Regulatory B cells in the liver

描述（由申请人提供）：有效区分无害和致病抗原构成了有效免疫功能的基础。在肝脏的独特环境中，适当抑制免疫应答是特别重要的，因为肝内细胞持续暴露于通过门静脉循环引入的来自肠道的外来抗原。一般来说，肝脏在组成上倾向于耐受性反应。同种异体肝移植通常被患者接受，对免疫抑制药物的要求最低，并且可以通过将血液从门静脉转移到体循环来消除对饮食抗原的口服耐受性。此外，诸如疟原虫和肝炎病毒等病原体对肝脏的慢性和持续感染是人类发病率和死亡率的常见和重要来源。操纵肝脏免疫应答的能力可能会发现广泛的临床适用性;然而，开发此类策略将需要更好地理解肝脏内免疫应答和免疫耐受之间平衡的机制。为此，该建议集中于肝B细胞在肝脏免疫应答调节中的作用。在小鼠中，肝B细胞表达免疫调节细胞因子IL-10，以响应在其自然生命周期中经历肠肝迁移的寄生线虫感染。当转移到缺乏内源性IL-10的小鼠体内时，这些B细胞控制了受体中发生的广泛的肝脏炎症。我们假设蠕虫激活的B细胞通过采用IL-10依赖性调节表型来下调肝脏中的炎症。我们打算通过首先确定肝B细胞是否代表B细胞的传统亚群或是否包含肝脏内的独特群体来检验这一假设。然后，我们将确定肝B细胞是否经历肝肠循环，以及是否需要抗原特异性来行使其调节作用。我们还将研究IL-10是否是产生调控表型和/或定向调控细胞功能所必需的。总之，这些研究将探索肝B细胞中调节生活方式的发展要求以及IL-10如何塑造这种表型。此外，这些实验将完善我们对肝脏中免疫反应如何控制的理解。公共卫生相关性：必须调节免疫反应，以防止过度炎症和随后的组织损伤。我们对控制炎症的机制的了解是不完整的，但很明显，平衡的免疫反应是维持健康所必需的。我们的研究可能会深入了解以不适当炎症为特征的疾病和病症，并为我们如何操纵免疫系统以减轻不必要的炎症提供线索。

DESCRIPTION (provided by applicant): Efficient discrimination between innocuous and pathogenic antigens forms the basis of effective immune function. Appropriate restraint of immune responsiveness is particularly important within the unique environment of the liver, since intrahepatic cells are continuously exposed to foreign antigens from the gut that is introduced via the portal circulation. In general, the liver is constitutively predisposed to tolerant responses. Allogeneic liver transplants are often accepted by patients with minimal requirements for immunosuppressive medications, and oral tolerance to dietary antigens can be abrogated by diversion of blood from the portal vein to the systemic circulation. In addition, chronic and persistent infection of the liver with pathogens such as Plasmodium and hepatitis viruses is a common and significant source of human morbidity and mortality. The ability to manipulate hepatic immune responses would likely find broad clinical applicability; however, development of such strategies will require a better understanding of the mechanisms underlying the balance between immune responsiveness and immune tolerance within the liver. To that end, this proposal focuses on the role of hepatic B cells in the regulation of immune responses in the liver. In mice, hepatic B cells express the immunomodulatory cytokine, IL-10, in response to infection with a parasitic nematode that undergoes enterohepatic migration during its natural life cycle. When transferred into mice lacking endogenous IL-10, these B cells control the extensive hepatic inflammation that otherwise develops in the recipients. We hypothesize that helminth-activated B cells down-regulate inflammation in the liver by adopting an IL-10- dependent regulatory phenotype. We intend to test this hypothesis by first establishing whether hepatic B cells represent a traditional subset(s) of B cells or comprise a unique population within the liver. We will then determine whether hepatic B cells undergo enterohepatic circulation and if antigen specificity is required for exercise of their regulatory effects. We also will examine whether IL-10 is required for generation of the regulatory phenotype and/or the function of committed regulatory cells. Together, these studies will explore the requirements for development of a regulatory lifestyle in hepatic B cells and how IL-10 shapes this phenotype. Moreover, the experiments will refine our understanding of how immune responses are controlled in the liver. PUBLIC HEALTH RELEVANCE: Immune responses must be regulated to prevent excessive inflammation and subsequent tissue injury. Our knowledge of the mechanisms involved in controlling inflammation is incomplete, but it is clear that a balanced immune response is necessary to maintain health. Our studies likely will generate insight into diseases and conditions that are characterized by inappropriate inflammation and provide clues as to how we may manipulate the immune system to alleviate unwanted inflammation.