Anti-Sm B Cell Regulation

抗 Sm B 细胞调节

• 批准号: 7685416
• 负责人: Stephen H Clarke
• 金额: $ 43.05万
• 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/7685416
• 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)：本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。目前抗B细胞治疗系统性红斑狼疮(SLE)和其他疾病的兴趣凸显了它的重要性。最重要的假设是，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的反自我反应中具有独特的作用。我们将重点研究Smith(Sm)抗原特异性B细胞的激活机制，Smith(Sm)抗原是SLE中常见的靶向核糖核蛋白。我们以前的工作表明，滤泡(FO)B细胞亚群中的抗Sm B细胞是无功能的，但矛盾的是，也表明一些抗Sm B细胞被选入边缘带(MZ)、浆前和B-1细胞亚群中，并具有功能。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对外来抗原的分层和相互依赖的保护性反应。然而，我们对这些亚群的B细胞之间在自身抗原应答中的相互作用知之甚少，但初步数据表明，它们在自身免疫中对抗Sm反应做出了独特的贡献，并可能与发病机制有关。我们还发现，树突状细胞(DC)激活抗Sm MZ B细胞，但正常情况下，这种能力受到仔细的调节，以防止同时激活T细胞。然而，在自身免疫中，激活受体Fas的缺陷允许抗Sm B细胞与T细胞同时激活，从而有可能产生致病抗体。我们提出了三个目标来确定每个亚群的B细胞在自身免疫中的作用以及DC激活抗Sm B细胞的机制。在第一个目标中，我们将确定在自身免疫小鼠中抗Sm反应的每个亚群中B细胞的贡献和相互依赖。在第二个目标中，我们将确定正常和Fas缺陷DC激活抗Sm B细胞的机制，并最终确定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识别影响B细胞激活的致病机制的新的治疗靶点。针对自身蛋白的抗体可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淋巴细胞是如何被激活的，在很大程度上还不清楚。在这项提案中，我们将确定这些B淋巴细胞是如何被激活的，以确定这些疾病患者的治疗靶向机制。