The Role of IL-10 Secreting MZ B cells in Response to a Bacterial Challenge

描述（由申请人提供）：本提案的总体目标是进一步了解脾B细胞的发育和功能。脾B细胞群根据解剖位置、细胞表面分子和功能性免疫反应可分为边缘区（MZ）和滤泡区（FO） B细胞亚群。我们特别感兴趣的是MZ B细胞群的发展，它在抗体反应中的作用，以及积极或消极调节细胞活动的受体。在观察到任何病理性自身免疫迹象之前，几乎所有已建立的自身免疫性疾病小鼠模型中都会出现mzb细胞的大量扩增。令人惊讶的是，这种现象的意义及其在自身免疫性疾病过程中的作用尚未得到充分研究。此外，细菌攻击后MZ B细胞激活和调节的机制尚不完全清楚。使用多种细胞和分子技术，我们建议测试MZ B细胞在应对血源性细菌攻击时通过IL-10分泌发挥免疫调节作用的假设。这些发现将更好地理解MZ B细胞在细菌感染期间的反应机制，并确定治疗干预的潜在靶点。以下具体目标旨在验证我们的假设：目标1：确定MZ B细胞是否在响应血源性细菌挑战时分泌IL-10。工作假设：抗原特异性MZ B细胞分泌IL-10响应肺炎链球菌的攻击。目的2：确定MZ B细胞在应对血源性细菌攻击时IL-10产生的作用。工作假设：抗原特异性MZ B细胞在肺炎链球菌攻击后通过IL-10分泌发挥免疫调节作用。目的3：确定B细胞被激活分泌IL-10的机制。工作假说：B细胞在革兰氏+和革兰氏-细菌攻击后分泌IL-10。与公众健康相关：这个项目的目标是了解免疫系统如何抵抗入侵细菌，并提供预防生病的保护。一旦我们了解了免疫系统是如何工作的，我们将能够开发新的药物和疫苗接种策略来对抗细菌感染。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to further our understanding of the development and function of splenic B cells. The splenic B cell population can be divided into the marginal zone (MZ) and follicular (FO) B cell subsets based on anatomical location, cellular surface molecules, and functional immune responses. We are particularly interested in the development of the MZ B cell population, the role it plays in antibody responses, and the receptors that positively or negatively regulate cellular activity. A large expansion of MZ B cells occurs in nearly all established mouse models of autoimmune disease before any signs of pathological autoimmunity are observed. The significance of this phenomenon and its role in the autoimmune disease process has, surprisingly, been poorly investigated. Additionally, the mechanisms governing the activation and regulation of the MZ B cells following a bacterial challenge are not fully understood. Using a variety of cellular and molecular techniques, we propose to test the hypothesis that MZ B cells play an immunoregulatory role via IL-10 secretion in response to a blood-borne bacterial challenge. The findings will provide a better understanding of the mechanism by which MZ B cells respond during a bacterial infection and identify potential targets for therapeutic intervention. The following specific aims are designed to test our hypothesis: Aim 1: Determine if MZ B cells secrete IL-10 in response to a blood-borne bacterial challenge. Working Hypothesis: Antigen-specific MZ B cells secrete IL-10 in response to S. pneumoniae challenge. Aim 2: Determine the role of MZ B cell IL-10 production during response to a blood-borne bacterial challenge. Working Hypothesis: Antigen-specific MZ B cells play an immunoregulatory role via IL-10 secretion following S. pneumoniae challenge. Aim 3: Determine the mechanism by which B cells are activated to secrete IL-10. Working Hypothesis: B cells secrete IL-10 following gram+ and gram- bacterial challenge. RELAVANCE TO PUBLIC HEALTH: The goal of this project is to understand how the immune system fights off invading bacteria and affords protection from becoming sick. Once we understand how the immune system works, we will be able to develop new drugs and vaccination strategies to combat bacterial infections.