Patients with T+/low NK+ IL‐2 receptor γ chain deficiency have differentially‐impaired cytokine signaling resulting in severe combined immunodeficiency. Issue 10 (28th August 2014)

• Record Type: Journal Article
• Authors: Fuchs, Sebastian; Rensing‐Ehl, Anne; Erlacher, Miriam; Vraetz, Thomas; Hartjes, Lara; Janda, Ales; Rizzi, Marta; Lorenz, Myriam R.; Gilmour, Kimberly; de Saint‐Basile, Geneviève; Roifman, Chaim M.; Cheuk, Steven; Gennery, Andrew; Thrasher, Adrian J.; Fuchs, Ilka; Schwarz, Klaus; Speckmann, Carsten; Ehl, Stephan
• Is Part Of: European journal of immunology. Volume 44:Issue 10(2014:Oct.)
• Page Start: 3129
• Page End: 3140
• Publication Date: 2014-08-28
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201444689
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>X‐linked severe combined immunodeficiency (X‐SCID) leads to a T<sup>−</sup>NK<sup>−</sup>B<sup>+</sup> immunophenotype and is caused by mutations in the gene encoding the IL‐2 receptor γ‐chain (IL2RG). IL2RG<sup>R222C</sup> 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<sup>R222C</sup> 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 Moreover, we identified nine additional unpublished patients with the same mutations, all with a full SCID phenotype, and confirmed selected immunological observations.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<sup>R222C</sup> on cytokine signal transduction, with a gradient IL‐4<IL‐2/IL‐15<IL‐21. Thus, IL2RG<sup>R222C</sup> causes a consistently severe clinical phenotype that is not predicted by the variable and moderate impairment of T‐cell immunity or TREC analysis.</p> </abstract>