Role of Islet-Infiltrating Lymphocytes in Obesity

 描述（由申请人提供）：肥胖已达到流行病的比例，影响超过三分之一的美国人，近10%的美国人患有2型糖尿病（T2 D）。T2 D被认为是一种代谢性疾病，主要由肥胖引起，而1型糖尿病（T1 D）是一种免疫介导的疾病。然而，在一些T2 D患者中可以检测到T1 D的多种标志，这表明肥胖和/或T2 D中可能存在胰岛特异性自身免疫组分。本申请将研究胰岛浸润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T细胞和B细胞浸润高脂肪喂养的饮食诱导的肥胖模型中的岛，其发展胰岛素抗性，导致前T2 D。这些胰岛浸润淋巴细胞具有高比例的调节性T细胞。然而，几乎没有人知道肥胖期间胰岛内淋巴细胞的功能。我们发现的人类疾病相关性得到了一项研究的支持，该研究发现T2 D患者胰岛中存在淋巴细胞浸润。肥胖症中还存在以循环炎性细胞因子为特征的全身性炎症以及由经典活化（M1）单核吞噬细胞的积累促进的局部胰岛和脂肪炎症。M1单核吞噬细胞促进β细胞功能障碍和死亡，而交替激活（M2）单核吞噬细胞与正常胰岛和胰岛修复相关。在肥胖症中，也有证据表明存在对脂肪组织抗原具有自身反应性的淋巴细胞。如果肥胖引起的炎症可以诱导对脂肪抗原的免疫耐受性的破坏，那么它也可以诱导对胰岛抗原的耐受性的破坏吗？我们假设，在肥胖症中，胰岛浸润效应淋巴细胞是胰岛特异性的，部分通过激活M1单核吞噬细胞促进β细胞功能障碍和死亡;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。为了检验这一假设，我们提出以下目标：（1）确定在肥胖症中，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β细胞死亡和功能障碍的影响;和（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。了解胰岛浸润淋巴细胞在肥胖中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T1 D和T2 D易感性的理解，从而揭示治疗干预的新领域，以支持β细胞功能和两种形式的糖尿病的生存。

 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.