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Identification of Specific Roles for Ets-1 in B Cell Tolerance

鉴定 Ets-1 在 B 细胞耐受中的具体作用

基本信息

批准号：
8651860
负责人：
LEE ANN Garrett-Sinha
金额：
$ 39.3万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651860
关键词：
Adaptor Signaling Protein Antibodies Antibody Formation Antigen-Antibody Complex Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses B cell differentiation B-Lymphocytes Binding Biological Biological Assay Blocking Antibodies Bone Marrow Cell Differentiation process Cell physiology Cells Cues DNA Binding DNA Binding Domain DNA Sequence Data Defect Development Enhancers Exhibits Gene Expression Gene Targeting Genes Glean Hematopoietic Homeostasis Immune response Immunoglobulin G Immunoglobulin M Immunoglobulin-Secreting Cells In Vitro Infection Kidney Diseases Knockout Mice Ligands Modeling Molecular Molecular Profiling Mus Nuclear Antigens Nucleic Acid Regulatory Sequences Organ Pathology Pathway interactions Peripheral Plasma Cells Prevention Process Production Proteins Receptor Signaling Regulation Relative (related person)Rheumatoid Factor Role Serum Signal Transduction T-Lymphocyte TLR7 gene Tissues Toll-like receptors Transcriptional Regulation Transgenic Mice Transgenic Model Transgenic Organisms anergy autoreactive B cell cell type cohort differentiated B cell fighting in vitro Assay in vivo inhibiting antibody insight mouse model novel pathogen prevent promoter public health relevance response transcription factor

项目摘要

DESCRIPTION (provided by applicant): The production of antibodies by antibody-secreting cells (ASCs) is critically important for immune responses to many different pathogens. However, in autoimmune diseases where B cell tolerance is broken, many ASCs secrete autoantibodies and contribute in a major way to organ pathology. The differentiation of B cells into ASCs is controlled by a cohort of key transcription factors including Ets-1, which serves as a negative regulator of this process. In the absence of Ets-1, B cells undergo enhanced differentiation into ASCs many of which secrete autoantibodies as demonstrated by high titers of IgM and IgG autoantibodies in the serum. Recently Toll- like receptor (TLR) signaling, particularly via TLR7 and TLR9, has been implicated in the activation of autoreactive B cells to differentiate into ASCs. Interestingly, Ets-1 deficient B cells exhibit enhanced responses to TLR7 and TLR9 ligands in vitro and Ets-1 knockout mice lacking the TLR adaptor protein Myd88 have reduced autoantibody production. Toll-like receptor signaling is a potent inducer of the expression of Blimp-1, a key transcription factor that drives ASC differentiation. Ets-1 physically interacts with Blimp-1 to inhibit the ability of Blimp-1 to bind target DNA sequences. In contrast, a closely related transcription factor Ets-2 is unable to block Blimp-1 binding or to inhibit ASC differentiation. Ets-1 also is thought to regulate the expression of critical target genes controlling ASC formation, but the identity of most of these targets remains unclear. In this application we propose a variety of assays to further define the role of Ets-1 in regulating target gene expression, Blimp-1 activity and ASC differentiation. These studies will be aided by comparing biological activities of Ets-1, which can block ASC differentiation, with the closely related Ets-2 protein, which lacks this activity. The specific aims of the proposal are (1) to determine which cell types require Ets-1 activity to limit ASC formation, autoantibody secretion and autoimmune disease, (2) to examine the in vivo role of TLR7 and 9 ligands in activating Ets-1 deficient B cells, (3) to identify Ets-1 dependent gene expression pathways regulating ASC formation and (4) to identify structural features of Ets-1 that impart a unique ability to regulate ASC development. Together our studies will provide novel insights into the transcriptional regulation of B cell differentiation particularly in situations of autoantibody secretion.

描述（由申请人提供）：抗体分泌细胞（ASCs）产生抗体对许多不同病原体的免疫反应至关重要。然而，在B细胞耐受性被破坏的自身免疫性疾病中，许多ASCs分泌自身抗体，并以主要方式促进器官病理。B细胞向ASCs的分化受一系列关键转录因子控制，其中包括Ets-1，它是这一过程的负调控因子。在缺乏Ets-1的情况下，B细胞向ASCs的分化增强，其中许多ASCs分泌自身抗体，如血清中IgM和IgG自身抗体的高滴度所示。最近，Toll样受体（TLR）信号，特别是通过TLR7和TLR9，被认为与自身反应性B细胞分化为ASCs的激活有关。有趣的是，Ets-1缺陷的B细胞在体外对TLR7和TLR9配体的反应增强，缺乏TLR接头蛋白Myd88的Ets-1敲除小鼠减少了自身抗体的产生。toll样受体信号是Blimp-1表达的有效诱导剂，Blimp-1是驱动ASC分化的关键转录因子。Ets-1与Blimp-1的物理相互作用抑制了Blimp-1结合目标DNA序列的能力。相反，一个密切相关的转录因子Ets-2不能阻断Blimp-1结合或抑制ASC分化。Ets-1也被认为调节控制ASC形成的关键靶基因的表达，但大多数这些靶基因的身份尚不清楚。在这项应用中，我们提出了多种检测方法来进一步确定Ets-1在调节靶基因表达、Blimp-1活性和ASC分化中的作用。这些研究将有助于比较能够阻断ASC分化的Ets-1蛋白与密切相关的Ets-2蛋白的生物活性，而后者缺乏这种活性。该提案的具体目的是：(1)确定哪种细胞类型需要Ets-1活性来限制ASC的形成、自身抗体的分泌和自身免疫性疾病，(2)检查TLR7和9配体在激活Ets-1缺陷B细胞中的体内作用，(3)鉴定调节ASC形成的Ets-1依赖基因表达途径，(4)鉴定赋予ASC发展独特能力的Ets-1结构特征。我们的研究将为B细胞分化的转录调控提供新的见解，特别是在自身抗体分泌的情况下。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic Interaction between Lyn, Ets1, and Btk in the Control of Antibody Levels.

DOI：
10.4049/jimmunol.1500165
发表时间：
2015-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Mayeux J;Skaug B;Luo W;Russell LM;John S;Saelee P;Abbasi H;Li QZ;Garrett-Sinha LA;Satterthwaite AB
通讯作者：
Satterthwaite AB

Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1.