Aberrant Signaling in B-1 Cells

B-1 细胞中的异常信号传导

• 批准号: 7936838
• 负责人: THOMAS L ROTHSTEIN
• 金额: $ 41.09万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936838
• 关键词: Address; Anti-Bacterial Agents; Antibodies; Antibody-Producing Cells; Antigen Presentation; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell differentiation; B-Lymphocytes; Binding; Cell Lineage; Cell Ontogeny; Cell physiology; Cells; Characteristics; Dendritic Cells; Development; Disease; Dysplasia; Family member; Gene Expression Regulation; Immune; Immune system; Immunity; Immunoglobulins; Laboratories; Learning; Ligands; Location; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Mediating; Patients; Play; Population; Production; Property; Recording of previous events; Regulatory Element; Reporting; Research; Rheumatoid Arthritis; Role; Signal Transduction; Specific qualifier value; Staging; Surface; System; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Vaccination; Work; cell behavior; fighting; improved; macrophage; novel; promoter; public health relevance; tool

DESCRIPTION (provided by applicant): B1 cells represent a distinct lymphocyte lineage and a fundamental component of the immune system. B1 cells are associated with autoimmunity and malignancy, and are responsible for the production of natural immunoglobulin that fulfills a critical anti-bacterial function. PD-L2 is a B7 family member previously reported to be expressed primarily by macrophages and dendritic cells but now shown by work from this laboratory to be expressed by B1 cells. Not only do B1 cells express PD-L2, but PD-L2 expression marks B1 cells that manifest enhanced repertoire skewing, increased autoantibody production, amplified replication history, and augmented antigen presentation, in comparison to PD-L2 nonexpressing B1 cells and to B2 cells. These characteristics have long been associated with B1 cells in general, but this new work indicates that these features predominantly segregate to a B1 cell subset defined by PD-L2 expression. The long term objective of this proposal, and of previous projects in this sequence, is to understand how B1 cells get to be the way they are, and what is the role and function of B1 cells within the immune system. PD-L2 expression by a subset of B1 cells provides a new and important tool to address these issues. Because PD-L2+ B1 cells preferentially express characteristics normally associated with the B1 cell lineage, these findings infer a new paradigm wherein PD-L2 plays a role in producing those characteristics, or is otherwise associated with them. Conversely, because PD-L2 expression is limited in scope and has not previously been reported by lymphocytes, these findings infer a new paradigm wherein a fraction of B1 cells participate in PD-L2-mediated effects. The specific aims of this proposal are to: 1) Determine the regulatory elements that control PD-L2 expression in B1 cells through an analysis of promoter sequences and binding factors; 2) Determine the developmental progression of PD-L2-expressing B1 cells through the study of phenotypically defined early stages in B cell differentiation; and, 3) Determine the role of PD-L2 in specifying the unique features of PD-L2- expressing B1 cells through manipulation of PD-L2 expression in mature and developing B1 cells. The results of this study are expected to provide new information regarding PD-L2 gene regulation in B1 cells, regarding PD-L2 expression during B cell ontogeny, and regarding the mechanism by which PD-L2 expression correlates with several characteristics previously attributed to B1 cells in general, particularly autoantibody production. These are fundamental issues that relate to B1 cell behavior and activity, and PD-L2 expression and function, through the study of which much new will be learned regarding the role and place of B1 cells within the immune system. Elucidation of these points is likely to provide new targets and strategies to ameliorate the progression of autoimmune dyscrasias, to influence the course of malignant diseases, and to assist in enhancing immunity in normal and immune-deficient patients. PUBLIC HEALTH RELEVANCE: B1 cells are a subpopulation of B lymphocytes, the immune cells that produce antibody. B1 cells behave differently from other B cells in many respects-they are especially valuable because they produce disease- fighting antibody without the need for vaccination, but they are problematical because they are involved in initiating or aggravating autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosis. The work described in this proposal builds on the discovery that some B1 cells express a surface molecule never before known to be expressed by lymphocytes, and that the B1 cells marked by this molecule have special properties in terms of making antibody, including autoimmune autoantibody, and other characteristics. The hypothesis that this molecule actually causes the special properties of B1 cells that express it will be tested. Ideally, this research will provide information useful for manipulating B1 cell activity-downward, to improve the condition of patients afflicted with autoimmune diseases, and upward, to improve the condition of patients afflicted with immune deficiency states.

描述（由申请人提供）：B1细胞代表一种独特的淋巴细胞谱系，是免疫系统的基本组成部分。B1细胞与自身免疫和恶性肿瘤有关，并负责产生天然免疫球蛋白，实现关键的抗菌功能。PD-L2是B7家族成员，此前报道主要由巨噬细胞和树突状细胞表达，但现在该实验室的工作表明由B1细胞表达。不仅B1细胞表达PD-L2，而且PD-L2表达标志着B1细胞与PD-L2非表达B1细胞和B2细胞相比表现出增强的库偏斜、增加的自身抗体产生、扩增的复制历史和增强的抗原呈递。这些特征长期以来一直与B1细胞相关，但这项新工作表明，这些特征主要分离到由PD-L2表达定义的B1细胞亚群。本提案的长期目标，以及此序列中以前的项目，是了解B1细胞如何成为它们的方式，以及B1细胞在免疫系统中的作用和功能是什么。B1细胞亚群的PD-L2表达为解决这些问题提供了一种新的重要工具。由于PD-L2+ B1细胞优先表达通常与B1细胞谱系相关的特征，因此这些发现推断了一种新的范式，其中PD-L2在产生这些特征中起作用，或者与它们相关。相反，由于PD-L2表达的范围有限，并且以前没有淋巴细胞的报道，这些发现推断了一种新的范式，其中一部分B1细胞参与PD-L2介导的作用。本提案的具体目的是：1）通过分析启动子序列和结合因子，确定控制B1细胞中PD-L2表达的调控元件; 2）通过研究B细胞分化中表型确定的早期阶段，确定表达PD-L2的B1细胞的发育进程;和，3）通过在成熟和发育中的B1细胞中操纵PD-L2表达，确定PD-L2在指定表达PD-L2的B1细胞的独特特征中的作用。本研究的结果有望提供有关B1细胞中PD-L2基因调控、B细胞个体发育期间PD-L2表达以及PD-L2表达与先前归因于B1细胞的几个特征（特别是自身抗体产生）相关的机制的新信息。这些是与B1细胞行为和活性以及PD-L2表达和功能相关的基本问题，通过研究这些问题，将了解B1细胞在免疫系统中的作用和位置。阐明这些点可能提供新的目标和策略，以改善自身免疫性恶液质的进展，影响恶性疾病的进程，并协助增强正常和免疫缺陷患者的免疫力。公共卫生相关性：B1细胞是B淋巴细胞的一个亚群，B淋巴细胞是产生抗体的免疫细胞。B1细胞在许多方面与其他B细胞的行为不同，它们特别有价值，因为它们不需要接种疫苗就能产生抗病抗体，但它们有问题，因为它们参与引发或加重自身免疫性疾病，如类风湿性关节炎和系统性狼疮性肾炎。本提案中描述的工作建立在以下发现的基础上：一些B1细胞表达一种以前从未被淋巴细胞表达过的表面分子，并且由该分子标记的B1细胞在制造抗体方面具有特殊性质，包括自身免疫性自身抗体和其他特征。这种分子实际上导致表达它的B1细胞的特殊性质的假设将被测试。理想情况下，这项研究将提供有用的信息操纵B1细胞活性向下，以改善患有自身免疫性疾病的患者的状况，向上，以改善患有免疫缺陷状态的患者的状况。