Androgens and Integrins in Salivary Glands in Sjögren’s Syndrome

2010 ◽  
Vol 37 (6) ◽  
pp. 1181-1187 ◽  
Author(s):  
PAULIINA POROLA ◽  
MIKAEL LAINE ◽  
ISMO VIRTANEN ◽  
RAIMO PÖLLÄNEN ◽  
BEATA D. PRZYBYLA ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Salivary Glands ◽  
Sjögren’S Syndrome ◽  
Messenger Rna ◽  
Sjögren's Syndrome ◽  
Acinar Cells ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Mrna Levels ◽  
Sjögren‘S Syndrome

Objective.Laminin α1-chain normally induces intercalated duct progenitors to differentiate to acinar cells through integrin (INT) α1ß1 and α2ß1 receptors. Maintenance of acinar cells is impaired in Sjögren’s syndrome (SS), which is also characterized by low levels of serum and salivary androgens. We hypothesized that androgens normally support salivary gland remodeling by upregulating either laminin α1 chain or its cellular α1 or α2 INT subunit-containing receptors.Methods.Intercalated duct and acinar human salivary gland (HSG) cells and labial salivary gland (LSG) biopsies from healthy controls and patients with SS were cultured without or with sex steroids. Laminin α1 chain and INT α1 and α2 subunits were studied using quantitative reverse-transcription real-time polymerase chain reaction and INT α1 and α2 subunits using immunofluorescence staining.Results.INT α1-subunit and α2-subunit messenger RNA (mRNA) levels were increased in intercalated duct and acinar cells by DHEA and testosterone. In contrast, laminin α1-chain mRNA levels were not affected. The upregulating effect of DHEA on INT subunits was also seen at the protein level. DHEA also increased mRNA levels of both INT subunits in healthy but not SS LSG.Conclusion.Androgens increased INT α1 and α2 subunits in tubuloepithelial cells and in healthy LSG, but in SS salivary glands this androgen regulation was defective, which is likely to contribute to defective outside-in signaling, acinar atrophy, and ductal cell hyperplasia.

Lacrimal and Salivary Gland Inflammation in the C3H/lpr Autoimmune Strain Mouse: A Potential Mode for Sjögren's Syndrome

1992 ◽  
Vol 106 (4) ◽  
pp. 394-399 ◽  
Author(s):  
Ilsa Schwartz ◽  
Bruce C. Johnson ◽  
Jane I. Morton ◽  
Dennis R. Trune
Keyword(s):  
Salivary Gland ◽  
Autoimmune Disease ◽  
Salivary Glands ◽  
Sjögren’S Syndrome ◽  
Lacrimal Gland ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Systemic Autoimmune Disease ◽  
Sjögren‘S Syndrome

Sjögren's syndrome is an autoimmune inflammatory disease that affects the lacrimal and salivary glands. To identify a potential animal model for study of Sjögren's syndrome, an evaluation was made of lacrimal and salivary glands in the C3H/ lpr autoimmune strain mouse at ages before (2 months) and after (5 months) systemic autoimmune disease onset at 3 to 4 months. Quantitative and qualitative analyses of, C3H/ lpr lacrimal and salivary (parotid, submandibular, and sublingual) gland histopathology were performed using age-matched C3H/HeJ nonautoimmune mice to control for inflammation of nonautoimmune origin. No lacrimal or salivary gland inflammation was seen in either of the strains at 2 months of age and measures of systemic autoimmune disease were negative. At 5 months of age, the nonautoimmune C3H/HeJ controls showed a slight increase in lacrimal gland inflammation, but this was not significantly different from the 2 month old controls. A significant increase in lacrimal gland inflammation was found in the 5 month old C3H/ lpr autoimmune mice in a histologic pattern similar to that of Sjögren's syndrome in human beings. Furthermore, the degree of inflammation was positively correlated with serum immune complexes and spleen weight. Sporadic inflammation of the submandibular gland was seen in both autoimmune and control mice, but this was neither statistically significant nor correlated with measures of autoimmunity. No significant inflammation was seen in the parotid or sublingual glands.

scholarly journals Cenerimod, a selective S1P1 receptor modulator, improves organ-specific disease outcomes in animal models of Sjögren’s syndrome

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Estelle Gerossier ◽  
Saba Nayar ◽  
Sylvie Froidevaux ◽  
Charlotte G. Smith ◽  
Celine Runser ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Mouse Model ◽  
Salivary Glands ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Clinical Parameters ◽  
Lymphoid Structures ◽  
Sjögren‘S Syndrome

Abstract Background Sjögren’s syndrome is a systemic autoimmune disease characterized by immune cells predominantly infiltrating the exocrine glands and frequently forming ectopic lymphoid structures. These structures drive a local functional immune response culminating in autoantibody production and tissue damage, associated with severe dryness of mucosal surfaces and salivary gland hypofunction. Cenerimod, a potent, selective and orally active sphingosine-1-phosphate receptor 1 modulator, inhibits the egress of lymphocytes into the circulation. Based on the mechanism of action of cenerimod, its efficacy was evaluated in two mouse models of Sjögren’s syndrome. Methods Cenerimod was administered in two established models of Sjögren’s syndrome; firstly, in an inducible acute viral sialadenitis model in C57BL/6 mice, and, secondly, in the spontaneous chronic sialadenitis MRL/lpr mouse model. The effects of cenerimod treatment were then evaluated by flow cytometry, immunohistochemistry, histopathology and immunoassays. Comparisons between groups were made using a Mann-Whitney test. Results In the viral sialadenitis model, cenerimod treatment reduced salivary gland immune infiltrates, leading to the disaggregation of ectopic lymphoid structures, reduced salivary gland inflammation and preserved organ function. In the MRL/lpr mouse model, cenerimod treatment decreased salivary gland inflammation and reduced T cells and proliferating plasma cells within salivary gland ectopic lymphoid structures, resulting in diminished disease-relevant autoantibodies within the salivary glands. Conclusions Taken together, these results suggest that cenerimod can reduce the overall autoimmune response and improve clinical parameters in the salivary glands in models of Sjögren’s syndrome and consequently may reduce histological and clinical parameters associated with the disease in patients.

scholarly journals Cytokine messenger rna expression in the labial salivary glands of patients with Sjögren's syndrome

1996 ◽  
Vol 39 (8) ◽  
pp. 1376-1384 ◽  
Author(s):  
Yukiko Ohyama ◽  
Seiji Nakamura ◽  
Goro Matsuzaki ◽  
Masanori Shinohara ◽  
Akiko Hiroki ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Sjögren’S Syndrome ◽  
Messenger Rna ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Rna Expression ◽  
Sjögren‘S Syndrome

scholarly journals Targeted TNF-α Overexpression Drives Salivary Gland Inflammation

2019 ◽  
Vol 98 (6) ◽  
pp. 713-719 ◽  
Author(s):  
A. Limaye ◽  
B.E. Hall ◽  
L. Zhang ◽  
A. Cho ◽  
M. Prochazkova ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Salivary Glands ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Genetic Recombination ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Aquaporin 5 ◽  
Tnf Α ◽  
Sjögren‘S Syndrome

Chronic inflammation of the salivary glands from pathologic conditions such as Sjögren’s syndrome can result in glandular destruction and hyposalivation. To understand which molecular factors may play a role in clinical cases of salivary gland hypofunction, we developed an aquaporin 5 (AQP5) Cre mouse line to produce genetic recombination predominantly within the acinar cells of the glands. We then bred these mice with the TNF-αglo transgenic line to develop a mouse model with salivary gland–specific overexpression of TNF-α; which replicates conditions seen in sialadenitis, an inflammation of the salivary glands resulting from infection or autoimmune disorders such as Sjögren’s syndrome. The resulting AQP5-Cre/TNF-αglo mice display severe inflammation in the salivary glands with acinar cell atrophy, fibrosis, and dilation of the ducts. AQP5 expression was reduced in the salivary glands, while tight junction integrity appeared to be disrupted. The immune dysregulation in the salivary gland of these mice led to hyposalivation and masticatory dysfunction.

scholarly journals SAT0214 ULTRASONOGRAPHIC CHANGES OF SALIVARY GLANDS IN PRIMARY SJOGREN’S SYNDROME: A LONGITUDINAL PROSPECTIVE STUDY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1050.2-1050
Author(s):  
H. R. Kim ◽  
K. A. Lee ◽  
S. H. Lee ◽  
S. H. Kim
Keyword(s):  
Salivary Gland ◽  
Salivary Glands ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Primary Sjögren’S Syndrome ◽  
Sicca Syndrome ◽  
Major Salivary Glands ◽  
Sjögren‘S Syndrome

Background:In the diagnosis of primary Sjogren’ syndrome (SS), salivary gland ultrasound is useful tool. Until now, there is no data for ultasonographic changes of major salivary glands over time.Objectives:This study aimed to evaluate the changes in abnormalities of salivary gland ultrasound (SGUS) over time in patients with pSS.Methods:Patients with pSS (n=70) and idiopathic sicca syndrome (n=18) underwent SGUS twice at baseline and 2 years later. The semi-quantitative SGUS score (0-48) was used, which comprises five parameters: parenchymal echogenicity, homogeneity, hypoechoic areas, hyperechogenic reflections, and clearness of posterior borders. The intraglandular power Doppler signal (PDS) was also assessed. The changes of these SGUS variables were compared in patients with pSS and idiopathic sicca syndrome.Results:The median (interquartile range) total SGUS scores at baseline was 27 (14) in patients with and 4 (3) in those with idiopathic sicca syndrome (p<0.001). In the pSS group, the total SGUS scores and the SGUS scores for bilateral parotid glands were significantly increased during median 23.4 month follow-up (p=0.013 andp=0.011, respectively). Homogeneity and hypoechoic areas were the domain to show statistically significant progression of SGUS scores. None of the SGUS scores changed significantly in the patients with idiopathic sicca syndrome. In patients with pSS, baseline and follow-up PDS sum scores of four salivary glands were significant higher in worsening SGUS group (n=13) than no change/improvement SGUS group (n=55/2).Conclusion:The structural abnormalities in major salivary glands assessed using SGUS scores progressed significantly in patients with pSS. In pSS group, 18.6% patients had worsening SGUS scores during 2 years. Intra-glandular hypervascularity was associated with worsening of salivary gland abnormalities.References:[1]Delli K, Dijkstra PU, Stel AJ, Bootsma H, Vissink A, Spijkervet FK. Diagnostic properties of ultrasound of major salivary glands in Sjogren’s syndrome: a meta-analysis. Oral diseases. 2015;21(6):792-800.[2]Jousse-Joulin S, Devauchelle-Pensec V, Cornec D, Marhadour T, Bressollette L, Gestin S, et al. Brief Report: Ultrasonographic Assessment of Salivary Gland Response to Rituximab in Primary Sjogren’s Syndrome. Arthritis & rheumatology (Hoboken, NJ). 2015;67(6):1623-8.[3]Gazeau P, Cornec D, Jousse-Joulin S, Guellec D, Saraux A, Devauchelle-Pensec V. Time-course of ultrasound abnormalities of major salivary glands in suspected Sjogren’s syndrome. Joint, bone, spine: revue du rhumatisme. 2018;85(2):227-32.[4]Lee KA, Lee SH, Kim HR. Diagnostic and predictive evaluation using salivary gland ultrasonography in primary Sjogren’s syndrome. Clinical and experimental rheumatology. 2018;36 Suppl 112(3):165-72.Acknowledgments: :This work was funded by the Konkuk University Medical Center Research Grant 2019.Disclosure of Interests:None declared

scholarly journals Fibroblasts in Sjögren’s Syndrome

2021 ◽  
Author(s):  
Kerstin Klein
Keyword(s):  
Salivary Gland ◽  
Salivary Glands ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Severe Disease ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Lymphoid Structures ◽  
Salivary Gland Epithelial Cells ◽  
Sjögren‘S Syndrome

The Sjögren’s syndrome is an autoimmune disease characterized by chronic inflammation of the exocrine glands, leading to dryness of mucosal surfaces, and often to severe systemic manifestations. Here, the immunomodulatory function of fibroblasts derived from salivary glands, a primary site affected by the Sjögren’s syndrome, is discussed. Specific subsets of these fibroblasts drive the formation of tertiary lymphoid structures, which are associated with severe disease and which constitute a risk factor for the development of lymphoma in Sjögren’s syndrome. Single cell RNA-sequencing has provided new insights into subsets of fibroblasts in inflamed salivary glands and has provided evidence for the existence of shared inflammation-associated fibroblasts across chronically inflamed tissues. These findings support the concept of targeting the fibroblast compartment in Sjögren’s syndrome and other chronic inflammatory diseases. In addition to the immunomodulatory role of fibroblasts, the interaction of the epithelium with fibroblasts is essential for salivary gland homeostasis. Fibroblasts provide essential signals for the regeneration of salivary gland epithelial cells, which is disturbed in Sjögren’s syndrome, and leading to the loss of saliva secreting cells and subsequent hyposalivation.

Androgen Deficiency and Defective Intracrine Processing of Dehydroepiandrosterone in Salivary Glands in Sjögren’s Syndrome

2008 ◽  
Vol 35 (11) ◽  
pp. 2229-2235 ◽  
Author(s):  
PAULIINA POROLA ◽  
LIISA VIRKKI ◽  
BEATA D. PRZYBYLA ◽  
MIKAEL LAINE ◽  
TUCKER A. PATTERSON ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Salivary Glands ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Sex Steroid ◽  
Type I ◽  
Androgen Deficiency ◽  
Sjögren‘S Syndrome

ObjectiveWe hypothesized that in addition to dehydroepiandrosterone (DHEA) depletion, Sjögren’s syndrome (SS) is characterized by local androgen deficiency in salivary glands and defects in local processing of DHEA.MethodsSex steroid levels in serum and saliva were measured using enzyme immunoassays. Androgen effects on salivary gland cells were analyzed using the cysteine-rich secretory protein-3 (CRISP-3) androgen biomarker.ResultsSerum and salivary concentrations of androgens were low in SS. Substrate to end-product ratios and correlations suggest that in SS salivary glands DHEA is effectively converted to testosterone, but that there are defects in converting testosterone further to dihydrotestosterone (DHT). In healthy controls no such phenomenon was seen, but testosterone is effectively converted to DHT. Salivary glands contained type I 5-α-reductase, and its inhibition with dutasteride completely blocked the upregulating effect of DHEA, but not of DHT, on CRISP-3 in human salivary gland acinar cells.ConclusionDHEA and DHT upregulate CRISP-3, which is reportedly low in SS. The effect of DHEA on CRISP-3 is indirect and is inhibited by dutasteride, showing that there is intracrine processing of DHEA in salivary glands. In healthy glands, but not in SS, DHEA is effectively taken up and converted to DHT. Sex steroid concentrations in saliva in part reflect glandular uptake of DHEAsulfate and local intracrine DHEA metabolism, which seem to be defective in SS. Our study demonstrates a prominent androgen deficiency and a defect in intracrine production of active androgens in SS salivary glands, also suggesting that salivary DHT cannot be maintained at a normal level in this female-dominant autoimmune exocrinopathy.

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