1. Efficacy of T-cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis.
- Author
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Chiang SCC, Covill LE, Tesi B, Campbell TM, Schlums H, Nejati-Zendegani J, Mördrup K, Wood S, Theorell J, Sekine T, Al-Herz W, Akar HH, Belen FB, Chan MY, Devecioglu O, Aksu T, Ifversen M, Malinowska I, Sabel M, Unal E, Unal S, Introne WJ, Krzewski K, Gilmour KC, Ehl S, Ljunggren HG, Nordenskjöld M, Horne A, Henter JI, Meeths M, and Bryceson YT
- Subjects
- Humans, Adolescent, Child, Adult, Female, K562 Cells, Male, Child, Preschool, Middle Aged, Infant, Young Adult, Aged, Sensitivity and Specificity, Prospective Studies, Receptors, Antigen, T-Cell metabolism, Receptors, Antigen, T-Cell genetics, Exocytosis, T-Lymphocytes, Cytotoxic immunology, Lymphohistiocytosis, Hemophagocytic diagnosis, Lymphohistiocytosis, Hemophagocytic immunology, Lymphohistiocytosis, Hemophagocytic genetics, Lymphohistiocytosis, Hemophagocytic pathology, Killer Cells, Natural immunology, Killer Cells, Natural metabolism
- Abstract
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 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., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)
- Published
- 2024
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