TY - JOUR
T1 - Revertant T lymphocytes in a patient with Wiskott-Aldrich syndrome
T2 - Analysis of function and distribution in lymphoid organs
AU - Trifari, Sara
AU - Scaramuzza, Samantha
AU - Catucci, Marco
AU - Ponzoni, Maurilio
AU - Mollica, Luca
AU - Chiesa, Robert
AU - Cattaneo, Federica
AU - Lafouresse, Fanny
AU - Calvez, Ronan
AU - Vermi, William
AU - Medicina, Daniela
AU - Castiello, Maria Carmina
AU - Marangoni, Francesco
AU - Bosticardo, Marita
AU - Doglioni, Claudio
AU - Caniglia, Maurizio
AU - Aiuti, Alessandro
AU - Villa, Anna
AU - Roncarolo, Maria Grazia
AU - Dupré, Loïc
PY - 2010/2
Y1 - 2010/2
N2 - 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.
AB - 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.
KW - Primary immunodeficiency
KW - secondary mutation
KW - Wiskott-Aldrich syndrome
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U2 - 10.1016/j.jaci.2009.11.034
DO - 10.1016/j.jaci.2009.11.034
M3 - Article
C2 - 20159256
AN - SCOPUS:75849163775
VL - 125
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 2
ER -