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。目前对抗b细胞治疗系统性红斑狼疮（SLE）和其他疾病的兴趣强调了它的重要性。总的假设是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。我们将集中精力研究B细胞特异性活化Smith （Sm）抗原的机制，这是SLE中常见的一种靶向核糖核蛋白。我们之前的研究表明，卵泡（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细胞被选择到边缘区（MZ）、前浆区和B-1细胞亚群中，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被设计为对外来抗原提供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，它们在自身免疫中的抗sm反应中做出了独特的贡献，并暗示了发病机制。我们还发现树突状细胞（dc）激活抗sm MZ B细胞，但通常这种能力被仔细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，具有产生致病性抗体的潜力。我们提出了三个目的来确定每个亚群的B细胞在自身免疫中的作用以及dc活化抗sm B细胞的机制。在第一个目标中，我们将确定自身免疫小鼠抗sm反应中每个亚群的B细胞的贡献和相互依赖性。在第二个目标中，我们提出确定正常和Fas缺陷dc激活抗sm B细胞的机制，并在最终目标中，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确定影响B细胞活化致病机制的新治疗靶点。针对自身蛋白的特异性抗体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在很大程度上是未知的。在这项提议中，我们将确定这些b淋巴细胞是如何被激活的，目的是确定这些疾病患者的治疗靶向机制。

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.