Plasma Cells in Health and Disease

抗体分泌细胞 (ASC) 负责保护性和致病性反应 通过赋予不同功能和寿命的人群的功能。因此，主要 人类健康和疾病中未满足的需求是对潜在过程的深刻理解 不同 B 细胞前体通过不同的分化途径产生 ASC；的 支持这些过程的代谢、转录和表观遗传程序，从而 促进不同寿命和功能的多样化 ASC 群体的产生；以及如何 这些过程可能在系统性红斑狼疮中被破坏，导致致病性自身反应的扩大 浆细胞。适当的 ASC 功能和失调分别提供保护 疫苗接种和感染并介导多种疾病，包括系统性红斑狼疮和其他自身免疫性疾病 条件、过敏反应和移植排斥。因此，了解这些过程 调节保护性 ASC 的分化和存活，同时避免积累 致病性病毒对于我们改善疫苗接种和治疗多种抗体的能力至关重要 介导的疾病。 在上一个周期中，尽管 COVID-19 大流行造成了严重破坏 一年多来，我们的工作在这些领域取得了重大进展，奠定了基础 对于此续订申请。结合起来，我们的工作将解决以下概念：主题 1 - 人类健康和自身免疫反应中 ASC 的异质性；主题 2 - 分子和 PC 发育和存活的表观遗传调控；主题 3 - ASC 的代谢调节 分化、功能和生存；主题4：ASC形成的微环境调控， 生存和功能。这些目标将由高度互动的调查人员通过以下方式来实现 以下项目和核心： 项目 1. 控制长寿的表观遗传和代谢机制 浆细胞池（Lund，PI）。 项目 2. 浆细胞异质性和代谢的表观遗传编程。 （老板、PI） 项目 3。细胞衰老在长寿命浆细胞生成中的作用。 （李，PI） 项目 4. 异质性。 SLE 中抗体分泌细胞的调节和功能（Sanz，PI） 核心 A. 行政核心（Sanz、PI） 核心 B. 表观基因组学、生物信息学和基因组工程（Scharer，PI）

Antibody secreting cells (ASC) are responsible for both protective and pathogenic responses through the function of populations endowed with different function and longevity. Hence, major unmet need in human health and disease is a deep understanding of the processes that underlie ASC generation from different B cell precursors through separate differentiation pathways; the metabolic, transcriptional and epigenetic programs that underpin these processes, thereby promoting the generation of diverse ASC populations of different longevity and function; and how these processes may be subverted in SLE leading to expansion of pathogenic autoreactive plasma cells. Proper ASC function and dysregulation respectively provide protection in vaccination and infection and mediate multiple diseases including SLE and other autoimmune conditions, allergic reactions and transplant rejection. Thus, understanding the processes that regulate differentiation and survival of protective ASC while avoiding the accumulation of pathogenic ones is essential for our ability to improve vaccination and treat multiple antibody- mediated diseases. Over the previous cycle, despite the severe disruption caused by the COVID-19 pandemic for over a year, our work has contributed major progress in these areas that provides the foundation for this renewal application. Combined, our work will address the following concepts: Theme 1 - ASC heterogeneity in human healthy and autoimmune responses; Theme 2 - Molecular and epigenetic regulation of PC development and survival; Theme 3 - Metabolic regulation of ASC differentiation, function and survival; Theme 4: Microenvironment regulation of ASC formation, survival and function. These goals will be accomplished by highly interactive investigators through the following Projects and cores: Project 1. Epigenetic and metabolic mechanisms governing commitment to the long-lived plasma cell pool (Lund, PI). Project 2. Epigenetic programming of plasma cell heterogeneity and metabolism. (Boss, PI) Project 3. Role of Cellular Senescence in long-lived plasma cell generation. (Lee, PI) Project 4. Heterogeneity. Regulation and Function of Antibody-Secreting Cells in SLE (Sanz, PI) Core A. Administrative Core (Sanz, PI) Core B. Epigenomics, Bioinformatics, and Genome Engineering (Scharer, PI)