NK cell activating receptor ligand expression in lymphangioleiomyomatosis is associated with lung function decline
Andrew R. Osterburg, … , Francis X. McCormack, Michael T. Borchers
Andrew R. Osterburg, … , Francis X. McCormack, Michael T. Borchers
Published October 6, 2016
Citation Information: JCI Insight. 2016;1(16):e87270. https://doi.org/10.1172/jci.insight.87270.
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Research Article Immunology Pulmonology

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 FEV1 decline (–32.7 ± 10 ml/year). These data suggest a role for NK cells, sNKG2DL, and the innate immune system in LAM pathogenesis.

Authors

Andrew R. Osterburg, Rebecca L. Nelson, Benyamin Z. Yaniv, Rachel Foot, Walter R.F. Donica, Madison A. Nashu, Huan Liu, Kathryn A. Wikenheiser-Brokamp, Joel Moss, Nishant Gupta, Francis X. McCormack, Michael T. Borchers

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Figure 1

NKG2D ligands are expressed in lymphangioleiomyomatosis (LAM) cells in lung biopsy specimens from LAM patients.

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NKG2D ligands are expressed in lymphangioleiomyomatosis (LAM) cells in l...
Serial diagnostic lung tissue sections from LAM patients were stained for the LAM cell markers HMB-45 and α-SMA, as well as for NKG2D ligands ULBP2 and ULBP3. (A) Representative cystic LAM lesion with LAM cell aggregates adjacent to the cyst (boxed area) identified by routine H&E staining. Scale bar: 400 μm. (B) Higher magnification image of the boxed region in A and images of serial sections of the same region IHC stained for (D) HMB-45, (E) α-SMA, (F) ULBP2, and (G) ULBP3, along with (C) a representative negative control. LAM cells comprising the cellular aggregate adjacent to the LAM cyst show characteristic strong focal staining (red) for HMB-45, diffuse staining for α-SMA, and positive staining for the NKG2D ligands ULBP2 and ULBP3. No staining was observed in multiple negative control sections for all antibodies, as depicted by the representative negative control image shown. Scale bars: 20 μm (B–G). Supplemental Figure 1 shows representative staining in diagnostic lung biopsies from 6 additional LAM patients.