title: Enhanced expression of programmed death-1 (PD-1)/PD-L1 in salivary glands of patients with Sjögren's syndrome.
abstract: OBJECTIVE
  Programmed death-1 (PD-1) mediates a negative signal and introduces tolerance for lymphocytes. Dysfunction of the PD-1 pathway is thought to result in autoimmune diseases such as rheumatoid arthritis (RA). To investigate the role of the PD-1/PD-L system in the pathology of Sjögren's syndrome (SS), we examined the expression of PD-1 and its ligand PD-L1 in salivary lymphocytes and salivary glands from patients with SS.
  
  
  METHODS
  Flow cytometry analysis was used to determine expression of PD-1 in SS salivary lymphocytes. Intracellular staining of interleukin 10 (IL-10) was performed after stimulation with PMA and ionomycin. Indirect immunohistochemistry was used to investigate the expression of PD-1 and PD-L1.
  
  
  RESULTS
  The mean fluorescence intensity of PD-1 expression in SS salivary lymphocytes was significantly higher than that from healthy controls and patients with RA or systemic lupus erythematosus. PD-1-positive SS salivary lymphocytes expressed IL-10 intracellularly upon PMA/ionomycin stimulation. Immunohistochemical analysis showed that PD-1 was expressed on infiltrating lymphocytes in salivary gland from 52% of SS patients, and PD-L1 was expressed on ductal and acinar epithelial cells from 68% of SS patients. In vitro analysis using HSG cells revealed that PD-L1 was induced by interferon-gamma but not by tumor necrosis factor-alpha and IL-1beta.
  
  
  CONCLUSIONS
  PD-1 is expressed on T lymphocytes and PD-L1 on epithelial cells from inflamed salivary glands of patients with SS, which suggests that dysfunction of the PD-1/PD-L1 pathway may be related to tolerance for lymphocytes, which causes SS.
authors.affiliation: Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Seiji
authors.initials: S
authors.lastname: Kawano
authors.forename: Saori
authors.initials: S
authors.lastname: Hatachi
authors.forename: Chiyo
authors.initials: C
authors.lastname: Kurimoto
authors.forename: Taku
authors.initials: T
authors.lastname: Okazaki
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwai
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Minato
authors.forename: Takahide
authors.initials: T
authors.lastname: Komori
authors.forename: Sakan
authors.initials: S
authors.lastname: Maeda
authors.forename: Shunichi
authors.initials: S
authors.lastname: Kumagai
mesh_terms: D015703:Antigens, CD; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism*; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism*; D060890:B7-H1 Antigen; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor; D012469:Salivary Glands / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D008562:Membrane Glycoproteins; C105992:PDCD1 protein, human; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma