Anti-Sm B Cell Regulation

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。目前对系统性红斑狼疮（SLE）和其他疾病的抗B细胞治疗的兴趣强调了其重要性。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性抗自身反应中具有独特的作用。我们将集中精力在B细胞的史密斯（Sm）抗原，一个核糖核蛋白，在SLE中常见的靶向激活的机制。我们以前的工作表明，抗Sm B细胞的滤泡（FO）B细胞亚群是非功能性的，但矛盾的是，也表明，一些抗Sm B细胞被选择到边缘区（MZ），前血浆，和B-1细胞亚群，是功能性的。每个亚群的B细胞的不同表型、活化状态和解剖位置被设计为提供对外来抗原的分层的和相互依赖的保护性应答。然而，我们对这些亚群的B细胞对自身抗原的反应之间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）激活抗Sm MZ B细胞，但通常这种能力是仔细调节，以防止并发的T细胞激活。然而，在自身免疫中，活化受体Fas的缺陷允许抗Sm B细胞与T细胞同时活化，具有产生致病性抗体的潜力。我们提出了三个目标，以确定每个子集的B细胞的作用，自身免疫和抗Sm B细胞活化的DC的机制。在第一个目标，我们将确定的贡献和相互依赖性的B细胞的每个子集的抗Sm反应在自身免疫小鼠。在第二个目标中，我们建议确定抗Sm B细胞激活正常和Fas缺陷的DC的机制，并在最终的目标，我们将确定Fas如何调节DC激活抗Sm B细胞的能力。所提出的实验将有助于鉴定影响B细胞活化的致病机制的新的治疗靶点。公共卫生相关性对自身蛋白质具有特异性的抗体会导致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在很大程度上是未知的。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，以确定可以在这些疾病患者中进行治疗的机制。

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.