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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.
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IMMUNOBIOLOGY
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, and
Daniela Pende
From the Istituto Giannina Gaslini, Genoa, Italy; the Sir William Dunn School of Pathology, Oxford, United Kingdom; the Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; the Onco Ematologia Pediatrica, Ospedale dei Bambini "G. Di Cristina," Palermo, Italy; Dipartimento di Medicina Sperimentale (DIMES), University of Genoa, Italy; and the Centro di Eccellenza per la Ricerca Biomedica, University of Genoa, Italy.
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.
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