Efficacy of T-cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis.
Samuel C C ChiangLaura E CovillBianca TesiTessa Mollie CampbellHeinrich SchlumsJelve Nejati-ZendeganiKarina MördrupStephanie WoodJakob TheorellTakuya SekineWaleed Al HerzHimmet Haluk AkarFatma Burcu BelenMei Yoke ChanOmer DeveciogluTekin AksuMarianne IfversenIwona MalinowskaMagnus SabelEkrem ÜnalSule UnalWendy J IntroneKonrad KrzewskiKimberley C GilmourStephan EhlHans-Gustaf LjunggrenMagnus NordenskjöldAnnaCarin HorneJan-Inge HenterMarie MeethsYenan T BrycesonPublished in: Blood (2024)
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.
Keyphrases
- nk cells
- end stage renal disease
- peripheral blood
- ejection fraction
- newly diagnosed
- high throughput
- chronic kidney disease
- single cell
- peritoneal dialysis
- early onset
- regulatory t cells
- stem cells
- cell proliferation
- signaling pathway
- patient reported outcomes
- autism spectrum disorder
- bone marrow
- clinical practice
- cell death
- patient reported
- endoplasmic reticulum stress
- transcription factor
- duchenne muscular dystrophy