title: IP3R deficit underlies loss of salivary fluid secretion in Sjögren's Syndrome.
abstract: The autoimmune exocrinopathy, Sjögren's syndrome (SS), is associated with secretory defects in patients, including individuals with mild lymphocytic infiltration and minimal glandular damage. The mechanism(s) underlying the secretory dysfunction is not known. We have used minor salivary gland biopsies from SS patients and healthy individuals to assess acinar cell function in morphologically intact glandular areas. We report that agonist-regulated intracellular Ca(2+) release, critically required for Ca(2+) entry and fluid secretion, is defective in acini from SS patients. Importantly, these acini displayed reduction in IP3R2 and IP3R3, but not AQP5 or STIM1. Similar decreases in IP3R and carbachol (CCh)-stimulated [Ca(2+)]i elevation were detected in acinar cells from lymphotoxin-alpha (LTα) transgenic (TG) mice, a model for (SS). Treatment of salivary glands from healthy individuals with LT α, a cytokine linked to disease progression in SS and IL14α mice, reduced Ca(2+) signaling. Together, our findings reveal novel IP3R deficits in acinar cells that underlie secretory dysfunction in SS patients.
authors.affiliation: Sjögren's Syndrome and Salivary Gland Dysfunction Unit MPTB, NIDCR, NIH, Bethesda, MD 20892.|Secretory and Physiology Section, MPTB, NIDCR, NIH, Bethesda, MD 20892.
authors.forename: Leyla Y
authors.initials: LY
authors.lastname: Teos
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Sjögren's Syndrome and Salivary Gland Dysfunction Unit MPTB, NIDCR, NIH, Bethesda, MD 20892.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Cotrim
authors.affiliation: Secretory and Physiology Section, MPTB, NIDCR, NIH, Bethesda, MD 20892.
authors.forename: William
authors.initials: W
authors.lastname: Swaim
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642.
authors.forename: Jon H
authors.initials: JH
authors.lastname: Won
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Medicine, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Julian
authors.initials: J
authors.lastname: Ambrus
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Medicine, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Long
authors.initials: L
authors.lastname: Shen
authors.affiliation: Sjögren's Syndrome and Salivary Gland Dysfunction Unit MPTB, NIDCR, NIH, Bethesda, MD 20892.
authors.forename: Lolita
authors.initials: L
authors.lastname: Bebris
authors.affiliation: Sjögren's Syndrome and Salivary Gland Dysfunction Unit MPTB, NIDCR, NIH, Bethesda, MD 20892.
authors.forename: Margaret
authors.initials: M
authors.lastname: Grisius
authors.affiliation: Sjögren's Syndrome and Salivary Gland Dysfunction Unit MPTB, NIDCR, NIH, Bethesda, MD 20892.
authors.forename: Shyh-Ing
authors.initials: SI
authors.lastname: Jang
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642.
authors.forename: David I
authors.initials: DI
authors.lastname: Yule
authors.affiliation: Secretory and Physiology Section, MPTB, NIDCR, NIH, Bethesda, MD 20892.
authors.forename: Indu S
authors.initials: IS
authors.lastname: Ambudkar
authors.affiliation: Sjögren's Syndrome and Salivary Gland Dysfunction Unit MPTB, NIDCR, NIH, Bethesda, MD 20892.
authors.forename: Ilias
authors.initials: I
authors.lastname: Alevizos
mesh_terms: D061354:Acinar Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D016022:Case-Control Studies; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D007378:Interleukins / Q000172:deficiency / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton; D012469:Salivary Glands / Q000378:metabolism* / Q000473:pathology; D012859:Sjogren's Syndrome / Q000378:metabolism / Q000473:pathology*; D033921:Vesicular Transport Proteins
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D007378:Interleukins; D008233:Lymphotoxin-alpha; C545985:TXLNA protein, mouse; D033921:Vesicular Transport Proteins; D002217:Carbachol; D002118:Calcium