Neutrophil heterogeneity in anti-neutrophil cytoplasm antibody associated vasculitis

ANCA相关性血管炎（AAV）是一种自身免疫性疾病。当我们的免疫系统通常对抗感染时，自身免疫就会发生，而不是将我们自己身体的一部分识别为“外来”而不是“自我”。在AAV中，这导致小血管的炎症，称为血管炎。身体许多不同部位的血管都可能受到影响，包括肠道、皮肤、神经、肺和肾脏。由于肺部严重出血或肾脏炎症，这种情况往往危及生命。即使接受治疗，患者也可能发生肾衰竭，需要长期透析治疗。我们知道中性粒细胞（一种白色血细胞）在AAV中非常重要。AAV患者产生抗体，称为ANCA，激活中性粒细胞，导致它们破坏血管。直到最近，中性粒细胞被认为是一种简单的细胞类型，寿命短，唯一的目的是对抗感染。然而，最近的研究表明，并不是所有的中性粒细胞都是相同的，可能有许多不同类型，具有不同的功能和目的。在我的初步研究中，我在未经治疗的AAV患者的血液中发现了不同类型的中性粒细胞，与健康个体的中性粒细胞相比，它们的外观和行为不同。然而，目前尚不清楚是什么原因导致这些细胞在AAV患者中发育，或者它们是否在导致疾病中起重要作用。AAV是一种终身病症，并且该疾病及其治疗通常导致严重并发症的发展，如糖尿病，感染，癌症或心脏病。这种疾病对受影响患者的生活质量有重大影响，复发（成功治疗后疾病复发）是一个主要问题。患者已经确定，感觉就像他们在“刀刃”上，在继续免疫抑制治疗（具有潜在的严重风险，如感染或癌症）与放弃治疗的复发风险之间左右为难。一些患有AAV的患者比其他患者更容易复发，虽然我们不完全了解原因，但部分原因可能是由于不同类型的抗体（ANCA）引起的疾病。目前迫切需要针对AAV的更具体的治疗方法，并更好地了解为什么有些患者复发而另一些患者没有复发。我认为中性粒细胞亚型的差异可能解释了为什么不同ANCA的AAV患者的病情表现不同。在本研究中，我计划充分了解AAV中存在的不同类型的中性粒细胞，并将使用几种方法来做到这一点，包括基因分析，细胞表面蛋白质和物理特征细胞的生长与细胞的大小（例如大小、形状、硬度）有关，因为较硬的细胞更可能滞留在小血管中并损伤小血管。我将从血液中分离出患者的中性粒细胞，并研究它们的功能是否与健康的中性粒细胞不同，重点是细胞损伤血管的能力。使用组织（当患者进行活检以诊断血管炎时留下的组织），我将使用一种新技术，该技术允许我查看组织中存在的中性粒细胞的遗传组成。这将使我能够看到我在血液中识别的相同细胞是否存在于血管炎的炎症组织部位。最后，使用大鼠血管炎模型，我将调查是否直接针对中性粒细胞可能是一种有效的治疗血管炎。我最初的实验将集中在通过使组织变软来防止中性粒细胞滞留在组织中。我的目标是，通过显着提高我们对患者感染腺相关病毒的原因以及患者之间病情表现不同的原因的了解，我们将能够针对这些细胞，为患者提供更好的治疗，这些患者根据他们所拥有的腺相关病毒类型进行“个性化”。我希望这项工作将直接导致临床研究，有可能直接造福于患者。

ANCA associated vasculitis (AAV) is a type of autoimmune disease. Autoimmunity occurs when our immune system, which normally fights infection, instead recognises parts of our own bodies as 'foreign' instead of 'self'. In AAV this leads to inflammation of small blood vessels, known as vasculitis. Blood vessels in many different parts of the body can be affected, including the gut, skin, nerves, lung and kidneys. The condition is often life-threatening, due to severe bleeding in the lungs or inflammation of the kidneys. Even with treatment, patients may develop kidney failure requiring long-term dialysis treatment. We know that neutrophils (a type of white blood cell) are very important in AAV. Patients with AAV make antibodies, called ANCA, that activate neutrophils leading them to damage blood vessels. Until recently neutrophils were thought of as a simple cell type with a short life span and the sole purpose of fighting infection. However, recent research has shown that not all neutrophils are the same and there may be many different types with different functions and purpose. In my preliminary studies, I have found different types of neutrophil in the blood of patients with untreated AAV, that look and behave differently compared to neutrophils from healthy individuals. It is not clear, however, what causes these cells to develop in patients with AAV or if they have an important role in causing the disease. AAV is a life-long condition and both the disease and its treatment often lead to the development of significant complications such as diabetes, infection, cancer or heart disease. The condition has a significant impact on the quality of life of affected patients and relapse (return of the disease after successful treatment) is a major concern. Patients have identified that it feels like they are on a 'knife-edge', caught between continuing immunosuppressive treatment (with potentially serious risks such as infection or cancer) versus risk of relapse with weaning of treatment. Some patients with AAV are more likely to relapse than others and although we do not fully understand why, it may in part be due to different types of antibodies (ANCA) causing disease. There is an urgent need for more specific treatments for AAV and for a better understanding of why some patients relapse and others do not. I suggest that differences in neutrophil subtypes may explain why the condition behaves differently between patients with AAV with different ANCA.In this Fellowship, I plan to fully understand the different types of neutrophil present in AAV and will use several methods to do this, including analysis of genes, proteins on the cell surface, and physical features (e.g. size, shape, stiffness) as cells which are stiffer are more likely to become lodged in and damage small blood vessels. I will isolate patient neutrophils from blood and investigate if they function differently from healthy neutrophils focussing on the capacity of the cells to damage blood vessels. Using tissue (leftover from when patients have a biopsy to diagnose vasculitis) I will use a new technique which allows me to look at the genetic make-up of neutrophils present in the tissues. This will enable me to see if the same cells I identify in blood are present at tissue sites of inflammation in vasculitis. Finally using a rat model of vasculitis I will investigate whether targeting neutrophils directly might be an effective treatment for vasculitis. My initial experiments will focus on preventing neutrophils becoming lodged in tissues by making them softer. My aim is that by significantly increasing our understanding of why patients get AAV and why the condition behaves differently between patients we will be able to target these cells leading to better treatments for patients which are 'personalised' to the type of AAV they have. I hope that this work will directly lead on to clinical studies with the potential for direct benefit to patients.