title: NK cell activating receptor ligand expression in lymphangioleiomyomatosis is associated with lung function decline.
abstract: Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that leads to progressive cyst formation and accelerated loss of pulmonary function. Neoplastic smooth muscle cells from an unknown source metastasize to the lung and drive destructive remodeling. Given the role of NK cells in immune surveillance, we postulated that NK cell activating receptors and their cognate ligands are involved in LAM pathogenesis. We found that ligands for the NKG2D activating receptor UL-16 binding protein 2 (ULBP2) and ULBP3 are localized in cystic LAM lesions and pulmonary nodules. We found elevated soluble serum ULBP2 (mean = 575 pg/ml ± 142) in 50 of 100 subjects and ULBP3 in 30 of 100 (mean = 8,300 pg/ml ± 1,515) subjects. LAM patients had fewer circulating NKG2D+NK cells and decreased NKG2D surface expression. Lung function decline was associated with soluble NKG2D ligand (sNKG2DL) detection. The greatest rate of decline forced expiratory volume in 1 second (FEV1, -124 ± 30 ml/year) in the 48 months after enrollment (NHLBI LAM Registry) occurred in patients expressing both ULBP2 and ULBP3, whereas patients with undetectable sNKG2DL levels had the lowest rate of FEV1decline (-32.7 ± 10 ml/year). These data suggest a role for NK cells, sNKG2DL, and the innate immune system in LAM pathogenesis.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Osterburg
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Nelson
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Benyamin Z
authors.initials: BZ
authors.lastname: Yaniv
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Foot
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Walter Rf
authors.initials: WR
authors.lastname: Donica
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Madison A
authors.initials: MA
authors.lastname: Nashu
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA.|Division of Pathology & Laboratory Medicine and Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Wikenheiser-Brokamp
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Nishant
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Borchers
mesh_terms: D000328:Adult; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008168:Lung / Q000378:metabolism; D018192:Lymphangioleiomyomatosis / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; C423230:ULBP2 protein, human