Anti-Sm B Cell Regulation

抗 Sm B 细胞调节

• 批准号: 8315909
• 负责人: Stephen H Clarke
• 金额: $ 43.47万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8315909
• 关键词: Activated B-Lymphocyte; Affect; Antibodies; Antigen Targeting; Antigens; 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; Health; 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; 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全身性红斑狼疮中自动反应性B细胞的机理。目前对全身性红斑狼疮（SLE）的抗B细胞疗法的兴趣和其他疾病强调了其重要性。总体假设是，SLE中不同子集的抗自我B细胞被不同的机制激活，并预先编程在致病性抗自身反应中具有独特的作用。我们将把精力集中在史密斯（SM）抗原的B细胞激活机理上，该抗原是SLE中通常针对的核糖核蛋白。我们以前的工作表明，卵泡（FO）B细胞子群的抗SM B细胞是非功能的，但矛盾地表明，一些抗SM B细胞被选择到边缘区（MZ），PR-PLASMA和B-1细胞亚群中，并且是功能性的。每个子集的B细胞的不同表型，激活状态和解剖位置旨在提供对异物抗原的分层和相互依存的保护反应。但是，我们对这些子集对自我抗原的反应中的B细胞之间的相互作用知之甚少，但是初步数据表明，它们对自身免疫中的抗SM反应做出了独特的贡献，对发病机理的影响。我们还发现树突状细胞（DCS）激活抗SM MZ B细胞，但通常会仔细调节该能力以防止并发T细胞激活。然而，在自身免疫性中，激活受体FAS的缺乏允许与T细胞同时同时激活抗SM B细胞，并具有产生致病性抗体的潜力。我们提出三个旨在确定每个子集的B细胞对自身免疫性的作用以及DC抗SM B细胞激活的机理。在第一个目标中，我们将确定每个子集中抗SM响应在自身免疫小鼠中的B细胞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。提出的实验将有助于鉴定影响B细胞激活致病机制的新治疗靶标。针对自蛋白的公共卫生相关性抗体会引起许多自身免疫性疾病，包括全身性红斑狼疮。如何激活这些致病性抗自身抗体的B淋巴细胞在很大程度上未知。在此提案中，我们将确定如何激活这些B淋巴细胞，目的是识别可以在这些疾病患者中针对治疗的机制。