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.
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.
Authors: Huie Jing; Qian Zhang; Yu Zhang; Brenna J Hill; Christopher G Dove; Erwin W Gelfand; T Prescott Atkinson; Gulbu Uzel; Helen F Matthews; Peter J Mustillo; David B Lewis; Fotini D Kavadas; I Celine Hanson; Ashish R Kumar; Raif S Geha; Daniel C Douek; Steven M Holland; Alexandra F Freeman; Helen C Su Journal: J Allergy Clin Immunol Date: 2014-05-03 Impact factor: 10.793
Authors: Umaimainthan Palendira; Carol Low; Andrew I Bell; Cindy S Ma; Rachel J M Abbott; Tri Giang Phan; D Sean Riminton; Sharon Choo; Joanne M Smart; Vassilios Lougaris; Silvia Giliani; Rebecca H Buckley; Bodo Grimbacher; Frank Alvaro; Amy D Klion; Kim E Nichols; Stephen Adelstein; Alan B Rickinson; Stuart G Tangye Journal: J Exp Med Date: 2012-04-09 Impact factor: 14.307
Authors: Francesca Prete; Marco Catucci; Mayrel Labrada; Stefania Gobessi; Maria Carmina Castiello; Elisa Bonomi; Alessandro Aiuti; William Vermi; Caterina Cancrini; Ayse Metin; Sophie Hambleton; Robbert Bredius; Luigi Daniele Notarangelo; Mirjam van der Burg; Ulrich Kalinke; Anna Villa; Federica Benvenuti Journal: J Exp Med Date: 2013-01-21 Impact factor: 14.307