Regulatory B cells in the liver

描述(申请人提供)：有效区分无害和致病抗原是有效免疫功能的基础。在肝脏这个独特的环境中，适当地抑制免疫反应尤为重要，因为肝内细胞持续暴露于来自肠道的外来抗原，这些外来抗原通过门静脉循环进入肝脏。一般来说，肝脏天生就容易产生耐受性反应。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，通过将血液从门静脉转移到体循环，可以消除口服对饮食抗原的耐受性。此外，慢性和持续性的肝脏感染病原体，如疟原虫和肝炎病毒，是人类发病率和死亡率的常见和重要来源。操纵肝脏免疫反应的能力可能会在临床上得到广泛的应用；然而，这种策略的开发将需要更好地理解肝脏内免疫反应和免疫耐受之间平衡的机制。为此，这项建议侧重于肝脏B细胞在调节肝脏免疫反应中的作用。在小鼠中，肝脏B细胞表达免疫调节细胞因子IL-10，以应对在其自然生命周期中经历肠道-肝脏迁移的寄生线虫的感染。当转移到缺乏内源性IL-10的小鼠体内时，这些B细胞控制了受体体内否则会发展成的广泛的肝脏炎症。我们假设蠕虫激活的B细胞通过采用IL-10依赖的调节表型来下调肝脏的炎症。我们打算通过首先确定肝B细胞是否代表传统的B细胞亚群(S)或包括肝脏内的一个独特群体来检验这一假设。然后我们将确定肝B细胞是否经历肠-肝循环，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是否是产生调节表型和/或承诺调节细胞功能所必需的。总之，这些研究将探索在肝B细胞中发展调节性生活方式的要求，以及IL-10如何塑造这种表型。此外，这些实验将加深我们对肝脏中免疫反应是如何控制的理解。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还不完全，但很明显，平衡的免疫反应对于维持健康是必要的。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状况，并提供关于我们如何操纵免疫系统以减轻不必要的炎症的线索。

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.