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J Allergy Clin Immunol. 2014 Dec;134(6):1381-1387.e7. doi: 10.1016/j.jaci.2014.04.043. Epub 2014 Jun 27.

Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis.

Author information

1
Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
2
Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.
3
Dipartimento Oncoematologia Pediatrica, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy; Pediatric Oncology Network, Istituto Toscano Tumori (I.T.T.), Florence, Italy.
4
Istituto Giannina Gaslini, Genoa, Italy.
5
Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Brescia, Italy.
6
Department of Medicine, Cambridge Institute for Medical Research, Cambridge, United Kingdom.
7
Dipartimento Oncoematologia Pediatrica, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy.
8
Dipartimento di Scienze della Sanità Pubblica e Pediatriche, Università degli Studi di Torino, Turin, Italy.
9
Oncoematologia Pediatrica e Centro Trapianti, Ospedale Infantile Regina Margherita, Turin, Italy.
10
Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.
11
Division of Immunology, Boston Children's Hospital, Boston, Mass.
12
Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy; Istituto Giannina Gaslini, Genoa, Italy.
13
Dipartimento Oncoematologia Pediatrica, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy; Pediatric Oncology Network, Istituto Toscano Tumori (I.T.T.), Florence, Italy. Electronic address: maurizio.arico@ittumori.it.

Abstract

BACKGROUND:

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, heterogeneous, hyperinflammmatory disorder. Prompt identification of inherited forms resulting from mutation in genes involved in cellular cytotoxicity can be crucial. X-linked lymphoproliferative disease 1 (XLP1), due to mutations in SH2D1A (Xq25) encoding signaling lymphocyte activation molecule-associated protein (SAP), may present with HLH. Defective SAP induces paradoxical inhibitory function of the 2B4 coreceptor and impaired natural killer (NK) (and T) cell response against EBV-infected cells.

OBJECTIVE:

To characterize a cohort of patients with HLH and XLP1 for SAP expression and 2B4 function in lymphocytes, proposing a rapid diagnostic screening to direct mutation analysis.

METHODS:

We set up rapid assays for 2B4 function (degranulation or (51)Cr-release) to be combined with intracellular SAP expression in peripheral blood NK cells. We studied 12 patients with confirmed mutation in SH2D1A and some family members.

RESULTS:

The combined phenotypic/functional assays allowed efficient and complete diagnostic evaluation of all patients with XLP1, thus directing mutation analysis and treatment. Nine cases were SAP(-), 2 expressed SAP with mean relative fluorescence intensity values below the range of healthy controls (SAP(dull)), and 1, carrying the R55L mutation, was SAP(+). NK cells from all patients showed inhibitory 2B4 function and defective killing of B-EBV cells. Carriers with SH2D1A mutations abolishing SAP expression and low percentage of SAP(+) cells showed neutral 2B4 function at the polyclonal NK cell level. Three novel SH2D1A mutations have been identified.

CONCLUSIONS:

Study of SAP expression is specific but may have insufficient sensitivity for screening XLP1 as a single tool. Combination with 2B4 functional assay allows identification of all cases.

KEYWORDS:

2B4 function; HLH; NK cells; SAP expression; XLP1

PMID:
24985396
DOI:
10.1016/j.jaci.2014.04.043
[Indexed for MEDLINE]

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