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

调节记忆 B 细胞激活的代谢编程以恢复自身免疫性疾病中的 B 细胞稳态

• 批准号: MR/T024968/1
• 负责人: Venkat Reddy
• 金额: $ 33.49万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT024968%2F1
• 关键词: Modulating; Metabolic; Programming; Memory; cell

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.

在许多细胞类型中，外部触发器与称为受体的细胞上的特定蛋白质相互作用，以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，并对疫苗接种作出反应。尚未接触外源蛋白的B细胞称为naïve B细胞，先前接触过的B细胞称为记忆B细胞，它们发育成浆细胞，产生一种称为抗体的蛋白质，以细菌和病毒上表达的外源蛋白为目标。然而，我们不知道与naïve B细胞相比，一些记忆B细胞如何能够对外部触发因素做出快速反应。在类风湿关节炎和系统性红斑狼疮（也称为狼疮或SLE）等“自身免疫性疾病”中，尤其是在疾病活动期，记忆性B细胞的比例更高。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出一种治疗方法，在不影响B细胞在需要时（例如对抗感染）激活的能力的情况下，关闭B细胞的激活。为此，了解B细胞如何通过B细胞受体将激活信号转化为成功发育为记忆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，并为细胞发育产生基础物质，下文称为代谢。相反，未激活的B细胞维持着不同的代谢程序。尽管naïve B细胞和记忆B细胞都表达B细胞受体，但迄今为止我们还不了解两者在激活方面的差异。因此，该提案试图验证B细胞受体可能招募其他蛋白质来协调响应外部触发的不同结果的假设。我与位于伦敦大学学院的阿克巴教授小组合作开展的初步工作表明，与naïve 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细胞受体合作的细胞表面蛋白。我们能够在从健康人群和少数狼疮患者的新鲜血液样本中分离出的B细胞中显示这些效果。阿克巴教授的研究小组最近报告称，一种被称为sestrins的蛋白质调节着一种密切相关的白细胞或淋巴细胞（称为T细胞）的代谢程序，因此也控制着一种特定类型T细胞的功能。然而，到目前为止，我们还不知道凝集素在B细胞中的作用。我与阿克巴教授的研究小组合作的初步数据显示，在健康人的血液样本中，表达与抗体分泌浆细胞相似的更高水平蛋白质的记忆B细胞，也具有更高的酶活性，这些酶有可能满足细胞对能量的需求，并为细胞发育提供基础。Sestrins也在记忆B细胞中表达，但在naïve B细胞中不表达。我们知道应激因子是在应激反应中表达的。因此，naïve与记忆B细胞之间的sestrin表达差异可能与记忆B细胞激活时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，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。

项目成果

Variability in counselling for adrenal insufficiency in COVID-19 and beyond: a survey of rheumatology practice.

• DOI: 10.1016/s2665-9913(20)30389-1
• 发表时间: 2021-03
• 期刊: The Lancet. Rheumatology
• 作者: Mehta P;Meeran K;Macphie E;Abbas A;Rippin J;Jeffery RC;Reddy V;Leandro MJ;Ciurtin C;Simpson HL;Mackie SL
• 通讯作者: Mackie SL

P167 Overcoming rituximab resistance in autoimmune disease: back to basics

P167 克服自身免疫性疾病中的利妥昔单抗耐药性：回到基础

• DOI: 10.1093/rheumatology/kead104.208
• 发表时间: 2023
• 期刊: Rheumatology
• 影响因子: 5.5
• 作者: Shah K

Phenotyping of lymphoproliferative tumours generated in xenografts of non-small cell lung cancer

非小细胞肺癌异种移植物中产生的淋巴增殖性肿瘤的表型分析

• DOI: 10.1101/2023.01.24.520089
• 发表时间: 2023
• 作者: Pearce D

Disrupting B and T cell Collaboration in Autoimmune Disease: T cell engagers versus CAR T cell therapy?

破坏 B 细胞和 T 细胞在自身免疫性疾病中的合作：T 细胞接合剂与 CAR T 细胞疗法？

• DOI: 10.31219/osf.io/fv7mn
• 发表时间: 2023
• 作者: Shah K

AB0124 DIMETHYL FUMARATE MODULATES T CELL METABOLISM AND FUNCTION IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENT SAMPLES

AB0124 富马酸二甲酯调节系统性红斑狼疮患者样本中的 T 细胞代谢和功能

• DOI: 10.1136/annrheumdis-2023-eular.5460
• 发表时间: 2023
• 作者: Kell L