Project summary Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (Hsa21) and is the most common genetic cause of intellectual disability. DS predisposes affected individuals to a wide range of comorbidities that shorten their life expectancy and lower quality of life. People with DS are strongly predisposed to develop autoimmune disorders, show consistent activation of interferon (IFN) responses, and produce significantly less saliva than healthy controls. These last set of features are shared with another syndrome, Sjogren’s Disease (SjD), an autoimmune disease affecting salivary (and lacrimal) glands resulting in reduced saliva, elevated autoantibodies (SSA, SSB) in serum, and lymphocytic infiltration of the glands. In DS, there is a triplication of the interferon receptor (IFNR) gene cluster resulting in chronic interferon hyperactivity and inflammation. In SjD, patients exbibit not only salivary gland inflammation and elevated levels of type 1 IFN. Because of the shorter life expectancy associated with DS and given that SjD predominantly affects middle-aged persons, this may have biased findings linking both conditions, although some case reports have described SjD in DS. Our preliminary data, obtained in our studies part of the parent grant, show that Dp16 mice hyposalivate, indicating abnormal salivary gland function. The aim of this supplement is to address if DS is a condition that predisposes individuals to develop Sjogren’s-like disease. To address this, we will challenge the Dp16 mice, a well-known DS mouse model, with agonists of both toll-like receptors (TLR), particularly TLR7 and TLR8, which we and others have been reported in salivary glands and in SjD, and interferon stimulation (e.g. DMXAA), and to test the ability of common blockers of IFN signaling, such as JAK inhibitors, to ameliorate inflammation and improve salivation. These studies enhance the goals of the parent award by assessing whether the salivary glands in Dp16 mice are prone to developing an inflammatory response typical of SjD.