title: Acute exacerbations of chronic obstructive pulmonary disease are associated with decreased CD4+ & CD8+ T cells and increased growth & differentiation factor-15 (GDF-15) in peripheral blood.
abstract: BACKGROUND
  Although T cells, especially CD8+, have been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, their role during acute exacerbations (AE-COPD) is uncertain.
  
  
  METHODS
  We recruited subjects with COPD and a history of previous AE-COPD and studied them quarterly to collect blood and spontaneously expectorated sputum while stable. During exacerbations (defined by a change in symptoms plus physician diagnosis and altered medications), we collected blood and sputum before administering antibiotics or steroids. We used flow cytometry to identify leukocytes in peripheral blood, plus Luminex® analysis or ELISA to determine levels of inflammatory biomarkers in serum and sputum supernatants.
  
  
  RESULTS
  Of 33 enrolled subjects, 13 participated in multiple stable visits and had ≥1 AE-COPD visit, yielding 18 events with paired data. Flow cytometric analyses of peripheral blood demonstrated decreased CD4+ and CD8+ T cells during AE-COPD (both absolute and as a percentage of all leukocytes) and significantly increased granulocytes, all of which correlated significantly with serum C-reactive protein (CRP) concentrations. No change was observed in other leukocyte populations during AE-COPD, although the percentage of BDCA-1+ dendritic cells expressing the activation markers CD40 and CD86 increased. During AE-COPD, sICAM-1, sVCAM-1, IL-10, IL-15 and GDF-15 increased in serum, while in sputum supernatants, CRP and TIMP-2 increased and TIMP-1 decreased.
  
  
  CONCLUSIONS
  The decrease in CD4+ and CD8+ T cells (but not other lymphocyte subsets) in peripheral blood during AE-COPD may indicate T cell extravasation into inflammatory sites or organized lymphoid tissues. GDF-15, a sensitive marker of cardiopulmonary stress that in other settings independently predicts reduced long-term survival, is acutely increased in AE-COPD. These results extend the concept that AE-COPD are systemic inflammatory events to which adaptive immune mechanisms contribute.
  
  
  BACKGROUND
  NCT00281216 , ClinicalTrials.gov.
authors.affiliation: Research Service and Pulmonary & Critical Care Medicine Section, Medicine Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, 48105, USA.|Pulmonary & Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, 48109, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Freeman
authors.affiliation: Pulmonary & Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, 48109, USA.
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Martinez
authors.affiliation: Pulmonary & Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, 48109, USA.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Todt
authors.affiliation: Pulmonary & Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, 48109, USA.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.affiliation: Pulmonary & Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, 48109, USA.
authors.forename: MeiLan K
authors.initials: MK
authors.lastname: Han
authors.affiliation: Pulmonary & Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, 48109, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Thompson
authors.affiliation: Pulmonary & Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, 48109, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: McCloskey
authors.affiliation: Pulmonary & Critical Care Medicine Section, Medicine Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, 48105, USA. jlcurtis@umich.edu.|Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, 48109, USA. jlcurtis@umich.edu.|Pulmonary & Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, 48109, USA. jlcurtis@umich.edu.|Department of Veterans Affairs Healthsystem, Pulmonary and Critical Care Medicine Section (506/111G), 2215 Fuller Road, Ann Arbor, MI, 48105-2303, USA. jlcurtis@umich.edu.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Curtis
mesh_terms: D000208:Acute Disease; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000175:diagnosis; D013183:Sputum / Q000378:metabolism
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15