Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose
Sjögren’s syndrome (SS) is a chronic autoimmune disease with unknown etiology. Affecting from 0.2% to 3.0% of the total population, with a 9:1 female to male ratio, Sjögren’s patients suffer from a reduction in salivary flow which leads to tenacious dry mouth and dry eyes symptoms causing debilitating oral complications, in addition to extra-glandular systemic manifestations. Our focus has been to assess the possible mechanism(s) underlying the reduction in salivary flow by examining cellular volume regulation and the trigger to this regulation which is calcium signaling. Saliva is an orchestrated process initiated by neurotransmitter stimulation which is critically regulated by an increase in cytosolic calcium. This increase in calcium triggers ion channel activities, leading to the secretion of fluid which can be detected as a decrease in cell volume. We hypothesized that alterations in calcium signaling in acinar cells (where secretion is produced) accounts for the reduction in salivary flow seen in SS.
Methods
A non-enzymatically dispersed organotypic tissue preparation was used to maintain the microenvironment. Human minor salivary gland biopsies were finely minced (0.5mm) to obtain cell clusters which were loaded with cytosolic calcium indicator (Fluo-2AM) or cell-volume indicator, calcein. The loaded cell clusters were then used for live-cell imaging using confocal microscopy. In addition we performed immunoflourescence to label key proteins involved in calcium and volume regulation in salivary glands such as AQP5, STIM1, and IP3 receptor 3 (IP3R3).
Results
Acinar cells from SS patients displayed significant attenuation of agonist-stimulated cytosolic calcium increases when compared to the function in cells from normal healthy volunteers. Both intracellular release and Ca2+ influx were substantially reduced. This was correlated with a loss of agonist stimulated decrease in cell volume. Decrease in cell volume is indicative of fluid secretion and is completely dependent on increase in [Ca2+]i. There was a significant correlation between agonist – induced volume decrease and saliva secretion within the patient population. Together these data demonstrate that the reduced salivary secretion in the SS patients is due to reduced Ca2+ signaling in acinar cells. To further determine underlying factors causing the functional defect we examined the expression of critical components involved in calcium mobilization and fluid secretion; AQP5, STIM1, and IP3R. Within the area of infiltration, there was cell damage and all proteins were disrupted. In the area around the infiltrate there was no change in AQP5. STIM1 was reduced in cells around the infiltrate, but not in areas further away infiltrating site. Importantly, IP3R was uniformly decreased in all areas of the gland.
Conclusion
Our findings reveal an underlying defect in IP3R in acinar cells that can account for loss of salivary secretion in patients with low levels of lymphocytic infiltration and minimal tissue damage. Further studies are required to determine what causes loss of IP3R.
Disclosure:
L. Y. Teos,
None;
B. Swaim,
None;
M. Grisius,
None;
A. P. Cotrim,
None;
S. I. Jang,
None;
L. Bebris,
None;
D. Yule,
None;
G. G. Illei,
None;
I. Ambudkar,
None;
I. Alevizos,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ip3r3-deficit-underlies-the-loss-of-fluid-secretion-in-salivary-glands-from-sjogrens-syndrome-patients/