Project 1

感染和疫苗接种后产生的抗体可以促进病原体的快速清除，如果 长时间使用，可以在再次暴露于相同或相关环境后提供保护 病原体然而，抗体也可能是有害的，如果针对错误的抗原或表位， 会导致而不是预防疾病病理性抗体最常在慢性炎症中观察到。 炎症性疾病，如自身免疫、过敏和器官移植。鉴于必须 抗体在促进健康和疾病方面的作用，有必要更好地了解 抗体分泌细胞（ASC）的维持。ASCs是终末分化的效应子， 成熟的幼稚和记忆B细胞池。虽然我们在对信号的理解上取得了很大的进步， 以及控制ASC从亲本幼稚和记忆B细胞发育的转录因子， 关于控制ASCs寿命的内在和外在因素，他们的研究非常少。在我们的初步调查中 我们的研究表明，特定的B细胞亚群分化为具有长期存活的ASCs的能力， 电位似乎是硬连线的，并限于记忆B细胞室，而不是幼稚B细胞 池我们鉴定了记忆B细胞的几个离散亚群，并表明这些记忆B细胞是不同的。 在它们的转录、表观遗传和代谢程序中表现出不同的功能能力。我们 鉴定了记忆B细胞的一个亚群（称为效应记忆B细胞），其在以下方面更类似于ASC： 它们的代谢潜力和表观遗传修饰剂如甲基化酶EZH 2和NAD依赖性的表达 脱乙酰酶SIRT 1。我们发现效应记忆B细胞比其他细胞更快地分化为ASCs。 记忆子集此外，来自效应记忆B细胞的ASC具有独特的能力， 在支持性微环境中培养时存活数周。最后，我们发现ASC存活率 高度依赖于新NAD代谢和阻断维生素B3指导的NAD生物合成的药物 将消融自身免疫和慢性感染动物中的ASC。在具体的测试中， 目的是，效应记忆B细胞，它经历了特定的表观遗传和代谢编程 步骤，被许可产生具有上级存活潜力的ASC。这项建议的近期目标是 （i）鉴定控制Bcirrhosis分化为长寿命Bcirrhosis的转录和表观遗传变化， （ii）确定EZH 2和SIRT 1在ASC存活中的作用;和（iii）评估NAD代谢的作用 在长寿ASCs的生存中。我们相信这些研究是重要的，因为它们将推动我们的 控制ASC寿命的因素的基本知识，并可能在未来导致新的治疗方法 抑制ASC应答以控制慢性炎性疾病中抗体介导的病理的方法 或恶性肿瘤。此外，这些研究可能有助于开发更持久的疫苗。

Antibodies, which are produced following infection and vaccination, promote rapid pathogen clearance and, if made for extended periods of time, can provide protection following re-exposure to the same or related pathogens. However, antibodies can also be detrimental and, if directed against the wrong antigen or epitopes, can cause, rather than prevent, disease. Pathologic antibodies are most often observed in the setting of chronic inflammatory diseases such as autoimmunity, allergy and organ transplantation. Given the importance of antibodies in promoting both health and disease there is a need to better understand the development and maintenance of the antibody secreting cells (ASCs). ASCs are the terminally differentiated effector progeny of the mature naïve and memory B cell pools. While we have made great gains in our understanding of the signals and transcription factors that control ASC development from the parent naïve and memory B cells, we know remarkably little about the factors, both intrinsic and extrinsic, that control the lifespan of ASCs. In our preliminary studies we show that the capacity of particular B cell subsets to differentiate into ASCs with a long survival potential appeared to be hardwired and limited to the memory B cell compartment rather than the naïve B cell pool. We identified several discrete subsets of memory B cells and showed that these memory B cells differed in their transcriptional, epigenetic and metabolic programs and exhibited distinct functional capabilities. We identified a subset of memory B cells (referred to as effector memory B cells), that were more similar to ASCs in their metabolic potential and expression of epigenetic modifiers like the methylase EZH2 and NAD-dependent deacetylase SIRT1. We showed that effector memory B cells differentiated into ASCs more rapidly than other memory subsets. Moreover, the ASCs derived from the effector memory B cells were uniquely capable of surviving for weeks when cultured in a supportive microenvironment. Finally, we showed that ASC survival is highly dependent on new NAD metabolism and that drugs which block vitamin B3-directed NAD biosynthesis will ablate ASCs in autoimmune and chronically infected animals. The central hypothesis tested in the Specific Aims is that the effector memory B cells, which have undergone specific epigenetic and metabolic programming steps, are licensed to give rise to ASCs with superior survival potential. The immediate objectives of this proposal are to: (i) identify the transcriptional and epigenetic changes controlling Bmem differentiation into long-lived ASCs; (ii) determine the role for EZH2 and SIRT1 in ASC survival; and (iii) assess the role of NAD metabolism in the survival of long-lived ASCs. We believe that these studies are important as they will advance our fundamental knowledge of the factors that control ASC lifespan and may in the future lead to new therapeutic approaches to dampen ASC responses to control antibody mediated pathology in chronic inflammatory disease or malignancy. Additionally, these studies may enable the development of more durable vaccines.