Tyk2 and Associated Cytokines in Salivary Gland Autoimmunity

项目总结 Sjögren病是一种以免疫调节为特征的慢性自身免疫性疾病 唾液和泪腺的破坏导致严重的口干和相关的口腔 健康并发症、威胁视力的干眼病和生活质量下降。这个 Sjögren‘s的免疫学机制知之甚少，也没有改变疾病的方法 治疗方法已经确定。迫切需要定义早期免疫学 为早期诊断和更有效的治疗确定靶点的机制。诊断学 发生在自身免疫过程启动数年后，使得对早期机制的研究 在人类身上是不现实的。非肥胖糖尿病(NOD)小鼠自发形成唾液腺 自身免疫具有与人类Sjögren相似的特征，包括特征病灶 淋巴细胞性涎腺炎，这是人类干燥症的一个特征。我们最近发现， 在NOD小鼠中进行基因编辑以破坏TYK2基因可防止唾液腺炎症 淋巴细胞--外在方式。TYK2是一种非受体酪氨酸激酶，与几种 炎性细胞因子和TYK2基因变异与人类的Sjögren‘s有关。我们的 该提案的目标是定义特定的先天免疫细胞亚群和上游 自身免疫性唾液发育需要TYK2介导的信号转导的细胞因子 腺病。我们的中心假设是IL-12和IL-23通过 唾液腺内的抗原提呈细胞中的TYK2需要驱动病灶 淋巴细胞性涎腺炎。检验这一假设的具体目的是：(1)识别 NOD小鼠唾液腺炎症需要TYK2信号；(2)定义要求 IL-12和IL-23在局灶性淋巴细胞性涎腺炎发生中的作用。我们将使用点头 基于小鼠的自发性疾病模型，基因编辑的NOD株，我们的领养转移 模型、骨髓嵌合体、体外培养和体内细胞因子阻断疗法 进行这些研究。完成这些研究的重大积极影响包括 确定TYK2及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记物的开发和识别 可以在Sjögren‘s治疗中靶向的免疫蛋白。值得注意的是，TYK2的抑制剂 正在开发中，IL-12和IL-23阻断疗法已经可以用于治疗其他 自身免疫性疾病。确定TYK2及其相关细胞因子在Sjögren遗嘱中的作用 帮助指导TYK2和相关细胞因子阻断疗法在卵巢癌亚群中的未来研究 患有Sjögren‘s的个人。

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.