eprintid: 21846
rev_number: 14
eprint_status: archive
userid: 1589
dir: disk0/00/02/18/46
datestamp: 2016-09-20 13:07:32
lastmod: 2024-03-10 11:53:05
status_changed: 2016-09-20 13:07:32
type: article
metadata_visibility: show
creators_name: Merkt, Wolfgang
creators_name: Claus, Maren
creators_name: Blank, Norbert
creators_name: Hundemer, Michael
creators_name: Cerwenka, Adelheid
creators_name: Lorenz, Hanns-Martin
creators_name: Watzl, Carsten
title: Active but not inactive granulomatosis with polyangiitis is associated with decreased and phenotypically and functionally altered CD56dim natural killer cells
subjects: ddc-610
divisions: i-850300
divisions: i-910100
abstract: Background: The role of natural killer (NK) cells in granulomatosis with polyangiitis (GPA) is poorly understood. We recently reported that peripheral blood NK cell percentages correlate with the suppression of GPA activity (cohort I). The purpose of the current study was to further characterize NK cell subsets, phenotype and function in a second GPA cohort (cohort II).   Methods: Peripheral blood lymphocyte subsets were analyzed at a clinical diagnostic laboratory. Clinical data were extracted from medical records and patients were grouped according to their activity state (remission vs. active/non-remission). Separate analysis (cohort II, n = 22) and combined analysis (cohorts I and II, n = 34/57) of NK cell counts/percentages was performed. NK cell subsets and phenotypes were analyzed by multicolor flow cytometry. Cytotoxicity assays were performed using 51Cr-labeled K562 target cells.   Results: In cohort II, NK cell counts were lower than the lower limit of normal in active GPA, despite normal percentages due to lymphopenia. NK cell counts, but not other lymphocyte counts, were significantly higher in remission. Combined analysis of cohorts I and II confirmed decreased NK cell counts in active GPA and increased percentages in long-term remission. Follow-up measurements of six patients revealed increasing NK cell percentages during successful induction therapy. Multicolor analysis from cohort II revealed that in active GPA, the CD56dim subset was responsible for decreased NK cell counts, expressed more frequently CD69, downregulated the Fc-receptor CD16 and upregulated the adhesion molecule CD54, the chemokine receptor CCR5 and the activating receptor NKG2C. In remission, these markers were unaltered or marginally altered. All other receptors investigated (NKp30, NKp44, NKp46, NKG2D, DNAM1, 2B4, CRACC, 41BB) remained unchanged. Natural cytotoxicity was not detectable in most patients with active GPA, but was restored in remission.   Conclusions: NK cell numbers correlate inversely with GPA activity. Reduced CD56dim NK cells in active GPA have an activated phenotype, which intriguingly is associated with profound deficiency in cytotoxicity. These data suggest a function for NK cells in the pathogenesis and/or modulation of inflammation in GPA. NK cell numbers, phenotype (CD16, CD69, NKG2C) or overall natural cytotoxicity are promising candidates to serve as clinical biomarkers to determine GPA activity.
date: 2016
publisher: BioMed Central
id_scheme: DOI
ppn_swb: 1658772547
own_urn: urn:nbn:de:bsz:16-heidok-218463
language: eng
bibsort: MERKTWOLFGACTIVEBUTN2016
full_text_status: public
publication: Arthritis Research & Therapy
volume: 18
number: 204
place_of_pub: London
pagerange: 1-12
issn: 1478-6362
citation:   Merkt, Wolfgang ; Claus, Maren ; Blank, Norbert ; Hundemer, Michael ; Cerwenka, Adelheid ; Lorenz, Hanns-Martin ; Watzl, Carsten  (2016) Active but not inactive granulomatosis with polyangiitis is associated with decreased and phenotypically and functionally altered CD56dim natural killer cells.  Arthritis Research & Therapy, 18 (204).  pp. 1-12.  ISSN 1478-6362     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/21846/1/13075_2016_Article_1098.pdf