In:
European Journal of Immunology, Wiley, Vol. 44, No. 10 ( 2014-10), p. 3129-3140
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 Moreover, we identified nine additional unpublished patients with the same mutations, all with a full SCID phenotype, and confirmed selected immunological observations.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.
Type of Medium:
Online Resource
ISSN:
0014-2980
,
1521-4141
DOI:
10.1002/eji.201444689
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
120108-6
detail.hit.zdb_id:
1491907-2
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