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Revertant T lymphocytes in a patient with Wiskott-Aldrich syndrome: analysis of function and distribution in lymphoid organs

Authors :
Sara Trifari
Marita Bosticardo
Ronan Calvez
William Vermi
Robert Chiesa
Maurilio Ponzoni
Luca Mollica
Maria Grazia Roncarolo
Fanny Lafouresse
Loïc Dupré
Daniela Medicina
Francesco Marangoni
Maurizio Caniglia
Anna Villa
Marco Catucci
Maria Carmina Castiello
Claudio Doglioni
Federica Cattaneo
Samantha Scaramuzza
Alessandro Aiuti
Trifari, S
Scaramuzza, S
Catucci, M
Ponzoni, Maurilio
Mollica, L
Chiesa, R
Cattaneo, F
Lafouresse, F
Calvez, R
Vermi, W
Medicina, D
Castiello, Mc
Marangoni, F
Bosticardo, M
Doglioni, Claudio
Caniglia, M
Aiuti, Alessandro
Villa, A
Roncarolo, MARIA GRAZIA
Dupre, L.
Source :
Journal of allergy and clinical immunology 125 (2010): 439–448., info:cnr-pdr/source/autori:Trifari S, Scaramuzza S, Catucci M, Ponzoni M, Mollica L, Chiesa R, Cattaneo F, Lafouresse F, Calvez R, Vermi W, Medicina D, Castiello MC, Marangoni F, Bosticardo M, Doglioni C, Caniglia M, Aiuti A, Villa A, Roncarolo MG, Dupré L/titolo:Revertant T lymphocytes in a patient with Wiskott-Aldrich syndrome: Analysis of function and distribution in lymphoid organs./doi:/rivista:Journal of allergy and clinical immunology/anno:2010/pagina_da:439/pagina_a:448/intervallo_pagine:439–448/volume:125
Publication Year :
2009

Abstract

Background: The Wiskott-Aldrich syndrome (WAS) is a rare genetic disease characterized by thrombocytopenia, immunodeficiency, autoimmunity, and hematologic malignancies. Secondary mutations leading to re-expression of WAS protein (WASP) are relatively frequent in patients with WAS. Objective: The tissue distribution and function of revertant cells were investigated in a novel case of WAS gene secondary mutation. Methods: A vast combination of approaches was used to characterize the second-site mutation, to investigate revertant cell function, and to track their distribution over a 18-year clinical follow-up. Results: The WAS gene secondary mutation was a 4-nucleotide insertion, 4 nucleotides downstream of the original deletion. This somatic mutation allowed the T-cell-restricted expression of a stable, full-length WASP with a 3-amino acid change compared with the wild-type protein. WASP(+) T cells appeared early in the spleen (age 10 years) and were highly enriched in a mesenteric lymph node at a later time (age 23 years). Revertant T cells had a diversified T-cell-receptor repertoire and displayed in vitro and in vivo selective advantage. They proliferated and produced cytokines normally on T-cell-receptor stimulation. Consistently, the revertant WASP correctly localized to the immunologic synapse and to the leading edge of migrating T cells. Conclusion: Despite the high proportion of functional revertant T cells, the patient still has severe infections and autoimmune disorders, suggesting that re-expression of WASP in T cells is not sufficient to normalize immune functions fully in patients with WAS. (J Allergy Clin Immunol 2010;125:439-48.) Background: The Wiskott-Aldrich syndrome (WAS) is a rare genetic disease characterized by thrombocytopenia, immunodeficiency, autoimmunity, and hematologic malignancies. Secondary mutations leading to re-expression of WAS protein (WASP) are relatively frequent in patients with WAS. Objective: The tissue distribution and function of revertant cells were investigated in a novel case of WAS gene secondary mutation. Methods: A vast combination of approaches was used to characterize the second-site mutation, to investigate revertant cell function, and to track their distribution over a 18-year clinical follow-up. Results: The WAS gene secondary mutation was a 4-nucleotide insertion, 4 nucleotides downstream of the original deletion. This somatic mutation allowed the T-cell-restricted expression of a stable, full-length WASP with a 3-amino acid change compared with the wild-type protein. WASP(+) T cells appeared early in the spleen (age 10 years) and were highly enriched in a mesenteric lymph node at a later time (age 23 years). Revertant T cells had a diversified T-cell-receptor repertoire and displayed in vitro and in vivo selective advantage. They proliferated and produced cytokines normally on T-cell-receptor stimulation. Consistently, the revertant WASP correctly localized to the immunologic synapse and to the leading edge of migrating T cells. Conclusion: Despite the high proportion of functional revertant T cells, the patient still has severe infections and autoimmune disorders, suggesting that re-expression of WASP in T cells is not sufficient to normalize immune functions fully in patients with WAS. (J Allergy Clin Immunol 2010;125:439-48.) BACKGROUND: The Wiskott-Aldrich syndrome (WAS) is a rare genetic disease characterized by thrombocytopenia, immunodeficiency, autoimmunity, and hematologic malignancies. Secondary mutations leading to re-expression of WAS protein (WASP) are relatively frequent in patients with WAS. OBJECTIVE: The tissue distribution and function of revertant cells were investigated in a novel case of WAS gene secondary mutation. METHODS: A vast combination of approaches was used to characterize the second-site mutation, to investigate revertant cell function, and to track their distribution over a 18-year clinical follow-up. RESULTS: The WAS gene secondary mutation was a 4-nucleotide insertion, 4 nucleotides downstream of the original deletion. This somatic mutation allowed the T-cell-restricted expression of a stable, full-length WASP with a 3-amino acid change compared with the wild-type protein. WASP(+) T cells appeared early in the spleen (age 10 years) and were highly enriched in a mesenteric lymph node at a later time (age 23 years). Revertant T cells had a diversified T-cell-receptor repertoire and displayed in vitro and in vivo selective advantage. They proliferated and produced cytokines normally on T-cell-receptor stimulation. Consistently, the revertant WASP correctly localized to the immunologic synapse and to the leading edge of migrating T cells. CONCLUSION: Despite the high proportion of functional revertant T cells, the patient still has severe infections and autoimmune disorders, suggesting that re-expression of WASP in T cells is not sufficient to normalize immune functions fully in patients with WAS. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Details

ISSN :
10976825
Volume :
125
Issue :
2
Database :
OpenAIRE
Journal :
The Journal of allergy and clinical immunology
Accession number :
edsair.doi.dedup.....b76d76eaec7021e24a7f57f29c5a3bf7