title: Lesional CD4+ IFN-γ+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis.
abstract: OBJECTIVE
  IgG4-related disease (IgG4-RD) is a chronic, systemic, inflammatory condition of unknown aetiology. We have recently described clonally expanded circulating CD4+cytotoxic T lymphocytes (CTLs) in IgG4-RD that infiltrate affected tissues where they secrete interleukin (IL)-1β and transforming growth factor -β1 (TGF-β1). In this study, we sought to examine the role of CD4+CTLs in the pathogenesis of IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) and to determine whether these cells secrete interferon-gamma (IFN-γ) at lesional sites.
  
  
  METHODS
  Salivary glands of 25 patients with IgG4-DS, 22 patients with Sjögren's syndrome (SS), 12 patients with chronic sialoadenitis (CS) and 12 healthy controls were analysed in this study. Gene expression analysis was performed on submandibular glands (SMGs) from five patients with IgG4-DS, three with CS and three healthy controls. Infiltrating CD4+CTLs were examined by quantitative multicolour imaging in tissue samples from 20 patients with IgG4-DS, 22 patients with SS, 9 patients with CS and 9 healthy controls.
  
  
  RESULTS
  In IgG4-DS tissues, nine genes associated with CD4+CTLs were overexpressed. The expression of granzyme A (GZMA) mRNA was significantly higher in samples from patients with IgG4-RD compared with corresponding tissues from SS and healthy controls. Quantitative imaging showed that infiltrating CD4+GZMA+CTLs were more abundant in patients with IgG4-DS than in the other groups. The ratio of CD4+GZMA+CTLs in SMGs from patients with IgG4-DS correlated with serum IgG4 concentrations and the number of affected organs. A large fraction of CD4+GZMA+CTLs in SMGs from patients with IgG4-DS secreted IFN-γ.
  
  
  CONCLUSIONS
  The pathogenesis of IgG4-DS is associated with tissue infiltration by CD4+GZMA+CTLs that secrete IFN-γ.
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Maehara
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Mattoo
authors.affiliation: Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Ohta
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Vinay S
authors.initials: VS
authors.lastname: Mahajan
authors.affiliation: Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.|Faculty of Dental Science, OBT Research Center, Kyushu University, Fukuoka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Moriyama
authors.affiliation: Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yamauchi
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jefte
authors.initials: J
authors.lastname: Drijvers
authors.affiliation: Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Stone
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shiv S
authors.initials: SS
authors.lastname: Pillai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D054407:Chemokine CCL4 / Q000235:genetics; D018946:Chemokine CCL5 / Q000235:genetics; D003607:Dacryocystitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D053804:Granzymes / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D012793:Sialadenitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000235:genetics; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013363:Submandibular Gland / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D055815:Young Adult; D000098815:T-bet Transcription Factor
chemical_list: C066507:CCL4 protein, human; C483024:CCL5 protein, human; D015704:CD4 Antigens; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D007074:Immunoglobulin G; D012333:RNA, Messenger; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C508960:TGFB1 protein, human; C439524:TNF protein, human; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; C509212:GZMA protein, human
keywords: Inflammation; Sjøgren's Syndrome; T Cells