期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 130, 期 5, 页码 1144-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2012.07.029
关键词
CD4; lymphopenia; autoinflammation; recurrent infections; LCK; SRC tyrosine kinase; genetic defect; immunodeficiency; T-cell receptor signaling
资金
- INSERM, Agence Nationale de la Recherche (France) [ANR-08-MIEN-012-01]
- European Research Council [ERC-2009-AdG_20090506]
- Centre National de la Recherche Scientifique (France)
- German Research Council/DFG [HA 5967/1 1]
- Fondation IMAGINE (France)
- Ministere de la Recherche and l'Ecole Polytechnique (France)
- Fondation ARC pour la Recherche sur le Cancer (ARC) (France)
- ANR (France)
- Robert A. Good/Jeffrey Modell fellowship
Background: Signals emanating from the antigen T-cell receptor (TCR) are required for T-cell development and function. The T lymphocyte-specific protein tyrosine kinase (Lck) is a key component of the TCR signaling machinery. On the basis of its function, we considered LCK a candidate gene in patients with combined immunodeficiency. Objective: We identify and describe a child with a T-cell immunodeficiency caused by a homozygous missense mutation of the LCK gene (c.1022T>C) resulting from uniparental disomy. Methods: Genetic, molecular, and functional analyses were performed to characterize the Lck deficiency, and the associated clinical and immunologic phenotypes are reported. Results: The mutant LCK protein (p.L341P) was weakly expressed with no kinase activity and failed to reconstitute TCR signaling in LCK-deficient T cells. The patient presented with recurrent respiratory tract infections together with predominant early-onset inflammatory and autoimmune manifestations. The patient displayed CD4(+) T-cell lymphopenia and low levels of CD4 and CD8 expression on the T-cell surface. The residual T lymphocytes had an oligoclonal T-cell repertoire and exhibited a profound TCR signaling defect, with only weak tyrosine phosphorylation signals and no Ca2+ mobilization in response to TCR stimulation. Conclusion: We report a new form of T-cell immunodeficiency caused by a LCK gene defect, highlighting the essential role of Lck in human T-cell development and responses. Our results also point out that defects in the TCR signaling cascade often result in abnormal T-cell differentiation and functions, leading to an important risk factor for inflammation and autoimmunity. (J Allergy Clin Immunol 2012;130:1144-52.)
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