Tyk2 and Associated Cytokines in Salivary Gland Autoimmunity

项目摘要 干燥病是一种以免疫介导为特征的慢性自身免疫性疾病 唾液腺和泪腺破坏，导致严重口干和相关口腔 健康并发症、威胁视力的干眼病和生活质量下降。的 干燥症的免疫机制知之甚少， 治疗方法已经确定。目前迫切需要确定早期免疫学 这些机制有助于确定早期诊断和更有效治疗的目标。诊断 发生在自身免疫过程开始后数年， 对人类来说不切实际。非肥胖型糖尿病（NOD）小鼠自发形成唾液腺 自身免疫性，具有与人类舍格伦病相似的特征，包括特征性局灶性 淋巴细胞性涎腺炎是人类干燥症的标志。我们最近发现， 基因编辑以破坏NOD小鼠中的Tyk 2基因，可预防 淋巴细胞外源性方式。Tyk 2是一种非受体酪氨酸激酶， 炎性细胞因子和TYK 2基因变体与人类的干燥症有关。我们 该提案的目标是定义特异性先天免疫细胞亚群和上游免疫细胞。 需要Tyk 2介导的信号传导以发展自身免疫性唾液腺炎的细胞因子 腺体疾病我们的中心假设是，白细胞介素（IL）-12和IL-23信号通过 唾液腺内抗原呈递细胞中的Tyk 2需要驱动病灶 淋巴细胞性涎腺炎检验这一假设的具体目标是：（1）鉴定 NOD小鼠中唾液腺炎症需要Tyk 2信号传导;（2）定义要求 IL-12和IL-23在局灶性淋巴细胞性涎腺炎发展中的作用。我们将使用NOD 基于小鼠的自发性疾病模型，基因编辑的NOD菌株，我们的过继转移 模型、骨髓嵌合体、体外培养物和体内精氨酸阻断疗法， 进行这些研究。完成这些研究的重大积极影响包括 定义Tyk 2和相关细胞因子驱动唾液腺的机制 自身免疫，这将导致早期诊断生物标志物的发展和识别 免疫蛋白可以治疗干燥症值得注意的是，Tyk 2的抑制剂 正在开发中，IL-12和IL-23阻断疗法已经可用于治疗其他 自身免疫性疾病确定Tyk 2和相关细胞因子在Sjögren意志中的作用 有助于指导Tyk 2和相关细胞因子阻断疗法在以下亚群中的未来研究： 与Sjogren的人。

PROJECT SUMMARY Sjögren’s disease is a chronic autoimmune disease characterized by immune-mediated destruction of salivary and lacrimal glands leading to profound dry mouth and associated oral health complications, vision-threatening dry eye disease, and decreased quality of life. The immunological mechanisms of Sjögren’s are poorly understood, and no disease-modifying therapies have been identified. There is a critical need to define the early immunological mechanisms to identify targets for earlier diagnostics and more effective therapies. Diagnosis occurs years after initiation of the autoimmune process making the study of early mechanisms impractical in humans. Nonobese diabetic (NOD) mice spontaneously develop salivary gland autoimmunity with features similar to Sjögren’s in humans including the characteristic focal lymphocytic sialadenitis that is a hallmark of Sjögren’s in humans. We have recently found that gene-editing to disrupt the Tyk2 gene in NOD mice prevents salivary gland inflammation in a lymphocyte-extrinsic manner. Tyk2 is a non-receptor tyrosine kinase associated with several inflammatory cytokines, and TYK2 gene variants are associated with Sjögren’s in humans. Our goals in this proposal are to define the specific innate immune cell subsets and the upstream cytokines that require Tyk2-mediated signaling for the development of autoimmune salivary gland disease. Our central hypothesis is that interleukin (IL)-12 and IL-23 signaling through Tyk2 in antigen presenting cells within the salivary glands are required to drive the focal lymphocytic sialadenitis. The specific aims to test this hypothesis are: (1) Identify cells that require Tyk2 signaling for salivary gland inflammation in NOD mice; (2) Define the requirements for IL-12 and IL-23 in the development of focal lymphocytic sialadenitis. We will use the NOD mouse-based spontaneous disease model, genetically edited NOD strains, our adoptive transfer model, bone marrow chimeras, in vitro cultures, and in vivo cytokine-blocking therapies to perform these studies. The significant positive impact of completing these studies include defining the mechanisms by which Tyk2 and associated cytokines drive salivary gland autoimmunity, which will lead to development of early diagnostic biomarkers and identification of immune proteins that can be targeted therapeutically in Sjögren’s. Notably, inhibitors of Tyk2 are in development, and IL-12 and IL-23 blocking therapies are already available to treat other autoimmune diseases. Identifying the roles of Tyk2 and associated cytokines in Sjögren’s will help guide future studies of Tyk2 and associated cytokine blocking therapies in subsets of individuals with Sjögren’s.