Abstract
Sjögren's syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining late-stage disease. Here, we identify tissue programs associated with disease onset using transcriptomic and immunohistological analysis of LGs from 5- and 7-week-old mice deficient in autoimmune response element (Aire). At 5 weeks of age (wk), Aire-/- mice show minimal tissue dysfunction and destruction compared to 7 wk Aire-/-, which exhibit severe dry eye, poor tear secretion, extensive lymphocytic infiltration, reduced functional innervation, and increased vascularization. Despite this mild phenotype, 5 wk Aire-/- LGs were highly enriched for signaling pathways previously associated with SS, including interferon gamma (IFNγ), interleukin 1 beta (IL1β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor (TLR) signaling, and interleukin-6/signal transducer and activator of transcription 3 (IL6/STAT3) signaling. Novel signaling pathways such as the semaphorin⁻plexin pathway were also noted. Intriguingly, we found an expansion of the ductal network with increasing disease. Activated STAT3, a blocker of apoptosis, was restricted to the ductal system and also increased with damage, highlighting its potential as a promoter of ductal cell survival. These data demonstrate the early activation of signaling pathways regulating inflammation, innervation, and cell survival before the onset of clinical disease indicators, suggesting their potential value as diagnostic biomarkers.