Antigen and lysophospholipid receptor regulation of lymphocyte development and fu

抗原和溶血磷脂受体对淋巴细胞发育和功能的调节

• 批准号: 8846018
• 负责人: Raul Martin Torres
• 金额: $ 38.85万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846018
• 关键词: Address; Affinity; Antibodies; Antibody Response; Antigen Receptors; Antigens; Attention; Autoimmune Process; Autoimmunity; B-Cell Development; B-Lymphocytes; Binding; Blood; Bone Marrow; Cell Lineage; Cell Survival; Cells; Chronic; Development; Disease; G-Protein-Coupled Receptors; Goals; Health; Humoral Immunities; Immune system; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Lead; Lipids; Lymphocyte; Lymphopoiesis; Lysophosphatidic Acid Receptors; Lysophospholipid Receptors; Lysophospholipids; Malignant Neoplasms; Mature B-Lymphocyte; Mature Lymphocyte; Molecular; Nature; Population; Production; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Relative (related person); Research; Role; Signal Pathway; Signal Transduction; Therapeutic Intervention; Virus Diseases; Work; adaptive immunity; base; cancer type; design; fMet-Leu-Phe receptor; immune function; in vivo; lysophosphatidic acid; mouse model; pathogen; research study; response; sphingosine 1-phosphate; trafficking

DESCRIPTION (provided by applicant): B cell antigen receptor (BCR) signaling controls the development, selection and function of B lymphocytes. Work in our lab has determined that the lysophospholipid, lysophosphatidic acid (LPA), signals to the LPA5 G-protein coupled receptor expressed by B lineage cells to suppress BCR signaling and subsequent antibody response. LPA binds and signals to LPA receptors with low nanomolar affinity and as a major lysophospholipid is present in blood at high nanomolar to low micromolar concentrations. However, despite that lymphocytes express several LPA receptors; relatively little is understood about how LPA influences humoral immunity. A long-term goal of our research has been to understand how BCR-derived signals intersect with those signals transmitted via GPCRs such as chemoattractant receptors and the goal of this application is to define how LPA signaling through LPA receptors on B lineage cells regulates the development and function of B lymphocytes. LPA has also been characterized as an inflammatory lipid and whose levels are considerably elevated in a number of chronic inflammatory disorders such as cancer, autoimmunity and viral infections. We show that at these heightened LPA levels BCR signaling is further inhibited. Thus, we also investigate how pathophysiological levels of LPA alter B cell tolerance induction in the bone marrow and antibody responses by marginal zone and follicular B cell populations. To address these issues, we propose in vitro and in vivo experiments that rely on well-characterized mouse models of B cell tolerance and antibody response to elucidate the role(s) of LPA receptors on B lymphocytes during their development in the bone marrow and their function as mature B cells in the periphery. These experiments are outlined in the following Specific Aims: Aim 1: Characterize how LPA regulates immature B cell development and tolerance induction. 1A. Establish if LPA receptors guide immature B cell localization in the bone marrow during These experiments ask how LPA receptor signaling influence B lymphopoeisis and if pathological LPA levels alters central B cell tolerance. Aim 2: Characterize the molecular and cellular mechanisms that lead to LPA suppression of B cell antibody responses. Here we define the extent to which LPA regulates B cell responses and the signaling pathways used by LPA receptors to inhibit BCR signaling. In particular, we determine if antigen-specific B cell responses are suppressed by all antigens or only antigens with certain (weak) affinity. Aim 3: Characterize how local autotaxin expression influences LPA regulation of B cell responses and if inflammatory and autoimmune settings alter the regulation of its expression. These experiments are designed to define the relative contributions of locally-restricted LPA production versus global systemic LPA levels in regulating the B cell antibody response and how LPA production may be altered in inflammatory and autoimmune settings. Significance. The sphingosine-1-phosphate (S1P) lysophospholipid has emerged as a critical regulator of lymphocyte development, trafficking and localization. However, lymphocytes and most other cells of the immune system also express G-protein coupled receptors that recognize another major lysophospholipid, lysophosphatidic acid (LPA). In contrast to S1P, that serves an important role under homeostatic conditions, LPA has features of an inflammatory lipid and has been associated with a chronic inflammatory disorders. Notably, how LPA regulates immune function and, specifically, humoral immunity is largely unexplored. The successful completion of these experiments is expected to illustrate how LPA functions to regulate the development, selection and antibody response by B lymphocytes. Furthermore, as LPA-LPA receptor signaling has been associated with a number of different types of cancer and has received considerable attention for possible therapeutic intervention, these findings will also be important to inform on how such strategies might alter adaptive immunity.

描述（由申请人提供）：B 细胞抗原受体 (BCR) 信号传导控制 B 淋巴细胞的发育、选择和功能。我们实验室的工作已确定，溶血磷脂、溶血磷脂酸 (LPA) 会向 B 谱系细胞表达的 LPA5 G 蛋白偶联受体发出信号，从而抑制 BCR 信号传导和随后的抗体反应。 LPA 以低纳摩尔亲和力与 LPA 受体结合并向其发出信号，并且作为主要溶血磷脂以高纳摩尔至低微摩尔浓度存在于血液中。然而，尽管淋巴细胞表达多种 LPA 受体；关于 LPA 如何影响体液免疫的了解相对较少。我们研究的长期目标是了解 BCR 衍生信号如何与通过 GPCR（例如趋化受体）传递的信号相交叉，本应用的目标是确定 B 谱系细胞上的 LPA 信号如何通过 LPA 受体调节发育和B淋巴细胞的功能。 LPA 还被认为是一种炎症脂质，其水平在许多慢性炎症性疾病（如癌症、自身免疫和病毒感染）中显着升高。我们发现，在 LPA 水平升高时，BCR 信号传导会进一步受到抑制。因此，我们还研究了 LPA 的病理生理水平如何改变骨髓中 B 细胞耐受诱导以及边缘区和滤泡 B 细胞群的抗体反应。为了解决这些问题，我们提出了体外和体内实验，这些实验依赖于 B 细胞耐受和抗体反应的良好表征的小鼠模型，以阐明 LPA 受体在 B 淋巴细胞在骨髓中发育过程中的作用以及它们的作用。发挥外周成熟 B 细胞的功能。这些实验概述如下具体目标： 目标 1：描述 LPA 如何调节未成熟 B 细胞发育和耐受诱导。 1A。确定 LPA 受体是否引导未成熟 B 细胞在骨髓中定位。这些实验探讨 LPA 受体信号传导如何影响 B 淋巴细胞生成，以及病理性 LPA 水平是否会改变中枢 B 细胞耐受性。目标 2：表征 LPA 抑制 B 细胞抗体反应的分子和细胞机制。在这里，我们定义了 LPA 调节 B 细胞反应的程度以及 LPA 受体用于抑制 BCR 信号传导的信号通路。特别是，我们确定抗原特异性 B 细胞反应是被所有抗原抑制还是仅被具有一定（弱）亲和力的抗原抑制。目标 3：表征局部自分泌运动因子表达如何影响 B 细胞反应的 LPA 调节，以及炎症和自身免疫环境是否改变其表达调节。这些实验旨在确定局部限制的 LPA 产生与全局系统 LPA 水平在调节 B 细胞抗体反应中的相对贡献，以及在炎症和自身免疫环境中如何改变 LPA 产生。意义。 1-磷酸鞘氨醇 (S1P) 溶血磷脂已成为淋巴细胞发育、运输和定位的关键调节因子。然而，淋巴细胞和免疫系统的大多数其他细胞也表达识别另一种主要溶血磷脂溶血磷脂酸 (LPA) 的 G 蛋白偶联受体。与在稳态条件下发挥重要作用的 S1P 不同，LPA 具有炎性脂质的特征，并且与慢性炎症性疾病有关。值得注意的是，LPA 如何调节免疫功能，特别是体液免疫在很大程度上尚未被探索。这些实验的成功完成预计将阐明 LPA 如何发挥作用来调节 B 淋巴细胞的发育、选择和抗体反应。此外，由于 LPA-LPA 受体信号传导与许多不同类型的癌症有关，并且在可能的治疗干预方面受到了相当多的关注，因此这些发现也很重要 告知此类策略如何改变适应性免疫。