NDLI: Characterization of Î¶-associated protein, 70 kd (ZAP70)-deficient human lymphocytes.

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Characterization of Î¶-associated protein, 70 kd (ZAP70)-deficient human lymphocytes.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Roifman, Chaim M. Dadi, Harjit Somech, Raz Nahum, Amit Sharfe, Nigel
Description	Country affiliation: Canada Author Affiliation: Roifman CM ( Division of Immunology and Allergy, Canadian Centre for Primary Immunodeficiency, Jeffrey Modell Research Laboratory for the diagnosis of Primary Immunodeficiency, Hospital for Sick Children, Toronto, Ontario, Canada. chaim.roifman@sickkids.ca)
Abstract	BACKGROUND: Î¶-associated protein, 70 kd (ZAP70), deficiency in human subjects results in a combined immunodeficiency characterized by normal numbers of circulating CD4 T cells and CD8 lymphocytopenia. Patients who live beyond infancy can also experience autoimmune manifestations. OBJECTIVES: We sought to further characterize the nature of the T-cell populations found in ZAP70-deficient patients and explored the mechanisms that might predispose them to autoimmunity. METHODS: T-cell development was assessed by examining T-cell receptor (TCR) gene rearrangements and thymopoiesis by measuring TCR exclusion circle levels. TCR repertoire on CD4 and CD8 T-cell populations was assessed by means of flow cytometry. T-cell gene expression patterns were examined by means of exonic microarray analysis and apoptotic responses by means of Annexin V binding and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. RESULTS: Cells displaying recombination events from all stages of TCR gene rearrangement were present in the peripheral blood of ZAP70-deficient patients; however, the late TCRD-deleting rearrangement was significantly reduced. TCR exclusion circle levels were also found to be low. Surprisingly, all Vß families were detected in both CD4(+) and CD8(+) circulating T cells. Several Vß families were significantly overrepresented, which is reminiscent of autoimmune disorders. Levels of mRNA for cytotoxic T lymphocyte-associated antigen 4, TGF-ß, and IL-10 were found to be low, a signature of autoimmunity. Finally, Fas-mediated CD4 T-cell apoptosis was found to be reduced in vitro, and staining of thymus biopsy specimens revealed reduced thymocyte apoptosis. CONCLUSION: We show that in the absence of ZAP70, thymopoiesis is altered and differentiation to double-positive cells is hampered. Circulating T cells appear poorly regulated, do not differentiate into T(H)2 T cells, lack a number of inhibitory growth controls, and display reduced apoptosis, all predisposing patients to exaggerated inflammation and autoimmunity.
File Format	HTM / HTML
ISSN	00916749
e-ISSN	10976825
Journal	Journal of Allergy and Clinical Immunology
Issue Number	6
Volume Number	126
Language	English
Publisher	Elsevier
Publisher Date	2010-12-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Immunology Cd4-positive T-lymphocytes Metabolism Cd8-positive T-lymphocytes Thymus Gland Zap-70 Protein-tyrosine Kinase Apoptosis Genetics Autoimmunity Immunology Pathology Cell Differentiation Cell Growth Processes Genes, T-cell Receptor Inflammation Lymphopenia Microarray Analysis Severe Combined Immunodeficiency Physiopathology Deficiency Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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