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Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis.
- Source :
-
The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2014 Dec; Vol. 134 (6), pp. 1381-1387.e7. Date of Electronic Publication: 2014 Jun 27. - Publication Year :
- 2014
-
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.<br />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.<br />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.<br />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.<br />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.<br /> (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
- Subjects :
- Adolescent
Adult
Child
Child, Preschool
Female
Humans
Infant
Intracellular Signaling Peptides and Proteins genetics
Killer Cells, Natural immunology
Leukocytes, Mononuclear immunology
Lymphohistiocytosis, Hemophagocytic genetics
Lymphohistiocytosis, Hemophagocytic immunology
Lymphoproliferative Disorders genetics
Lymphoproliferative Disorders immunology
Male
Mutation
Signaling Lymphocytic Activation Molecule Associated Protein
Signaling Lymphocytic Activation Molecule Family
Young Adult
Antigens, CD immunology
Intracellular Signaling Peptides and Proteins immunology
Lymphohistiocytosis, Hemophagocytic diagnosis
Lymphoproliferative Disorders diagnosis
Receptors, Immunologic immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-6825
- Volume :
- 134
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of allergy and clinical immunology
- Publication Type :
- Academic Journal
- Accession number :
- 24985396
- Full Text :
- https://doi.org/10.1016/j.jaci.2014.04.043