title: Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension.
abstract: BACKGROUND
  Beyond their role as innate immune effectors, natural killer (NK) cells are emerging as important regulators of angiogenesis and vascular remodeling. Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling and has long been associated with immune dysfunction. Despite this association, a role for NK cells in disease pathology has not yet been described.
  
  
  RESULTS
  Analysis of whole blood lymphocytes and isolated NK cells from PAH patients revealed an expansion of the functionally defective CD56(-)/CD16(+) NK subset that was not observed in patients with chronic thromboembolic pulmonary hypertension. NK cells from PAH patients also displayed decreased levels of the activating receptor NKp46 and the killer immunoglobulin-like receptors 2DL1/S1 and 3DL1, reduced secretion of the cytokine macrophage inflammatory protein-1β, and a significant impairment in cytolytic function associated with decreased killer immunoglobulin-like receptor 3DL1 expression. Genotyping patients (n=222) and controls (n=191) for killer immunoglobulin-like receptor gene polymorphisms did not explain these observations. Rather, we show that NK cells from PAH patients exhibit increased responsiveness to transforming growth factor-β, which specifically downregulates disease-associated killer immunoglobulin-like receptors. NK cell number and cytotoxicity were similarly decreased in the monocrotaline rat and chronic hypoxia mouse models of PAH, accompanied by reduced production of interferon-γ in NK cells from hypoxic mice. NK cells from PAH patients also produced elevated quantities of matrix metalloproteinase 9, consistent with a capacity to influence vascular remodeling.
  
  
  CONCLUSIONS
  Our work is the first to identify an impairment of NK cells in PAH and suggests a novel and substantive role for innate immunity in the pathobiology of this disease.
authors: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Rd., Cambridge, United Kingdom. nwm23@cam.ac.uk
authors: Mark L
authors: ML
authors: Ormiston
authors: Chiwen
authors: C
authors: Chang
authors: Lu L
authors: LL
authors: Long
authors: Elaine
authors: E
authors: Soon
authors: Des
authors: D
authors: Jones
authors: Rajiv
authors: R
authors: Machado
authors: Carmen
authors: C
authors: Treacy
authors: Mark R
authors: MR
authors: Toshner
authors: Kate
authors: K
authors: Campbell
authors: Alex
authors: A
authors: Riding
authors: Mark
authors: M
authors: Southwood
authors: Joanna
authors: J
authors: Pepke-Zaba
authors: Andrew
authors: A
authors: Exley
authors: Richard C
authors: RC
authors: Trembath
authors: Francesco
authors: F
authors: Colucci
authors: Mark
authors: M
authors: Wills
authors: John
authors: J
authors: Trowsdale
authors: Nicholas W
authors: NW
authors: Morrell
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019002:CD56 Antigen / Q000032:analysis; D054407:Chemokine CCL4 / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins / Q000032:analysis; D005838:Genotype; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000737:chemistry / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D055627:Natural Cytotoxicity Triggering Receptor 1; D011655:Pulmonary Embolism / Q000150:complications; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017452:Receptors, IgG / Q000032:analysis; D054342:Receptors, KIR2DL1 / Q000096:biosynthesis / Q000235:genetics; D054341:Receptors, KIR3DL1 / Q000096:biosynthesis / Q000235:genetics; D054349:Receptors, KIR3DS1 / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D019002:CD56 Antigen; D054407:Chemokine CCL4; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C522918:NCAM1 protein, human; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D017452:Receptors, IgG; D054342:Receptors, KIR2DL1; D054341:Receptors, KIR3DL1; D054349:Receptors, KIR3DS1; D016212:Transforming Growth Factor beta; D020780:Matrix Metalloproteinase 9