Cytokines driving T cell dysregulation in lacrimal gland autoimmunity

项目摘要 干燥综合征是一种慢性自身免疫性疾病， 泪腺和唾液腺的破坏导致威胁视力的干眼病， 严重的口干和整体生活质量下降。干燥综合征的免疫发病机制 综合征是知之甚少，治疗未能阻止自身免疫性破坏的 目标腺体。迫切需要确定疾病发生的机制，以克服 设计有效疗法的障碍。疾病起始先于临床表现， 几年（甚至几十年）排除了在人类中进行此类研究。非肥胖糖尿病（NOD）小鼠 发展泪腺和唾液腺的自发性自身免疫，具有几个特征 类似于人类的舍格伦综合征，包括T细胞在介导 自身免疫系统攻击这些腺体我们最近发现泪腺 NOD小鼠中的自身免疫需要白细胞介素27（IL 27）和I型干扰素（IFN）。这些 细胞因子具有免疫刺激和免疫调节作用， 在上下文中。因此，直接靶向IL 27或I型IFN可能不适合于治疗。 干燥综合征的治疗我们研究的长期目标是确定新的 干燥综合征的治疗靶点我们在本建议书中的目标是确定 IL 27和I型IFN驱动NOD小鼠泪腺自身免疫的机制 干燥综合征模型。我们的中心假设是先天免疫信号（例如，I型 IFN）促进泪腺抗原呈递细胞产生IL 27，其驱动致病性 效应T细胞靶向泪腺。我们检验这一假设的具体目标是：（1）识别 IL 27的细胞靶点和对泪腺所需的效应T细胞的下游作用 （2）定义IL 27的上游触发因子，包括I型IFN在驱动IL 27的自身免疫中的作用。 男性特有的泪腺疾病。我们将使用NOD小鼠自发性疾病 模型，基因编辑的NOD菌株，我们的过继转移模型，骨髓嵌合体， 进行这些研究。完成这些工作的重大积极影响 研究包括确定人类疾病相关细胞因子驱动T细胞的机制， 泪腺自身免疫失调，这将导致新的疗法，以阻止 自身免疫攻击考虑到IL 27和I型IFN在其他自身免疫性疾病中的作用， 这一发现也可能为其他自身免疫性疾病的治疗提供线索。

PROJECT SUMMARY Sjögren syndrome is a chronic autoimmune disease characterized by immune-mediated destruction of lacrimal and salivary glands leading to vision-threatening dry eye disease, profound dry mouth, and overall decreased quality of life. The immunopathogenesis of Sjögren syndrome is poorly understood, and treatments fail to halt the autoimmune destruction of the targeted glands. There is a critical need to identify mechanisms of disease initiation to overcome barriers to designing effective therapies. Disease initiation precedes clinical manifestations by years (even decades) precluding such studies in humans. Nonobese diabetic (NOD) mice develop spontaneous autoimmunity of lacrimal and salivary glands with several features resembling Sjögren syndrome in humans including the central role of T cells in mediating the autoimmune attack on these glands. We have recently discovered that lacrimal gland autoimmunity in NOD mice requires interleukin 27 (IL27) and type I interferons (IFN). These cytokines are complex with both immunostimulatory and immunomodulatory effects depending on the context. Thus, directly targeting IL27 or type I IFN may not be appropriate in the treatment of Sjögren syndrome. The long-term goal of our research is to identify new therapeutic targets for Sjögren syndrome. Our objectives in this proposal are to identify mechanisms by which IL27 and type I IFN drive lacrimal gland autoimmunity in the NOD mouse model of Sjögren syndrome. Our central hypothesis is that innate immune signals (eg, type I IFN) promote lacrimal gland antigen presenting cells to produce IL27, which drives pathogenic effector T cells to target lacrimal glands. Our specific aims to test this hypothesis are: (1) Identify the cellular targets of IL27 and downstream effects on effector T cells required for lacrimal gland autoimmunity; (2) Define the upstream triggers of IL27 including the role of type I IFN in driving male-specific lacrimal gland disease. We will use the NOD mouse-based spontaneous disease model, genetically edited NOD strains, our adoptive transfer model, bone marrow chimeras, and in vitro cultures to pursue these studies. The significant positive impact of completing these studies includes identifying mechanisms by which human disease-relevant cytokines drive T cell dysregulation in lacrimal gland autoimmunity, which will lead to novel therapies to halt the autoimmune attack. Given the roles of IL27 and type I IFN in other autoimmune diseases, these findings may lead to therapies for other autoimmune diseases as well.