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Efficacy of T-cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis

Chiang, Samuel C.C. ; Covill, Laura E. ; Tesi, Bianca ; Campbell, Tessa M. ; Schlums, Heinrich ; Nejati-Zendegani, Jelve ; Mördrup, Karina ; Wood, Stephanie ; Theorell, Jakob and Sekine, Takuya , et al. (2024) In Blood 144(8). p.873-887
Abstract

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK)–cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Assessment of... (More)

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK)–cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Assessment of Fc receptor–triggered NK-cell and T-cell receptor (TCR)–triggered CTL exocytosis displayed higher sensitivity and improved specificity for the diagnosis of primary HLH than routine K562 cell–based assays, with these assays combined providing a sensitivity of 100% and specificity of 98.3%. By comparison, NK-cell exocytosis after K562 target cell stimulation displayed a higher interindividual variability, in part explained by differences in NK-cell differentiation or large functional reductions after shipment. We thus recommend combined analysis of TCR-triggered CTL and Fc receptor–triggered NK-cell exocytosis for the diagnosis of patients with suspected familial HLH or atypical manifestations of congenital defects in lymphocyte exocytosis.

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LU ; LU and LU orcid
author collaboration
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type
Contribution to journal
publication status
published
subject
in
Blood
volume
144
issue
8
pages
15 pages
publisher
American Society of Hematology
external identifiers
  • scopus:85199462144
  • pmid:38958468
ISSN
0006-4971
DOI
10.1182/blood.2024024499
language
English
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yes
additional info
Publisher Copyright: © 2024 American Society of Hematology
id
cf7220ef-5223-4f3b-9bf9-c0e76b686679
date added to LUP
2024-08-30 05:43:36
date last changed
2025-07-05 11:32:38
@article{cf7220ef-5223-4f3b-9bf9-c0e76b686679,
  abstract     = {{<p>Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK)–cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Assessment of Fc receptor–triggered NK-cell and T-cell receptor (TCR)–triggered CTL exocytosis displayed higher sensitivity and improved specificity for the diagnosis of primary HLH than routine K562 cell–based assays, with these assays combined providing a sensitivity of 100% and specificity of 98.3%. By comparison, NK-cell exocytosis after K562 target cell stimulation displayed a higher interindividual variability, in part explained by differences in NK-cell differentiation or large functional reductions after shipment. We thus recommend combined analysis of TCR-triggered CTL and Fc receptor–triggered NK-cell exocytosis for the diagnosis of patients with suspected familial HLH or atypical manifestations of congenital defects in lymphocyte exocytosis.</p>}},
  author       = {{Chiang, Samuel C.C. and Covill, Laura E. and Tesi, Bianca and Campbell, Tessa M. and Schlums, Heinrich and Nejati-Zendegani, Jelve and Mördrup, Karina and Wood, Stephanie and Theorell, Jakob and Sekine, Takuya and Al-Herz, Waleed and Akar, Himmet Haluk and Belen, Fatma Burcu and Chan, Mei Yoke and Devecioglu, Omer and Aksu, Tekin and Ifversen, Marianne and Malinowska, Iwona and Sabel, Magnus and Unal, Ekrem and Unal, Sule and Introne, Wendy J. and Krzewski, Konrad and Gilmour, Kimberly C. and Ehl, Stephan}},
  issn         = {{0006-4971}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{8}},
  pages        = {{873--887}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{Efficacy of T-cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis}},
  url          = {{http://dx.doi.org/10.1182/blood.2024024499}},
  doi          = {{10.1182/blood.2024024499}},
  volume       = {{144}},
  year         = {{2024}},
}