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Inhibitory effects of autoantibodies on the muscarinic receptors in Sjogren's syndrome

Cited 68 time in Web of Science Cited 79 time in Scopus
Issue Date
2004-11
Publisher
Nature Publishing Group
Citation
Laboratory Investigation 2004;84:1430-1438
Keywords
sjogren`s syndromesalivary glandscholinergic receptoraquaporin-5
Abstract
Sjögren's syndrome (SS) is a systemic autoimmune disease that involves reduced salivary secretions. Recently, circulating autoantibodies from SS patients against the type 3 muscarinic cholinergic receptor (M3R) has been reported in the sera of SS patients. However, the role of these autoantibodies in the development of SS has not been elucidated. In this study, purified IgG was obtained from the sera of 11 SS patients, and its inhibitory effect on the M3R of the salivary glands was evaluated using RT-PCR, microspectrofluorimetry, immunohistochemistry, and Western blot analysis. Stimulation with carbachol (CCh) evoked a [Ca 2+ ] i transient in the fura-2 loaded HSG cells. However, pretreatment of the cells with SS IgG (0.5 mg/ml) for 12 or 24 h significantly reduced the magnitude of the CCh-induced [Ca 2+ ] i transient (CICT). We found that the magnitude of CICT was decreased by 62-45% when cells were pretreated with the SS IgG. However, the [Ca 2+ ] i response to ATP was not altered by the pretreatment of SS IgG. The effect of SS IgG on CICT was abrogated by the inclusion of excessive competitive peptides that encode the amino-acid sequence of M3R, which was not recapitulated by nonspecific peptides. The inhibitory effect of SS IgG on the aquaporin (AQP)-5 expression was also examined. After confirming the apical localization of AQP-5 along with its increase by pilocarpine (10 -5 M), we examined whether SS IgG had an effect on pilocarpine-induced AQP-5 trafficking to the apical membrane (APM) using rat parotid acinar cells. After incubating the cells with SS IgG for 12 h, the amount of pilocarpine-induced AQP-5 significantly decreased compared to the control groups. In conclusion, autoantibodies from the SS patients inhibit the function of the human M3R that is mediated by Ca 2+ mobilization and AQP-5 trafficking. Our results could partly explain the underlying mechanisms of glandular dysfunction and associated features of impaired autonomic function in SS patients.Laboratory Investigation (2004) 84, 1430-1438, advance online publication, 27 September 2004; doi:10.1038/labinvest.3700173
ISSN
0023-6837
Language
English
URI
https://hdl.handle.net/10371/69780
DOI
https://doi.org/10.1038/labinvest.3700173
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College of Dentistry/School of Dentistry (치과대학/치의학대학원)Dept. of Dentistry (치의학과)Journal Papers (저널논문_치의학과)
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