A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes

Bryceson, Yenan T.; Pende, Daniela; Maul-Pavicic, Andrea; Gilmour, Kimberly C.; Ufheil, Heike; Vraetz, Thomas; Chiang, Samuel C.C.; Marcenaro, Stefania; Meazza, Raffaella; Bondzio, Ilka; Walshe, Denise; Janka, Gritta; Lehmberg, Kai; Beutel, Karin; Stadt, Udo zur; Binder, Nadine; Aricò, Maurizio; Moretta, Alessandro; Henter, Jan‐Inge; Ehl, Stephan

doi:10.1182/blood-2011-08-374199

Cited by 263 publications

(247 citation statements)

References 47 publications

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“…The absence of STXBP2 protein in the neutrophils of patients A and C was confirmed by western blot analysis, whereas patient B carrying a homozygous exon 15 splice site mutation, which is known to be associated with residual NK function and a milder clinical phenotype, 11 did express substantial levels of a STXBP2 protein (supplemental Figure 1A). As reported previously, 3 this splice site mutation yields a variant STXBP2 protein (supplemental Figure 1B), most likely with a partially impaired function.…”

Section: Resultsmentioning

confidence: 81%

Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations

Zhao

Gazendam

Drewniak

et al. 2013

Blood

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Section: Resultsmentioning

confidence: 81%

Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations

Zhao

Gazendam

Drewniak

et al. 2013

Blood

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“…Inclusion criteria were: 1) a known hereditary defect predisposing to HLH, i.e. familial HLH (FHL2-5), X-linked lymphoproliferative syndrome (XLP) type 1, deficiency of X-linked inhibitor of apoptosis (XIAP), Griscelli syndrome 2, and ChediakHigashi syndrome, or if no genetic defect was identifiable, a degranulation defect as determined by the CD107 assay in resting NK cells; 7 2) the administration of an HSCT conditioning regimen containing fludarabine (150-180 mg/m² or 5-6 mg/kg), treosulfan (42 g/m² or 36 g/m² if <12 kg), and facultative thiotepa (10 mg/kg or 7 mg/kg if <12 kg). Alemtuzumab was administered at a dose of 0.3-1.0 mg/kg.…”

Section: Methodsmentioning

confidence: 99%

Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis

et al. 2013

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“…In XLP1 NK cells the 2B4 cross-linking does not impair the activity of NKG2D and DNAM-1 receptors XLP1 patients were characterized by different SH2D1A mutations, defective expression of SAP (evaluated by intracytoplasmic flow cytometry), and inhibitory 2B4 function (in reverse antibody-dependent cellular cytotoxicity (R-ADCC) assay against the FcγRc + P815) (Table 1) [16,22,27]. To analyze the capability of 2B4 to inhibit various activating pathways, polyclonal-activated NK-cell populations from XLP1 patients were used as effectors in R-ADCC assays in the presence of the anti-2B4 mAb used in combination with mAbs specific for one or another activating NK receptor ( Fig.…”

Section: Resultsmentioning

confidence: 99%

XLP1 inhibitory effect by 2B4 does not affect DNAM‐1 and NKG2D activating pathways in NK cells

et al. 2014

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X-linked lymphoproliferative disease 1 (XLP1) is a rare congenital immunodeficiency caused by SH2D1A (Xq25) mutations resulting in lack or dysfunction of SLAM-associated protein adaptor molecule. In XLP1 patients, upon ligand (CD48) engagement, 2B4 delivers inhibitory signals that impair the cytolytic activity of NK (and T) cells. This causes the selective inability to control EBV infections and the occurrence of B-cell lymphomas. Here, we show that in the absence of SLAM-associated protein, co-engagement of 2B4 with different activating receptors, either by antibodies or specific ligands on target cells, inhibits different ITAM-dependent signaling pathways including activating killer Ig-like receptors. In XLP1 NK cells, 2B4 affected both the cytolytic and IFN-γ production capabilities, functions that were restored upon disruption of the 2B4/CD48 interactions. Notably, we provide evidence that 2B4 dysfunction does not affect the activity of DNAM-1 and NKG2D triggering receptors. Thus, while CD48 + B-EBV and lymphoma B cells devoid of NKG2D and DNAM-1 ligands were resistant to lysis, the preferential usage of these receptors allowed XLP1 NK cells to kill lymphomas that expressed sufficient amounts of the specific ligands. The study sheds new light on the XLP1 immunological defect and on the cross-talk of inhibitory 2B4 with triggering NK (and T) receptors. [6][7][8]. In general, virus-infected or neoplastic cells become susceptible to NK-cell-mediated lysis because they downregulate HLA-class I ("missing self-recognition") and upregulate ligands for activating NK receptors ("induced self-recognition") [9]. X-linked lymphoproliferative disease 1 (XLP1, Duncan disease, OMIM#308240) is a rare congenital immunodeficiency caused by mutations in SH2D1A (Xq25), the gene encoding the signaling lymphocyte activation molecule (SLAM) associated protein (SAP) [10,11]. SAP is a cytoplasmic adaptor protein that associates with members of the SLAM family, which includes SLAM (CD150), LY9 (CD229), CRACC (CD319), CD84, NTB-A (CD352), and 2B4 (CD244) [12]. 2B4 is a surface molecule expressed in NK and T lymphocytes specifically recognizing CD48, which is present solely on hematopoietic cells. 2B4 engagement causes tyrosine phosphorylation of immunoreceptor tyrosine-based switch motifs present in its cytoplasmic tail and recruitment of SAP, which transduces activating signals via Fyn-dependent processes [13,14]. In the presence of SAP, 2B4 potentiates the NCR-mediated signaling thus acting as a co-receptor molecule [15]. In the absence of SAP, 2B4 associates with protein tyrosine phosphatases and delivers inhibitory signals [16,17]. In NK cells, this occurs in physiological conditions such as during NK-cell development [18] and pregnancy [19]. On the other hand, in XLP1, the lack (or dysfunction) of SAP causes the selective inability to control infection by EBV, a γ-herpes virus that infects and sequesters itself in B cells [16,[20][21][22]. This causes severe manifestations including fulminant mononucleosis and B-cell lymphomas [...

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A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes

Abstract: Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder

Cited by 263 publications

References 47 publications

Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations

Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations

Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis

XLP1 inhibitory effect by 2B4 does not affect DNAM‐1 and NKG2D activating pathways in NK cells

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