title: Endogenous programmed death ligand-1 restrains the development and onset of Sjӧgren's syndrome in non-obese diabetic mice.
abstract: Programmed death-ligand 1 (PD-L1) down-modulates various immune responses by engaging the co-inhibitory receptor programmed death-1. Expression of PD-L1 and programmed death-1 is elevated in the salivary glands of patients with Sjögren's syndrome (SS). The objective of this study is to define the role of endogenous PD-L1 in SS pathogenesis in non-obese diabetic (NOD) mouse model of this disease. We inhibited endogenous PD-L1 function by intraperitoneal administration of a blocking antibody to 6 week-old female NOD/ShiLtJ mice repeatedly during a 9-day period. PD-L1 blockade accelerated leukocyte infiltration and caspase-3 activation in the submandibular gland (SMG), production of antinuclear and anti-M3 muscarinic acetylcholine receptor (M3R) autoantibodies and impairment of saliva secretion, indicative of accelerated development and onset of SS. The effect of PD-L1 blockade was associated with increased T- and B cells and T helper 1 cytokine IFN-γ in the SMG. Local administration of exogenous IFN-γ to the SMG led to impaired salivary secretion accompanied by down-regulation of aquaporin 5 and an increase in anti-M3R autoantibodies. Conversely, neutralization of IFN-γ markedly improved salivary secretion and aquaporin 5 expression in anti-PD-L1-treated NOD/ShiLtJ mice. Hence, endogenous PD-L1 hinders the development and onset of SS in NOD mice, in part by suppressing IFN-γ production.
authors.affiliation: Department of Immunology and Infectious Diseases, the Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA.|Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Immunology and Infectious Diseases, the Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA.
authors.forename: Jun-O
authors.initials: JO
authors.lastname: Jin
authors.affiliation: Department of Immunology and Infectious Diseases, the Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA.|Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Department of Immunology and Infectious Diseases, the Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA.|Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage* / Q000494:pharmacology; D001323:Autoantibodies / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000378:metabolism; D013363:Submandibular Gland / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation
chemical_list: D019138:Antibodies, Blocking; D001323:Autoantibodies; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C000611649:IFNG protein, mouse; D007371:Interferon-gamma