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的特定蛋白质（称为受体）相互作用，以驱动细胞发育并采用不同的方式满足细胞发育的需要。一种称为B细胞或B淋巴细胞的白色血细胞对我们的免疫系统至关重要。B细胞在其表面上表达一种称为B细胞受体的蛋白质。B细胞受体特异性识别外来蛋白质，以促进我们对细菌和病毒的免疫防御，并对疫苗接种做出反应。尚未与外源蛋白接触的B细胞被称为幼稚B细胞，先前接触过的称为记忆B细胞，它们发育成浆细胞，产生抗体蛋白，以靶向细菌和病毒上表达的外源蛋白。然而，我们不知道一些记忆B细胞，与幼稚的B细胞相比，如何能够快速响应外部触发。记忆B细胞在"自身免疫性疾病"如风湿性关节炎和系统性红斑狼疮（也称为狼疮或SLE）中的比例更大，特别是在活动性疾病期间。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关闭B细胞激活的治疗方法，而不会损害在需要时打开的能力，例如，对抗感染。重要的是理解B细胞如何通过B细胞受体将激活信号转向成功发育成记忆B细胞和浆细胞。我们知道，在活化状态下，B细胞使用特定的酶来满足能量需求，并产生细胞发育的构件，下文称为代谢。相反，未被激活的B细胞维持不同的代谢程序。尽管幼稚B细胞和记忆B细胞都表达B细胞受体，但到目前为止，我们还不了解它们在激活方面的差异。因此，该提案旨在验证B细胞受体可能会招募其他蛋白质来协调不同结果以响应外部触发的假设。我与伦敦大学学院Akbar教授的团队合作开展的初步工作表明，与幼稚B细胞相比，记忆B细胞更有效地将B细胞受体信号转化为细胞发育的成功代谢程序。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新鲜抽取的血液样本中分离的B细胞中显示这些作用。Akbar教授的研究小组最近报告说，被称为sestrin的蛋白质调节一种密切相关的白色血细胞或淋巴细胞（称为T细胞）的代谢程序，因此，调节一种特定类型T细胞的功能。然而，我们还不知道sestrins在B细胞中的作用。我与Akbar教授团队合作的初步数据显示，在健康人的血液样本中，表达更高水平蛋白质的记忆B细胞类似于抗体分泌浆细胞，也具有更高的酶活性，有可能满足细胞对能量的需求和细胞发育的基石。Sestrin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在应激反应中表达。因此，幼稚和记忆B细胞之间sestrin表达的差异可能与记忆B细胞在激活时采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细胞谱的改变，从而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.