Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:134

Article

Meazza, Raffaella¹  Tuberosa, Claudia^1,2  Cetica, Valentina^3,4  Falco, Michela⁵  Parolini, Silvia⁶  Grieve, Sam⁷  Griffiths, Gillian M.⁷  Marcenaro, Stefania⁵  Micalizzi, Concetta⁵  Montin, Davide⁸  Fagioli, Franca⁹  Moretta, Alessandro²  Mingari, Maria C.^1,2  Moretta, Lorenzo⁵  Notarangelo, Luigi D.¹⁰  Bottino, Cristina^2,5  Arico, Maurizio^3,4  Pende, Daniela¹ 

[1] Univ San Martino, Azienda Osped, Ist Nazl Ric Cancro, Ist Ricovero & Cura Carattere Sci, Genoa, Italy

[2] Univ Genoa, Dipartimento Med Sperimentale, Genoa, Italy

[3] Univ Meyer, Azienda Osped, Dipartimento Oncol Pediat, Florence, Italy

[4] ITT, Pediat Oncol Network, I-50139 Florence, Italy

[5] Ist Giannina Gaslini, I-16148 Genoa, Italy

[6] Univ Brescia, Dipartimento Med Mol & Traslaz, Brescia, Italy

[7] Cambridge Inst Med Res, Dept Med, Cambridge, England

[8] Univ Turin, Dipartimento Sci Sanita Publ & Pediat, Turin, Italy

[9] Osped Infantile Regina Margherita, Oncoematol Pediat & Ctr Trapianti, Turin, Italy

[10] Boston Childrens Hosp, Div Immunol, Boston, MA USA

关键词: HLH;    XLP1;    SAP expression;    2B4 function;    NK cells;   

DOI  :  10.1016/j.jaci.2014.04.043

来源: Elsevier

【 摘 要 】

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, 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 1. 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 1 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.

【 授权许可】

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