Novel Mechanisms of Chronic Inflammation in Sjogren's Syndrome

描述（由申请人提供）：干燥综合征（SS）是一种自身免疫性疾病，其特征是泪腺和唾液腺的炎症和破坏，导致液体分泌减少（口干症），通常与组织淋巴细胞浸润有关。SS患者的唾液腺活检显示，在浸润的CD4+ T细胞包围的小静脉中，血管细胞粘附分子-1 （VCAM-1）和细胞间粘附分子-1 （ICAM-1）的表达显著。我们的研究表明，P2Y2核苷酸受体（P2Y2R）在包括唾液腺在内的组织中由于应激和损伤而上调，并调节粘附分子的表达和炎症反应。然而，P2Y2R的上调是否调控导致唾液腺淋巴细胞浸润的特异性粘附分子的表达尚不清楚。由于P2Y2R激动剂ATP和DTP从受损或应激细胞中释放，P2Y2R在体内的表达和激活无疑增加了SS中其他促炎剂的有害作用。我们假设SS中唾液腺的慢性炎症是由P2Y2R信号通路介导的，导致细胞粘附分子的上调，从而促进淋巴细胞的结合。提出的研究将验证P2Y2R激活上调特异性细胞粘附分子以促进淋巴细胞粘附唾液腺细胞的假设（specific Aim 1）。其他研究将确定p2y2r介导的细胞粘附分子和淋巴细胞粘附唾液腺细胞的信号通路，包括生长因子受体反激活和基质金属蛋白酶的作用（Specific Aim 2）。此外，我们将确定体内P2Y2Rs的激活是否介导粘附分子表达，从而促进淋巴细胞浸润到唾液腺（Specific Aim 3A）。进一步，研究将探讨NOD的黏附分子表达和淋巴细胞浸润情况。体内P2Y2R沉默可抑制B10小鼠SS模型（Specific Aim 3B）。这些研究将导致更好的治疗策略，以尽量减少导致SS患者口干的唾液腺自身免疫相关炎症。

DESCRIPTION (provided by applicant): Sjogren's syndrome (SS) is an autoimmune disorder characterized by inflammation and destruction of lacrimal and salivary glands leading to decreased fluid secretion (xerostomia) often associated with lymphocytic infiltration of the tissue. Salivary gland biopsies from SS patients show a marked expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in venules surrounded by infiltrating CD4+ T cells. Our studies have shown that a P2Y2 nucleotide receptor (P2Y2R) is up-regulated in tissues, including salivary gland, due to stress and injury and regulates adhesion molecule expression and inflammatory responses. However, it is unknown whether P2Y2R up-regulation regulates the expression of specific adhesion molecules leading to lymphocyte infiltration in salivary gland. Since P2Y2R agonists ATP and DTP are released from damaged or stressed cells, P2Y2R expression and activation in vivo undoubtedly augments the deleterious effects of other pro-inflammatory agents in SS. We hypothesize that chronic inflammation of salivary glands in SS is mediated by P2Y2R signaling pathways leading to the up-regulation of cell adhesion molecules that promote the binding of lymphocytes, a novel pathway that can be exploited to retard the development of SS. Proposed studies will test the hypothesis that specific cell adhesion molecules are up-regulated by P2Y2R activation to promote lymphocyte adherence to salivary gland cells (Specific Aim 1). Other studies will define the signaling pathways involved in P2Y2R-mediated expression of cell adhesion molecules and lymphocyte adherence to salivary gland cells, including the contribution of growth factor receptor transactivation and matrix metalloproteases (Specific Aim 2). In addition, we will determine whether activation of P2Y2Rs in vivo mediates adhesion molecule expression to promote lymphocyte infiltration into salivary gland (Specific Aim 3A). Furthermore, studies will investigate whether adhesion molecule expression and lymphocyte infiltration into salivary glands of the NOD.B10 mouse model of SS can be inhibited by silencing of the P2Y2R in vivo (Specific Aim 3B). These studies should lead to better therapeutic strategies for minimizing autoimmune-associated inflammation of salivary gland that contributes to xerostomia in patients with SS.