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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2316-2323.
Prepublished online as a Blood First Edition Paper on June 15, 2006; DOI 10.1182/blood-2006-04-015693.
 Previous Article | Next Article 
Submitted April 10, 2006
Accepted May 30, 2006
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 Arico, Lorenzo Moretta, and Daniela Pende*
Istituto G. Gaslini, Genova, Italy
Sir William Dunn School of Pathology, Oxford, United Kingdom
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
Onco Ematologia Pediatrica, Ospedale dei Bambini 'G. Di Cristina', Palermo, Italy
Istituto G. Gaslini; DIMES and Centro di Eccellenza per la Ricerca Biomedica, University of Genova.
* Corresponding author; email: daniela.pende{at}istge.it.
Natural killer (NK) cells from patients with familial hemophagocytic lymphohistiocytosis due to 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. Upon target interaction and degranulation, FHL3 NK cells displayed low levels of surface CD107a staining, in contrast to normal controls or perforin-deficient NK cells.
B-EBV cell lines and dendritic cell targets reveal the FHL3 NK cell defect while 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 normal controls. However, when cytokine production was induced by co-culture with 721.221 B-EBV cells, FHL NK cells resulted high producers, whereas control cells were almost ineffective. This could reflect survival versus elimination of B-EBV cells i.e. the source of NK cell stimulation, in patients versus healthy controls, thus mimicking the pathophysiological scenario of FHL.
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