Aberrant Signaling in B-1 Cells

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，并负责产生具有重要抗菌功能的天然免疫球蛋白。PD-L2是B7家族成员，先前报道主要由巨噬细胞和树突状细胞表达，但现在该实验室的研究表明B1细胞也表达PD-L2。B1细胞不仅表达PD-L2，而且与PD-L2不表达的B1细胞和B2细胞相比，PD-L2的表达标志着B1细胞表现出增强的库倾斜、增加的自身抗体产生、放大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。这个提议的长期目标，以及之前在这个序列中的项目，是了解B1细胞是如何形成的，以及B1细胞在免疫系统中的作用和功能。B1细胞亚群表达PD-L2为解决这些问题提供了一个新的重要工具。由于PD-L2+ B1细胞优先表达通常与B1细胞谱系相关的特征，这些发现推断出PD-L2在产生这些特征中起作用，或者与它们相关的新模式。相反，由于PD-L2的表达范围有限，并且以前没有在淋巴细胞中报道过，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B1细胞中控制PD-L2表达的调控元件；2)通过研究表型定义的B细胞分化早期阶段，确定表达pd - l2的B1细胞的发育进程；3)通过调控成熟和发育B1细胞中PD-L2的表达，确定PD-L2在阐明表达PD-L2的B1细胞独特特征中的作用。本研究的结果有望为B1细胞中PD-L2基因的调控、B细胞个体发育过程中PD-L2的表达以及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）相关的机制提供新的信息。这些都是与B1细胞行为和活性以及PD-L2表达和功能相关的基本问题，通过对B1细胞在免疫系统中的作用和地位的研究，将了解到许多新的信息。阐明这些观点可能为改善自身免疫失调的进展、影响恶性疾病的进程以及帮助增强正常和免疫缺陷患者的免疫力提供新的靶点和策略。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细胞表现不同——它们特别有价值，因为它们不需要接种疫苗就能产生对抗疾病的抗体，但它们存在问题，因为它们参与引发或加重自身免疫性疾病，如类风湿关节炎和系统性红斑狼疮。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，并且这种分子标记的B1细胞在制造抗体（包括自身免疫抗体）和其他特征方面具有特殊性质。这个分子实际上导致B1细胞表达它的特殊性质的假设将被验证。理想情况下，这项研究将为控制B1细胞活性提供有用的信息——向下，改善自身免疫性疾病患者的状况；向上，改善免疫缺陷状态患者的状况。

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.