Role of Islet-Infiltrating Lymphocytes in Obesity

 描述(申请人提供)：肥胖已经达到流行的程度，超过三分之一的美国人受到影响，近10%的美国人患有2型糖尿病(T2D)。T2D被认为是一种主要由肥胖引起的代谢性疾病，而1型糖尿病(T1D)是一种免疫介导的疾病。然而，在一些T2D患者中可以检测到T1D的多个特征，这表明肥胖症和/或T2D可能存在胰岛特异性自身免疫成分。这项应用将研究胰岛浸润性淋巴细胞在肥胖中的作用，目的是了解淋巴细胞耐受性的破坏如何导致β功能改变。我们发现，在高脂饮食诱导的肥胖模型中，T细胞和B细胞渗入胰岛，导致胰岛素抵抗，导致Pre-T2D。这些胰岛浸润性淋巴细胞具有较高比例的调节性T细胞。然而，对肥胖期间胰岛内淋巴细胞的功能几乎一无所知。我们的发现与人类疾病的相关性得到了一项研究的支持，该研究发现T2D患者的胰岛中有淋巴细胞渗透。肥胖中还存在全身性炎症，其特征是循环中的炎性细胞因子和局部胰岛以及脂肪炎症，这些炎症是由经典激活的(M1)单核吞噬细胞的积累促进的。M1单核巨噬细胞促进β细胞功能障碍和死亡，而交替激活的(M2)单核巨噬细胞与正常胰岛和胰岛修复有关。在肥胖症患者中，也有证据表明，存在对脂肪组织抗原具有自身反应的淋巴细胞。如果肥胖引起的炎症可以导致对脂肪抗原的免疫耐受性的打破，它是否也会导致对胰岛抗原的耐受性的打破？我们假设在肥胖中，胰岛浸润性效应淋巴细胞是胰岛特异性的，并促进β细胞功能障碍和死亡，部分是通过激活M1单核吞噬细胞；然而，局部调节淋巴细胞控制M1单核吞噬细胞介导的炎症以维持β细胞功能。为了验证这一假说，我们提出了以下目标：(1)确定在肥胖患者中，胰岛浸润性T细胞和B细胞是否是胰岛抗原特异性的；(2)确定胰岛浸润性淋巴细胞亚群对胰岛细胞死亡和功能障碍的影响；(3)确定胰岛浸润性淋巴细胞亚群如何影响胰岛中单核吞噬细胞的数量、表型和功能。了解肥胖症中胰岛浸润性淋巴细胞的功能可以改变我们对肥胖如何改变淋巴细胞耐受性导致对T1D和T2D易感性的理解，从而揭示支持这两种形式的糖尿病的β细胞功能和生存的治疗干预的新领域。

 DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions, affecting more than one third of Americans with almost 10 percent of Americans affected by type 2 diabetes (T2D). T2D is considered a metabolic disease that is largely induced by obesity, while type 1 diabetes (T1D) is an immune-mediated disease. However, multiple hallmarks of T1D can be detected in some T2D patients, suggesting that an islet-specific autoimmune component could be present in obesity and/or T2D. This application will investigate the role of islet-infiltrating lymphocytes in obesity with the goal of understanding how breaks in lymphocyte tolerance lead to altered beta function. We discovered that T cells and B cells infiltrate the isles in the high fat fed, diet induced obesity model which develops insulin resistance resulting in pre-T2D. These islet-infiltrating lymphocytes had a high percentage of regulatory T cells. However, virtually nothing is known about the function of lymphocytes within the islets during obesity. The human disease relevance of our finding is supported by a study that found lymphocyte infiltration in the islets of T2D patients. Also present in obesity is systemic inflammation that i characterized by circulating inflammatory cytokines and local islet and adipose inflammation that is promoted by the accumulation of classically activated (M1) mononuclear phagocytes. M1 mononuclear phagocytes promote beta cell dysfunction and death, while alternatively activated (M2) mononuclear phagocytes are associated with normal islets and islet repair. In obesity, there is also evidence to suggest that there are lymphocytes that are autoreactive for adipose tissue antigens. If obesity-induced inflammation can induce a break in immunological tolerance to adipose antigens can it also induce a break in tolerance to islet antigens? We hypothesize that in obesity, islet-infiltrating effector lymphocytes are islet-specific and promote beta cell dysfunction and death, in part through activation of M1 mononuclear phagocytes; however, local regulatory lymphocytes control M1 mononuclear phagocyte- mediated inflammation to maintain beta cell function. To test this hypothesis we propose the following aims: (1) to determine if in obesity, islet-infiltrating T cells and B cells are islet-antigen specific; (2) to determine the efect of islet-infiltrating lymphocyte subsets on beta cell death and dysfunction; and (3) to determine how islet- infiltrating lymphocyte subsets affect the number, phenotype and function of mononuclear phagocytes in the islets. Understanding the function of islet-infiltrating lymphocytes in obesity could change our understanding of how obesity alters lymphocyte tolerance leading to susceptibility to both T1D and T2D, thereby revealing new areas of therapeutic intervention to support beta cell function and survival in both forms of diabetes.