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.
Highlights
Sjögren’s syndrome (SS) is a complex autoimmune exocrinopathy that has been extensively reported in the clinical literature
In order to begin to define pathways activated during early disease onset we utilized the autoimmune response element (Aire)-/mice which exhibit epithelial barrier disruption, poor tear secretion, extensive lymphocytic infiltration, and vascularization of both lacrimal glands and cornea, as well as severe corneal pathologies and loss of lacrimal acini by 8 weeks of age as compared to age-matched wild types (WT) (Figure 1) [17]
We found a significant increase in duct cell proliferation (5 wk: 0.98% ± 0.60 vs. 6.12% ± 1.59, p = 0.04; 7 wk: 0.33% ± 0.33 vs. 9.90% ± 2.33, p = 0.02, Figure 3C) and limited cell death (5 wk: 0.11% ± 0.11 vs. 0.31% ± 0.14, p = 0.28; 7 wk: 0.19% ± 0.11 vs. 0.92% ± 0.16, p = 0.01, Figure 3D) in both the 5 and 7 wk lacrimal glands (LG) compared to WT LG
Summary
Sjögren’s syndrome (SS) is a complex autoimmune exocrinopathy that has been extensively reported in the clinical literature. While several important discoveries have been made in the clinical diagnosis and management of SS, many of the molecular pathways that mediate the pathogenesis of SS-associated exocrinopathy remain poorly articulated This is due, in part, to a limited understanding of the genetic framework that underpins the disease process and the lack of meaningful genetic biomarkers that are strongly associated with the disease. By 7–8 weeks the lacrimal glands of Aire-/- mice exhibit extensive lymphocytic infiltration combined with corneal pathologies and severe dry eye. It is not known when these disease outcomes are initiated in the Aire-/- mouse. Aire-/-, but the time course of disease development is slower, the extent of multi-organ involvement is less, and the average life span extends up to ~16 weeks Our findings provide a holistic overview of genetic changes associated with early disease processes, as well as specific genetic biomarkers that can be used to define the mechanism of disease development and progression
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