Human Transitional B Cells: Homeostasis, Function, and Impact of BCDT

人类移行 B 细胞：稳态、功能和 BCDT 的影响

• 批准号: 8308293
• 负责人: Jennifer Howitt Anolik
• 金额: $ 28.33万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308293
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen-Antibody Complex; Apoptosis; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B Cell Proliferation; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological Assay; Biostatistics Core; Blood; Bone Marrow; Cell Cycle; Cell Death; Cell Survival; Cell physiology; Cells; Cellular biology; Chronic; Clinical; Collaborations; Cues; Deuterium Oxide; Development; Disease; Disease remission; Equilibrium; Excision; Flow Cytometry; Frequencies; Gene Expression Profile; Genetic Recombination; Goals; Health; Heterogeneity; Home environment; Homeostasis; Human; Human Biology; Immune; Immune response; Immunocompetence; Immunologics; In Vitro; Instruction; Interferons; Interleukin-10; Kinetics; Label; Laboratories; Length; Longevity; Lupus; Mature B-Lymphocyte; Measures; Mediating; Memory; Memory B-Lymphocyte; Microarray Analysis; Modeling; Molecular; Outcome; Pathogenesis; Patients; Peripheral; Physiological; Play; Predisposition; Process; Production; Recording of previous events; Recurrent disease; Regulation; Regulatory T-Lymphocyte; Research; Rheumatoid Arthritis; Role; Serum; Signal Transduction; Staging; Staining method; Stains; Systemic Lupus Erythematosus; TGFB1 gene; TNF gene; Tissues; Transitional Cell; Work; annexin A5; autoreactive B cell; autoreactivity; base; chemokine; clinical remission; cytokine; early experience; in vivo; progenitor; reconstitution; research study; restoration; systemic autoimmune disease; tool

PROJECT SUMMARY (See instructions): B cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). A major focus of Project I is to define the bone marrow developmental cues and peripheral turnover of transitional B cells and how cytokine milieu, which may be perturbed in systemic autoimmunity, regulates this process. It is hypothesized that autoimmune disease is as.sociated with dysregulation of transitional B cell homeostasis during B cell development with alterations in the numbers of transitional B cells emerging from the bone marrow (BM), the inicroenvironmenlal signals that modulate this process (IFN, TNF), and the signaling threshold for progression to the mature compartinent (BAFF). On the other hand, we have found that SLE patients with a prominent expansion of circulating transitional cells after B cell depletion therapy (BCDT) enter long-term clinical remission, whereas both SLE and RA patients with more rapid memory reconstitution experience earlier relapse of disease. The focus of this proposal is to understand early B cell homeostasis and the factors that regulate B cell reconstitution after BCDT in SLE and RA through the following specific aims which will define: 1. the perturbations in homeostasis of human transitional B cells in autoimmune di.sease; 2. the factors which regulate the balance of reconstitution of distinct B cell subsets after BCDT; and 3. the reciprocal regulation of transitional B cells and regulatory T cells and how this is altered in autoimmune disease and after BCDT. Specifically, we will define the dynamics of B cell development in humans using B cell depletion as a tool and multi-parameter flow cytometry. The lifespan and turnover of transitional B cells will be assessed by heavy water labeling, replication history, cell cycle, and delineation of survival and .selection. The effects of cytokine milieu on new BM B cell lyinphopoeisis will be examined. This project will explore the hypothesis that the outcome of BCDT rellects the balance between protective (regulatory, anti-inflammatory) and effector (prointlammatoiy) B cells and their corresponding cytokines. Transitional B cell functions to delineate include the production of anti-intlammatory cytokines such as IL-10 and TGFB and support of regulatory T cell (Treg) development. We will define whether human B cell subsets differentially support Treg expansion or are differentially susceptible to Treg suppression, if this function changes in autoimmune settings, and how these abnormalities are modified by BCDT. Elucidation of the homeostatic regulation of human transitional B cells will represent a major advance in human B cell biology. The research proposed will also help us understand how B cell development is dysregulated in autoimmune disease and how depletion induces improvement and, in some cases, long-lasting disea.se remission.

项目摘要（请参阅说明）： B细胞在全身性红斑狼疮（SLE）和类风湿关节炎（RA）的发病机理中起关键作用。一个 项目I的主要重点是定义骨髓发育线索和过渡B细胞的周围周转率 以及在系统性自身免疫性中可能会扰动的细胞因子环境如何调节这一过程。它是假设的 这种自身免疫性疾病与B细胞发育过程中过渡B细胞稳态失调相关 随着从骨髓（BM）出现的过渡B细胞数量的变化，InicroenvironMenlal 调节此过程的信号（IFN，TNF）以及向成熟倾斜的信号传导阈值 （Baff）。另一方面，我们发现SLE患者具有明显的循环过渡的扩张 B细胞耗竭治疗（BCDT）后的细胞进入长期临床缓解，而SLE和RA患者均患有 更快的记忆重建经历早期疾病复发。该提议的重点是尽早了解 B细胞体内平衡以及在SLE和RA中BCDT后调节B细胞重构的因素。 定义的具体目的：1。自身免疫中人类过渡B细胞体内稳态的扰动 疾病; 2。调节BCDT后不同B细胞子集的重建平衡的因素；和3 过渡B细胞和调节性T细胞的相互调节以及在自身免疫性疾病和 BCDT之后。具体而言，我们将使用B细胞耗竭作为工具来定义人类B细胞发育的动力学 和多参数流式细胞仪。过渡B细胞的寿命和营业额将由重水评估 标记，复制历史，细胞周期以及生存和选择的描述。细胞因子环境对新的影响 将检查BM B细胞lyinphopoeisis。该项目将探讨以下假设：bcdt的结果 保护性（调节性，抗炎）和效应子（Prointlammatoiy）B细胞之间的平衡及其之间的平衡 相应的细胞因子。过渡性B细胞功能描述包括产生抗创伤性 IL-10和TGFB等细胞因子以及调节T细胞（TREG）发育的支持。我们将定义是否 B细胞子集差异地支持Treg扩展或差异化受到Treg抑制作用，如果此功能 自身免疫性设置的变化，以及如何通过BCDT修改这些异常。阐明体内平衡 人类过渡B细胞的调节将代表人类B细胞生物学的重大进展。研究提出了 还将帮助我们了解自身免疫性疾病中B细胞发育的失调以及耗竭如何诱导 改进，在某些情况下是持久的疾病。