title: Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmonary veno-occlusive disease.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD) both display occlusive remodeling of the pulmonary vasculature responsible for increased pulmonary vascular resistances. Cytotoxic T (CTL), natural killer (NK), and natural killer T (NKT) cells play a critical role in vascular remodeling in different physiological and pathological conditions. Granulysin (GNLY) represents a powerful effector protein for all these subpopulations.
  
  
  OBJECTIVE
  To analyze the cytolytic compartment of inflammatory cells in patients with PAH and PVOD.
  
  
  METHODS
  The overall functional status of the cytolytic compartment was studied through epigenetic analysis of the GNLY gene in explanted lungs and in peripheral blood mononuclear cells. Flow cytometry technology allowed analysis of specific circulating cytolytic cells and GNLY contents. A GNLY-specific ELISA allowed measurement of GNLY serum concentrations.
  
  
  RESULTS
  A decrease in GNLY demethylation in the gDNA extracted from peripheral blood mononuclear cells and explanted lungs was found specifically in PVOD but not in PAH. This was associated with a decrease in populations and subpopulations of CTL and NKT and an increase of NK populations. Despite the reduced granulysin-containing cells in patients with PVOD, GNLY serum levels were higher, suggesting these cells were wasting their content. Furthermore, the increase of GNLY concentration in the serum of PVOD was significantly higher than in patients with PAH.
  
  
  CONCLUSIONS
  PVOD is characterized by alterations of circulating cytotoxic cell subpopulations and by epigenetic dysregulation within the GNLY gene. Our findings may be helpful in the quest to develop needed diagnostic tools, including flow cytometry analyses, to screen for suspected PVOD in patients with pulmonary hypertension.
authors.affiliation: INSERM U999, Centre Chirurgical Marie Lannelongue, 133, Avenue de la Resistance, F-92350 Le Plessis Robinson, France. frederic.perros@inserm.fr
authors.forename: Frédéric
authors.initials: F
authors.lastname: Perros
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cohen-Kaminsky
authors.forename: Natalia
authors.initials: N
authors.lastname: Gambaryan
authors.forename: Barbara
authors.initials: B
authors.lastname: Girerd
authors.forename: Nicolas
authors.initials: N
authors.lastname: Raymond
authors.forename: Isabelle
authors.initials: I
authors.lastname: Klingelschmitt
authors.forename: Alice
authors.initials: A
authors.lastname: Huertas
authors.forename: Olaf
authors.initials: O
authors.lastname: Mercier
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.forename: Gerald
authors.initials: G
authors.lastname: Simonneau
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.forename: David
authors.initials: D
authors.lastname: Montani
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000097:blood / Q000502:physiology*; D019175:DNA Methylation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D044127:Epigenesis, Genetic / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000503:physiopathology*; D007694:Killer Cells, Natural / Q000502:physiology; D008168:Lung / Q000502:physiology / Q000503:physiopathology; D016131:Lymphocyte Subsets; D055611:Natural Killer T-Cells / Q000502:physiology; D011668:Pulmonary Veno-Occlusive Disease / Q000097:blood / Q000503:physiopathology*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C075005:GNLY protein, human