Anti-Sm B Cell Regulation

抗 Sm B 细胞调节

• 批准号: 7896501
• 负责人: Stephen H Clarke
• 金额: $ 43.91万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896501
• 关键词: Activated B-Lymphocyte; Affect; Antibodies; Antigen Targeting; Antigens; Antinuclear Antibodies; Apoptotic; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; CD95 Antigens; Cell Surface Receptors; Cell Therapy; Cells; Clinical; Data; Dendritic Cells; Disease; Human; Immune system; In Vitro; Ingestion; Location; Lymphoid; Mature B-Lymphocyte; Mediating; Memory B-Lymphocyte; Molecular; Mus; Myelogenous; Pathogenesis; Pathway interactions; Patients; Phenotype; Plasma; Plasma Cells; Process; Production; Proteins; RNP antigen; Receptor Activation; Regulation; Ribonucleoproteins; Role; Signal Transduction; Sm antigen; Spleen; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Work; autoreactive B cell; cytokine; design; in vivo; interest; macrophage; mouse model; new therapeutic target; plasma cell differentiation; prevent; programs; public health relevance; research study; response; therapeutic target

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to determine the mechanism of autoreactive B cells in systemic lupus erythematosus. The present interest in anti-B cell therapy for systemic lupus erythematosus (SLE) and other diseases underscores its importance. The overarching hypothesis is that anti-self B cells of different subsets in SLE are activated by different mechanisms and pre-programmed to have unique roles in pathogenic anti-self responses. We will focus our efforts on the mechanism of activation of B cell specific for the Smith (Sm) antigen, a ribonucleoprotein commonly targeted in SLE. Our previous work indicates that anti-Sm B cells of the follicular (FO) B cell subset are non-functional, but, paradoxically, also indicates that some anti-Sm B cells are selected into the marginal zone (MZ), pre-plasma, and B-1 cell subsets, and are functional. The distinct phenotypes, activation states, and anatomical locations of B cells of each subset are designed to provide a layered and interdependent, protective response to foreign antigens. However, we know little about the interplay between the B cells of these subsets in responses to self-antigen, but preliminary data indicates that they make unique contributions to the anti-Sm response in autoimmunity with implications for pathogenesis. We also find that dendritic cells (DCs) activate anti-Sm MZ B cells, but normally this ability is carefully regulated to prevent concurrent T cell activation. However, in autoimmunity, a deficiency in the activation receptor Fas, allows anti-Sm B cell activation concurrently with T cells, with the potential to generate pathogenic antibodies. We propose three aims to determine the role of B cells of each subset to autoimmunity and the mechanism of anti-Sm B cell activation by DCs. In the first aim, we will determine the contributions and interdependence of B cells of each subset the anti-Sm responses in autoimmune mice. In the second aim, we propose to determine the mechanism of anti-Sm B cell activation by normal and Fas-deficient DCs, and in the final aim, we will determine how Fas regulates the ability of DCs to activate anti-Sm B cells. The proposed experiments will aid in the identification of new therapeutic targets that affect pathogenic mechanisms for B cell activation. PUBLIC HEALTH RELEVANCE Antibodies specific for self-proteins cause many autoimmune diseases, including systemic lupus erythematosus. How B-lymphocytes that produce these pathogenic anti-self antibodies are activated is largely unknown. In this proposal, we will determine how these B-lymphocytes are activated for the purpose of identifying mechanisms that can be therapeutically targeted in patients with these diseases.

描述（由申请人提供）：该提案的长期目标是确定系统性红斑狼疮中自身反应性 B 细胞的机制。目前对系统性红斑狼疮 (SLE) 和其他疾病的抗 B 细胞疗法的兴趣强调了其重要性。总体假设是，SLE 中不同亚群的抗自身 B 细胞被不同的机制激活，并被预先编程为在致病性抗自身反应中发挥独特的作用。我们将重点研究史密斯 (Sm) 抗原特异性 B 细胞的激活机制，史密斯 (Sm) 抗原是 SLE 中常见的一种核糖核蛋白。我们之前的工作表明，滤泡 (FO) B 细胞亚群的抗 Sm B 细胞没有功能，但矛盾的是，也表明一些抗 Sm B 细胞被选入边缘区 (MZ)、前浆和 B-1 细胞亚群，并且具有功能。每个亚群的 B 细胞的不同表型、激活状态和解剖位置旨在提供针对外来抗原的分层且相互依赖的保护性反应。然而，我们对这些亚群的 B 细胞之间对自身抗原反应的相互作用知之甚少，但初步数据表明，它们对自身免疫中的抗 Sm 反应做出了独特的贡献，并对发病机制产生了影响。我们还发现树突状细胞 (DC) 会激活抗 Sm MZ B 细胞，但通常这种能力会受到仔细调节，以防止 T 细胞同时激活。然而，在自身免疫中，激活受体 Fas 的缺陷使得抗 Sm B 细胞与 T 细胞同时激活，并有可能产生致病性抗体。我们提出了三个目标，以确定每个亚群的 B 细胞对自身免疫的作用以及 DC 激活抗 Sm B 细胞的机制。第一个目标是，我们将确定自身免疫小鼠中每个亚群的 B 细胞对抗 Sm 反应的贡献和相互依赖性。在第二个目标中，我们建议确定正常和Fas缺陷的DC激活抗Sm B细胞的机制，在最终目标中，我们将确定Fas如何调节DC激活抗Sm B细胞的能力。拟议的实验将有助于确定影响 B 细胞激活致病机制的新治疗靶点。公众健康相关性 自身蛋白特异性抗体会引起许多自身免疫性疾病，包括系统性红斑狼疮。产生这些致病性抗自身抗体的 B 淋巴细胞如何被激活尚不清楚。在本提案中，我们将确定这些 B 淋巴细胞是如何被激活的，以便确定可以针对这些疾病患者进行治疗的机制。