title: Impaired survival of regulatory T cells in pulmonary sarcoidosis.
abstract: BACKGROUND
  Impaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear. Moreover, it is not known if increased apoptotic susceptibility of Tregs may contribute to an impaired immunosuppressive function in sarcoidosis. Therefore, the aim of this study is to analyze proportions, phenotype, survival, and apoptotic susceptibility of Tregs in sarcoidosis.
  
  
  METHODS
  Patients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis. Tregs were analyzed in broncho-alveolar lavage fluid and peripheral blood of patients and healthy controls (HC).
  
  
  RESULTS
  In sarcoidosis patients no evidence was found for a relative deficit of Tregs, neither locally nor systemically. Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease. Sarcoidosis circulating Tregs displayed adequate expression of FoxP3, CD25 and CTLA4. Remarkably, in sarcoidosis enhanced CD95 expression on circulating activated CD45RO(+) Tregs was observed compared with HC, and proportions of these cells were significantly increased. Specifically sarcoidosis Tregs--but not Th cells--showed impaired survival compared with HC. Finally, CD95L-mediated apoptosis was enhanced in sarcoidosis Tregs.
  
  
  CONCLUSIONS
  In untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L. Increased apoptosis likely contributes to the insufficient immunosuppressive function of sarcoidosis Tregs. Further research into this field will help determine whether improvement of Treg survival holds a promising new therapeutic approach for chronic sarcoidosis patients.
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Broos
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: van Nimwegen
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Kleinjan
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Bregje
authors.initials: B
authors.lastname: ten Berge
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Muskens
authors.affiliation: Department of Pulmonology, Sint Franciscus Gasthuis, Kleiweg 500, 3045 PM, Rotterdam, The Netherlands.
authors.forename: Johannes C C M
authors.initials: JC
authors.lastname: in 't Veen
authors.affiliation: Department of Pulmonology, Academic Medical Centre/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Jouke T
authors.initials: JT
authors.lastname: Annema
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.|Laboratory of immunoregulation and mucosal immunology, VIB Inflammation Research Center, Technologiepark 927, 9052, Ghent, Belgium.|Department of Respiratory Medicine, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium.
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Henk C
authors.initials: HC
authors.lastname: Hoogsteden
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Kool
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. b.vandenblink@erasmusmc.nl.
authors.forename: Bernt
authors.initials: B
authors.lastname: van den Blink
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D060908:CTLA-4 Antigen / Q000378:metabolism; D016022:Case-Control Studies; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017565:Sarcoidosis, Pulmonary / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C505661:FASLG protein, human; C418974:FOXP3 protein, human; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit