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Regulation of GC B Cells by Transcription Factor STAT3

转录因子 STAT3 对 GC B 细胞的调节

基本信息

批准号：
9234461
负责人：
JUN YAN
金额：
$ 11.55万
依托单位：
UNIVERSITY OF LOUISVILLE
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：
2016-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9234461
关键词：
Ablation Address Affinity Antibodies Antigens Apoptotic Autoantibodies Autoantigens Autoimmune Diseases B Cell Proliferation B cell differentiation B-Cell Development B-Lymphocytes CD19 gene CD4 Positive T Lymphocytes Cell Culture System Cell Maintenance Cell Survival Cells Development Disease Progression Etiology Goals Helper-Inducer T-Lymphocyte Human Immunization Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin M In Vitro Inflammatory Interleukin-6 Kidney Kinetics Knock-out Knockout Mice Lupus Maintenance Measures Memory B-Lymphocyte Messenger RNA Molecular Mus Pathogenesis Pathology Pathway interactions Patients Phase Phosphorylation Plasma Cells Play Process Production Reaction Regulation Role STAT protein STAT1 protein Serum Signal Pathway Signal Transduction Small Interfering RNA Source Structure Structure of germinal center of lymph node Systemic Lupus Erythematosus T-Cell Activation Testing Time Transcript Transcription Factor 3 Treatment Efficacy autoreactive B cell cytokine differentiated B cell extracellular innovation lupus prone mice mouse model novel novel strategies plasma cell differentiation public health relevance response successful intervention systemic autoimmune disease transcription factor

项目摘要

DESCRIPTION (provided by applicant): Germinal centers (GCs) are unique microenvironment that has proliferative B cells undergoing class switching, somatic hypermuation, and affinity maturation. Although alternative pathways exist, GCs are the major source of long-lived antibody (Ab)-secreting plasma cells and memory B cells. Previous studies have demonstrated that SLE may develop as a result of enhanced GC activity. Spontaneous GC formation has been found in the lupus-prone mice. In addition, active lupus patients have abnormal GC reactions and increased plasma cells. Therefore, understanding signaling pathways that regulate the GC formation and GC B cell differentiation may identify novel targets for the successful intervention of SLE. The signal transducer and activator of transcription factor 3 (STAT3) signaling pathway is critical for human B cells to differentiate into Ab-secreting plasma cells. Dysregulation of STAT3 pathway has also been implicated in the development of SLE. However, the role of STAT3 in the GC B cell response has been controversial. A previous study has demonstrated that B cell-specific STAT3 deficient mice have lower T- dependent IgG response but display normal GC formation. Paradoxically, GC is the major source of both memory B cells and long-lived plasma cells. One caveat of this study is that they only examined GC response at day 12. Our preliminary studies demonstrated that B cell-specific STAT-3 KO mice had significantly decreased GC formation, GC B cells, and Tfh cells in the later phase (days 21 and 28) but not in the early time point (days 7 and 12). Furthermore, STAT3-deficient autoreactive B cells had defective autoAb responses and GC B cell differentiation upon immunization. We hypothesize that STAT3 signaling is essential for the maintenance of the GC formation and GC B cell differentiation. Two Aims are proposed to address this hypothesis. Aim 1 determines the mechanisms by which STAT3 signaling regulates the maintenance of the GC formation and GC B cell response. We will test the hypothesis that STAT3 signaling is required for the GC B cell survival. The specific stage of GC B cell differentiation that requires STAT3 signaling will be determined. Aim 2 examines whether B cell intrinsic STAT3 signaling is required for autoAb production and disease progression in lupus-prone MRL/lpr mouse model. In addition, we will use anti-CD19 single chain variable fragment (scFv) miniAb to specifically deliver STAT3 siRNA into B cells in MRL/lpr mice. The therapeutic efficacy of this intervention will be determined. The overall goal of this proposal is to determine how STAT3 signaling regulates the GC formation and GC B cell response and whether ablation of STAT3 signaling specifically in autoreactive B cells provides benefit for lupus treatment.

描述（由申请人提供）：老年中心（GC）是具有经历类别转换、体细胞超突变和亲和力成熟的增殖性B细胞的独特微环境。虽然存在替代途径，但GC是长寿命抗体（Ab）分泌浆细胞和记忆B细胞的主要来源。以往的研究表明，SLE的发展可能是GC活性增强的结果。在狼疮易感小鼠中发现了自发GC形成。此外，活动性狼疮患者有异常的GC反应和浆细胞增加。因此，了解调控GC形成和GC B细胞分化的信号通路可能为成功干预SLE确定新的靶点。信号转导和转录激活因子3（STAT 3）信号通路是人B细胞向分泌Ab的浆细胞分化的关键。STAT 3通路的失调也与SLE的发展有关。然而，STAT 3在GC B细胞应答中的作用一直存在争议。先前的研究已经证明，B细胞特异性STAT 3缺陷小鼠具有较低的T依赖性IgG应答，但显示正常的GC形成。巧合的是，GC是记忆B细胞和长寿浆细胞的主要来源。这项研究的一个警告是，他们只检查了第12天的GC反应。我们的初步研究表明，B细胞特异性STAT-3 KO小鼠在晚期（第21天和第28天）具有显著降低的GC形成、GC B细胞和Tfh细胞，但在早期时间点（第7天和第12天）没有。此外，STAT 3缺陷型自身反应性B细胞在免疫后具有缺陷型自身抗体应答和GC B细胞分化。我们推测STAT 3信号通路对于维持GC形成和GC B细胞分化是必不可少的。提出了两个目标来解决这个假设。目的1明确STAT 3信号通路调控GC形成和GC B细胞应答的机制。我们将检验STAT 3信号传导是GC B细胞存活所必需的这一假设。将确定需要STAT 3信号传导的GC B细胞分化的特定阶段。目的2在狼疮易感MRL/lpr小鼠模型中检查B细胞内在STAT 3信号传导是否是自身抗体产生和疾病进展所需的。此外，我们将使用抗CD 19单链可变片段（scFv）miniAb将STAT 3 siRNA特异性地递送到MRL/lpr小鼠的B细胞中。将确定这种干预的治疗效果。该提案的总体目标是确定STAT 3信号传导如何调节GC形成和GC B细胞应答，以及在自身反应性B细胞中特异性地消融STAT 3信号传导是否为狼疮治疗提供益处。