Modulating Metabolic Programming of Memory B cell Activation to Restore B-cell Homeostasis in Autoimmune Disease

在许多细胞类型中，外部触发器与细胞上称为受体的特定蛋白质相互作用，驱动细胞发育，并采用不同的方式来满足细胞发育的需要。一种被称为B细胞或B淋巴细胞的白细胞对我们的免疫系统至关重要。B细胞在其表面表达一种被称为B细胞受体的蛋白质。B细胞受体专门识别外来蛋白质，以促进我们对细菌和病毒的免疫防御，也是对疫苗接种的反应。尚未接触过外源蛋白的B细胞被称为幼稚B细胞，那些之前接触过外源蛋白的B细胞被称为Memory B细胞，它们会发育成浆细胞，产生抗体，从而针对细菌和病毒上表达的外源蛋白。然而，与幼稚的B细胞相比，我们不知道一些记忆B细胞是如何对外部触发快速反应的。在自身免疫性疾病中，记忆B细胞的比例较大，如类风湿性关节炎和系统性红斑狼疮，也称为狼疮或系统性红斑狼疮，特别是在疾病活动期。更好地了解B细胞如何使用B细胞受体信号来适应成功的发育，可能有助于我们开发治疗方法来关闭B细胞的激活，而不损害在需要时开启的能力，例如，对抗感染。为此，了解B细胞如何通过B细胞受体将激活信号转化为记忆性B细胞和浆细胞是很重要的。我们知道，在激活状态下，B细胞使用特定的酶来满足对能量的需求，并为细胞发育产生积木，以下称为新陈代谢。相比之下，未被激活的B细胞维持着不同的新陈代谢程序。尽管幼稚B细胞和记忆B细胞都表达B细胞受体，但目前我们还不清楚两者在激活方面的差异。因此，该提议旨在验证B细胞受体可能招募其他蛋白质来协调不同结果以应对外部触发的假设。我与阿克巴教授在伦敦大学学院的团队合作开发的初步工作表明，与幼稚的B细胞相比，记忆B细胞在将B细胞受体信号转化为细胞发育的成功代谢程序方面更有效。此外，记忆B细胞表达与B细胞受体协同作用的细胞表面蛋白。我们能够在从健康人和少数狼疮患者的新鲜血液样本中分离出的B细胞中显示这些效应。阿克巴尔教授的团队最近报告称，一种名为Sestrins的蛋白质调节一种密切相关的白细胞或淋巴细胞(即T细胞)的代谢编程，从而调节一种特定类型T细胞的功能。然而，到目前为止，我们还不知道Sestrins在B细胞中的作用。我与阿克巴教授的团队合作的初步数据显示，在健康人的血液样本中，表达类似于抗体分泌浆细胞的更高水平蛋白质的记忆B细胞也具有更高的酶活性，有可能满足细胞对能量的需求，并为细胞发育提供基础。Sestrins在记忆B细胞中也有表达，但在幼稚B细胞中不表达。我们知道Sestrins是在应对压力时表达的。因此，幼稚细胞和记忆B细胞在Sestrin表达上的差异可能与记忆B细胞在激活时所使用的代谢应激或程序有关。我们现在想在狼疮患者的样本中进行实验，以了解干扰这一途径是否有助于我们更好地靶向B细胞，以更好地控制B细胞图谱的变化，以改善狼疮等自身免疫性疾病患者的预后。

In many cell types outside triggers interact with specific proteins on the cells known as receptors to drive the cells to develop and adopt different ways to meet the cellular needs for development. A type of white blood cell known as B cell or B lymphocyte is critical to our immune system. B cell expresses a protein on its surface known as B cell receptor. B cell receptors specifically recognise foreign proteins to promote our immune defense against bacteria and viruses and also in response to vaccination. B cells that have not yet come in contact with a foreign protein are known as naïve B cells and those that had prior exposure are known as memory B cells, which develop into plasma cells that make proteins known as antibodies to target the foreign proteins expressed on bacteria and viruses. However, we do not know how some memory B cells, compared to naïve B cells, are able to respond rapidly to external triggers. A greater proportion of memory B cells are noted in 'Autoimmune Disease' as Rheumatoid Arthritis and Systemic Lupus Erythematosus, also known as Lupus or SLE, particularly during periods of active disease. A better understanding of how B cells use the B cell receptor signal to adapt for successful development may help us to develop treatment to switch off B cell activation without compromising the ability to switch on at times of need, for example, to fight infections.To this end, it is important to understand how B cells turn the activation signal via the B cell receptor toward successful development into memory B cells and plasma cells. We know that during a state of activation B cells employ specific enzymes to meet the demands on energy and also to generate building blocks for cell development, referred to hereafter as metabolism. In contrast, B cells that are not activated maintain a different program of metabolism. As yet we do not understand the disparity in activation of naïve B cells and memory B cells despite both expressing B cell receptors. Therefore, the proposal seeks to test the hypothesis that the B cell receptors may recruit other proteins to orchestrate different outcomes in response to external triggers.My preliminary work developed in collaboration with Prof Akbar's group based at University College London suggests that, compared to naïve B cells, memory B cells are more efficient at turning B cell receptor signal into successful metabolic program for cell development. Further, memory B cells express cell surface proteins that co-operate with the B cell receptor. We are able to show these effects in B cells isolated from freshly drawn blood samples from healthy people and also from a small number of people with Lupus. Prof Akbar's group has recently reported that proteins known as sestrins regulate metabolic programming in a closely related type of white blood cell or lymphocyte known as T cell, consequently, the function of a specific type of T cell. However, as yet we do not know the role of sestrins in B cells. My preliminary data in collaboration with Prof Akbar's group showed that, in blood samples from healthy people, memory B cells that express higher level of proteins similar to antibody secreting plasma cells also had higher activity of enzymes with the potential to serve the cellular demands for energy and building blocks for cell development. Sestrins were also expressed in memory B cells, but not in naïve B cells. We know that sestrins are expressed in response to stress. Therefore, the discrepancy in sestrin expression between naïve and memory B cells is likely related to the metabolic stress or program that memory B cells employ upon activation. We would now like to perform experiments in samples from people with Lupus to understand whether disturbing this pathway may help our efforts to better target B cells to better control the alterations in B-cell profile to improve outcomes for people with autoimmune disease such as Lupus.