了一个新的领域 莱姆病发病机制的发现，并可能导致更好的诊断试验和新的 了解这种疾病的发病机制。

ABSTRACT As an organism that persists in its natural hosts for long periods of time, Borrelia burgdorferi, the causative agent of Lyme disease, has adapted many strategies for survival and evasion of host immune responses. It has a very small genome and is unable to produce many essential nutrients for itself and is instead, dependent upon utilizing them from its environment. We have recently shown that B. burgdorferi is able to acquire host phospholipids and deploy them, intact, in its membrane. A cost of utilizing host phospholipids is that it may result in production, or de-repression of autoantibodies to host phospholipid targets. Indeed, in our preliminary studies, we found that mice and humans infected with B. burgdorferi produce antibodies to host phospholipids that the organism itself does not produce. Antibodies to phospholipids arise quicker than other antibodies to B. burgdorferi and also appear to resolve more quickly, as might be expected since autoantibody production is typically tightly regulated. However, in patients with PTLDS as compared with patients who resolve their symptoms after treatment for Lyme, there appears to be increased levels of anti-phospholipid antibodies. It is unknown whether these antibodies may be pathogenic or are just a marker for PTLDS. In this proposal, we will explore the development of anti-lipid/phospholipid antibodies during Lyme disease and their potential role in PTLDS. In Aim 1, we will determine the extent of anti-lipid/phospholipid development at different stages of disease and determine their relationship to disease resolution/persistent symptoms in patients with Lyme disease. In Aim 2, we will examine binding of these antibodies to human cells and tissues and look for the presence of immune complexes which are often deposited in auto-immune diseases. Finally, in Aim 3, we will explore a new animal model for PTLDS. A recent study has shown that injection of antibodies from patients with fibromyalgia, a disease with marked similarities to PTLDS in symptoms, into mice results in hypersensitivity to pain and cold as well as changes in locomotion. Histological studies have shown binding of the human antibodies to neural tissues and macrophages. We will test a similar model using serum from patients with PTLDS, recovered Lyme disease and fibromyalgia. In our preliminary studies, we have found increased binding of antibodies from PTLDS patients to mouse brain tissue compared with binding from healthy control antibodies. The discovery of autoantibodies to lipids/phospholipids opens a new area for discovery in the pathogenesis for Lyme disease and may lead to better diagnostic tests and a new understanding of the pathogenesis of this disease.