Novel Mechanisms of Chronic Inflammation in Sjogren's Syndrome

描述(申请人提供)：干燥综合征(SS)是一种自身免疫性疾病，以泪腺和唾液腺的炎症和破坏为特征，导致液体分泌减少(口干症)，通常与组织中的淋巴细胞渗透有关。SS患者涎腺组织中血管细胞黏附分子-1(VCAM-1)和细胞间黏附分子-1(ICAM-1)在小静脉内有明显的表达，周围小静脉周围有大量的CD4+T细胞。我们的研究表明，由于应激和损伤，P2Y2核苷酸受体(P2Y2R)在包括唾液腺在内的组织中表达上调，并调节黏附分子的表达和炎症反应。然而，目前尚不清楚P2Y2R上调是否调节了特异性黏附分子的表达，从而导致唾液腺中的淋巴细胞浸润。由于P2Y2R激动剂ATP和DTP是从受损或应激的细胞中释放出来的，因此在体内表达和激活P2Y2R无疑会增强其他促炎剂在SS中的有害作用。我们推测，SS唾液腺的慢性炎症是由P2Y2R信号通路介导的，该信号通路导致促进淋巴细胞结合的细胞黏附分子上调，这是一条可以用来延缓SS发展的新途径。拟议的研究将检验这样一个假设，即特定的细胞黏附分子被P2Y2R激活上调，以促进淋巴细胞对唾液腺细胞的黏附(特定目标1)。其他研究将确定P2Y2R介导的细胞黏附分子的表达和淋巴细胞对唾液腺细胞的黏附的信号通路，包括生长因子受体反式激活和基质金属蛋白酶的作用(特异性目标2)。此外，我们将确定体内激活的P2Y2Rs是否介导了黏附分子的表达，以促进淋巴细胞向唾液腺的渗透(特定目标3A)。此外，研究还将探讨黏附分子的表达和淋巴细胞向唾液腺的渗透是否可以通过体内沉默P2Y2R(特异性目标3B)来抑制SS的B10小鼠模型。这些研究应该导致更好的治疗策略，以最大限度地减少导致SS患者口干症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.