Defining pathogenic B cell regulation and role in scleroderma-associated interstitial lung disease (SSc-ILD)

硬皮病(SSC)是一种严重的自身免疫性疾病，具有组织损伤导致过早死亡的高风险。它有三种主要的连锁异常：自身免疫、组织和器官的炎症和纤维化。这些器官包括血管、肺和心脏。这些器官受到影响的严重程度和程度因患者而异。值得注意的是，肺纤维化是这些患者中约50%的死亡原因。肺部受累与自身反应性B细胞产生的自身抗体类型密切相关。这两个中心的研究结果表明，患者无法清除这些自身反应的B淋巴细胞。最近的证据表明，靶向B淋巴细胞可以改善患者的预后，特别是那些受肺纤维化影响的患者，但这种治疗似乎只对一部分患者有利。现在出现了新的生物制剂(tocilizumab和rituximab)和抗纤维化药物(Inetedanib)，分别有利于疾病早期和晚期的肺纤维化患者。因此，我提出，在SSc中，推动肺纤维化的疾病特异性途径对于具有不同自身抗体特异性的患者和处于不同疾病阶段的患者是不同的。以此类推，阻断作为纤维化关键介质的高水平白介素6表达的特定B细胞的激活似乎在自身免疫性神经疾病(视神经脊髓炎)中是有益的，进一步支持了我在SSC作为抗体驱动疾病的建议策略。我将回顾UCL接受tocilizumab/rituximab治疗的患者组，以评估区分肺纤维化有效和无效的临床特征。这将帮助我确定患有肺纤维化的患者亚群，我将从他们那里获取血液样本，以分离使用tocilizumab/rituximab治疗前后的B细胞。然后，我将有机会在QMUL获得新的实验室技术，这些技术将提供令人兴奋的工具来评估血液中不同数量的B细胞。我建议使用的技术已经应用于类风湿性关节炎和多发性硬化症，取得了显着的成功。这是向前迈出的重要一步，因为这一现代科学方法的当前应用将允许在单细胞水平上研究B细胞的来源和对tocilizumab/rituximab治疗的反应的生物学特征。这将确定不同自身抗体亚型和疾病阶段的患者的不同类型的B细胞、抗体特征和这些细胞表达的关键介质，并进一步了解它们在SSC肺纤维化中的潜在重要性。通过对这些B细胞的分析，我希望识别出不同的细胞和抗体特征，以区分治疗前对生物制剂的临床应答者和无应答者。这些数据将被用来开发一个新的模型，以预测B细胞的反应如何影响总体疾病结局(特别是肺功能)，以及直接参与肺部疤痕形成过程的成纤维细胞等其他细胞类型。B细胞的详细特性和功能及其生物学特征的定义将促进更好的靶向治疗，并确定哪种新兴的B细胞导向疗法对个别患者的肺纤维化最有效，这将对精确医学产生未来的影响。考虑到SSc非常高的临床负担和当前对可用药物的反应变化，这是至关重要的。除了提供有关B细胞免疫学和对治疗的影响的信息外，这项研究还将对影响肺部的其他常见自身免疫性或纤维性疾病，包括特发性肺部疾病，B细胞可能以不同方式与驱动疾病的其他细胞类型相互作用，以及类似的研究或治疗方法可能适用。

Scleroderma (SSc) is a severe autoimmune disease with high risk of tissue damage leading to premature death. It has three main interlinking abnormalities: autoimmunity, inflammation and fibrosis of tissues and organs. These include blood vessels, lungs and the heart. The severity and extent to which these organs are affected vary among the patients. Notably, lung fibrosis contributes to the cause of death in approximately 50% of these patients. Involvement of the lung is strongly linked to the type of autoantibodies that are produced by autoreactive B cells. Findings from the two centres indicate that patients fail to purge these autoreactive B lymphocytes. Recent evidence suggests that targeting B lymphocytes improves patient outcome in particular those affected by lung fibrosis but it appears that this treatment only benefits a proportion of patients. There are now emerging biologic agents (tocilizumab and rituximab) and anti-fibrotic agents (nintedanib) that benefit patients with lung fibrosis at early and late stages of disease, respectively. I, therefore, propose that the disease-specific pathways that drive lung fibrosis in SSc differ for patients with different autoantibody specificities and at different stages of disease. By analogy, blocking the activation of specific B cells that express high levels of interleukin-6 as a key mediator of fibrosis appear to be beneficial in an autoimmune neurological condition (neuromyelitis optica) further supporting my proposed strategy in SSc as an antibody-driven disease. I will review patient groups at UCL that are treated with tocilizumab/rituximab to assess clinical characteristics that distinguish responders from non-responders for lung fibrosis. This will help me identify patient subgroups with lung fibrosis from whom I will obtain blood samples to isolate B cells before and after treatment with tocilizumab/rituximab. I will then have access to new laboratory techniques at QMUL that will provide exciting tools to evaluate the different populations of B cells in the bloods. The technique I propose to use has already been applied in rheumatoid arthritis and multiple sclerosis with remarkable success. This is a major step forward because this present application with modern scientific approaches will allow B cells to be studied at single cells levels for their origin and biological signatures in response to tocilizumab/rituximab treatment. This will define the distinct types of B cells, antibody signatures and the key mediators expressed by these cells from patients with different autoantibody subtypes and stage of disease, and further understanding of their potential importance in SSc lung fibrosis. From the analysis of these B cells, I expect to identify distinct cellular and antibody signature that will distinguish clinical responders from non-responders to the biologic agents pre-treatment. The data will be used to develop a new model to predict how B cells responses impact on overall disease outcome (specifically lung function) and on other cell types like fibroblasts that are directly involved in the scarring process in the lungs. Definition of the detailed properties and functions of B cells and their biologic signatures will have future implications in precision medicine by facilitating better targeted treatments and determine which of the emerging B cell-directed therapies for SSc will work best for lung fibrosis for an individual patient. This is vital considering the very high clinical burden of SSc and current variations in response to available drugs. As well as providing information about B cell immunology and impact on treatments, this study will also have wider implications on other common autoimmune or fibrotic diseases affecting the lungs including idiopathic pulmonary disease where B cells may interact in different ways with other cell types driving the disease, and that similar investigative or therapeutic approaches may be applicable.