Patients with T⁺/low NK⁺ IL-2 receptor γ chain deficiency have differentially-impaired cytokine signaling resulting in severe combined immunodeficiency - PubMed (original) (raw)

Case Reports

. 2014 Oct;44(10):3129-40.

doi: 10.1002/eji.201444689. Epub 2014 Aug 28.

Anne Rensing-Ehl, Miriam Erlacher, Thomas Vraetz, Lara Hartjes, Ales Janda, Marta Rizzi, Myriam R Lorenz, Kimberly Gilmour, Geneviève de Saint-Basile, Chaim M Roifman, Steven Cheuk, Andrew Gennery, Adrian J Thrasher, Ilka Fuchs, Klaus Schwarz, Carsten Speckmann, Stephan Ehl

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Case Reports

Patients with T⁺/low NK⁺ IL-2 receptor γ chain deficiency have differentially-impaired cytokine signaling resulting in severe combined immunodeficiency

Sebastian Fuchs et al. Eur J Immunol. 2014 Oct.

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Abstract

X-linked severe combined immunodeficiency (X-SCID) leads to a T(-) NK(-) B(+) immunophenotype and is caused by mutations in the gene encoding the IL-2 receptor γ-chain (IL2RG). IL2RG(R222C) leads to atypical SCID with a severe early onset phenotype despite largely normal NK- and T-cell numbers. To address this discrepancy, we performed a detailed analysis of T, B, and NK cells, including quantitative STAT phosphorylation and functional responses to the cytokines IL-2, IL-4, IL-15, and IL-21 in a patient with the IL2RG(R222C) mutation. Moreover, we identified nine additional unpublished patients with the same mutations, all with a full SCID phenotype, and confirmed selected immunological observations. T-cell development was variably affected, but led to borderline T-cell receptor excision circle (TREC) levels and a normal repertoire. T cells showed moderately reduced proliferation, failing enhancement by IL-2. While NK-cell development was normal, IL-2 enhancement of NK-cell degranulation and IL-15-induced cytokine production were absent. IL-2 or IL-21 failed to enhance B-cell proliferation and plasmablast differentiation. These functional alterations were reflected by a differential impact of IL2RG(R222C) on cytokine signal transduction, with a gradient IL-4<IL-2/IL-15<IL-21. Thus, IL2RG(R222C) causes a consistently severe clinical phenotype that is not predicted by the variable and moderate impairment of T-cell immunity or TREC analysis.

Keywords: Atypical SCID; Common gamma chain; Cytokine signaling; Leaky SCID; Severe combined immunodeficiency.

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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