Plasma Cells in Health and Disease

健康和疾病中的浆细胞

基本信息

批准号：
10621320
负责人：
Ignacio E. Sanz
金额：
$ 269.13万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-25 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621320
关键词：
Acute Allergic Reaction Animals Antibodies Antigens Area Autoimmune Diseases Autoimmune Responses B-Lymphocytes Bioinformatics Biological Response Modifier Therapy Bone Marrow COVID-19 pandemic CRISPR/Cas technology Cell Aging Cell Compartmentation Cell Differentiation process Cell Maturation Cell Survival Cell physiology Cells Chromatin Complementary DNA Computer Analysis DNA Methylation Data Set Development Disease EZH2 gene Endowment Ensure Epigenetic Process Foundations Generations Genetic Transcription Genome engineering Goals Graft Rejection Health Heme Heterogeneity Human Hypersensitivity Immune system Immunoglobulin A Immunoglobulin G Immunoglobulin M Immunoglobulin-Secreting Cells Infection Information Dissemination Institution Investigation Iron Laboratory Personnel Libraries Longevity Mediating Memory Memory B-Lymphocyte Metabolic Metabolism Molecular Nature Pathogenicity Pathway interactions Plasma Cells Plasmablast Population Preparation Process Production Regulation Research Personnel Role SIRT1 gene Safety Serology Systemic Lupus Erythematosus Transcriptional Regulation Vaccination Work arm autoreactivity base data sharing design effective therapy epigenetic regulation epigenomics histone modification human tissue immune function immunogenic improved methylation pattern overexpression programs response transcriptome vaccine response

项目摘要

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)

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；这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）

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Understanding B-cell activation and autoantibody repertoire selection in systemic lupus erythematosus: A B-cell immunomics approach.

了解系统性红斑狼疮中的 B 细胞激活和自身抗体库选择：B 细胞免疫组学方法。

DOI：
发表时间：
2018
期刊：
影响因子：
8.7
作者：
Tipton, Christopher M;Hom, Jennifer R;Fucile, Christopher F;Rosenberg, Alexander F;Sanz, Inaki
通讯作者：
Sanz, Inaki

Editorial: IgA Responses and Future Development of Rheumatoid Arthritis.

社论：IgA 反应和类风湿性关节炎的未来发展。

DOI：
发表时间：
2016-10
期刊：
影响因子：
0
作者：
Sanz; Ignacio
通讯作者：
Ignacio

Immediate Reactions After the First Dose of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Messenger RNA Vaccines Do Not Preclude Second-Dose Administration.

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 信使 RNA 疫苗第一剂后的立即反应并不妨碍第二剂给药。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Vanijcharoenkarn, Kristine;Lee, Frances Eun;Martin, Lindsay;Shih, Jennifer;Sexton, Mary Elizabeth;Kuruvilla, Merin Elizabeth
通讯作者：
Kuruvilla, Merin Elizabeth

Systemic lupus erythematosus: Extent and patterns of off-label use of rituximab for SLE.

系统性红斑狼疮：超说明书使用利妥昔单抗治疗 SLE 的程度和模式。

DOI：
发表时间：
2016
期刊：
影响因子：
0
作者：
Sanz; Iñaki
通讯作者：
Iñaki

SLE Antibody-Secreting Cells Are Characterized by Enhanced Peripheral Maturation and Survival Programs.

SLE 抗体分泌细胞的特点是外周成熟和生存程序增强。

DOI：
发表时间：
2023-06-27
期刊：
影响因子：
0
作者：
Chen, Weirong;Hong, So;Jenks, Scott A;Anam, Fabliha A;Tipton, Christopher M;Woodruff, Matthew C;Hom, Jennifer R;Cashman, Kevin S;Faliti, Caterina Elisa;Wang, Xiaoqian;Kyu, Shuya;Wei, Chungwen;Scharer, Christopher D;Mi, Tian;Hicks, Sakeen
通讯作者：
Hicks, Sakeen