Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): Defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease

Stefania Marcenaro, Federico Gallo, Stefania Martini, Alessandra Santoro, Gillian M. Griffiths, Maurizio Aricó, Lorenzo Moretta, Daniela Pende

Research output: Contribution to journalArticle

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Abstract

Natural killer (NK) cells from patients with familial hemophagocytic lymphohistiocytosis because of PRF1 (FHL2, n = 5) or MUNC13-4 (FHL3, n = 8) mutations were cultured in IL-2 prior to their use in various functional assays. Here, we report on the surface CD107a expression as a novel rapid tool for identification of patients with Munc13-4 defect. On target interaction and degranulation, FHL3 NK cells displayed low levels of surface CD107a staining, in contrast to healthy control subjects or perforin-deficient NK cells. B-EBV cell lines and dendritic cell targets reveal the FHL3 NK-cell defect, whereas highly susceptible tumor targets were partially lysed by FHL3 NK cells expressing only trace amounts of Munc13-4 protein. Perforin-deficient NK cells were completely devoid of any ability to lyse target cells. Cytokine production induced by mAb-crosslinking of triggering receptors was comparable in patients and healthy control subjects. However, when cytokine production was induced by coculture with 721.221 B-EBV cells, FHL NK cells resulted in high producers, whereas control cells were almost ineffective. This could reflect survival versus elimination of B-EBV cells (ie, the source of NK-cell stimulation) in patients versus healthy control subjects, thus mimicking the pathophysiologic scenario of FHL.

Original languageEnglish
Pages (from-to)2316-2323
Number of pages8
JournalBlood
Volume108
Issue number7
DOIs
Publication statusPublished - Oct 1 2006

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Hemophagocytic Lymphohistiocytosis
Inborn Genetic Diseases
Natural Killer Cells
Perforin
Defects
Human Herpesvirus 4
Cells
Cytokines
Healthy Volunteers
Crosslinking
Interleukin-2
Tumors
Assays
Coculture Techniques
Dendritic Cells
Proteins
Staining and Labeling
Cell Line
Mutation
Survival

ASJC Scopus subject areas

  • Hematology

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Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL) : Defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease. / Marcenaro, Stefania; Gallo, Federico; Martini, Stefania; Santoro, Alessandra; Griffiths, Gillian M.; Aricó, Maurizio; Moretta, Lorenzo; Pende, Daniela.

In: Blood, Vol. 108, No. 7, 01.10.2006, p. 2316-2323.

Research output: Contribution to journalArticle

Marcenaro, Stefania ; Gallo, Federico ; Martini, Stefania ; Santoro, Alessandra ; Griffiths, Gillian M. ; Aricó, Maurizio ; Moretta, Lorenzo ; Pende, Daniela. / Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL) : Defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease. In: Blood. 2006 ; Vol. 108, No. 7. pp. 2316-2323.
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