TY - JOUR
T1 - Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency
AU - Fuchs, Sebastian
AU - Rensing-Ehl, Anne
AU - Pannicke, Ulrich
AU - Lorenz, Myriam R.
AU - Fisch, Paul
AU - Jeelall, Yogesh
AU - Rohr, Jan
AU - Speckmann, Carsten
AU - Vraetz, Thomas
AU - Farmand, Susan
AU - Schmitt-Graeff, Annette
AU - Krüger, Marcus
AU - Strahm, Brigitte
AU - Henneke, Philipp
AU - Enders, Anselm
AU - Horikawa, Keisuke
AU - Goodnow, Christopher
AU - Schwarz, Klaus
AU - Ehl, Stephan
N1 - Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Omenn syndrome (OS) is a severe immunodeficiency associated with erythroderma, lymphoproliferation, elevated IgE, and hyperactive oligoclonal T cells. A restricted T-cell repertoire caused by defective thymic T-cell development and selection, lymphopeniawith homeostatic proliferation, and lack of regulatory T cells are considered key factors inOS pathogenesis.Wereport 2 siblings presentingwith cytomegalovirus (CMV) and Pneumocystis jirovecii infections and recurrent sepsis; one developed all clinical features of OS. Both carried homozygous germline mutations in CARD11 (p.Cys150∗), impairing NF-κB signaling and IL-2 production. A somatic second-site mutation reverting the stop codon to a missense mutation (p.Cys150Leu) was detected in tissue-infiltrating T cells of the OS patient. Expression of p.Cys150Leu in CARD11-deficient T cells largely reconstituted NF-κB signaling. The reversion likely occurred in a prethymic T-cell precursor, leading to a chimeric T-cell repertoire. We speculate that in our patient the functional advantage of the revertant T cells in the context of persistent CMV infection, combined with lack of regulatory T cells, may have been sufficient to favor OS. This first observation of OS in a patient with a T-cell activation defect suggests that severely defective T-cell development or homeostatic proliferation in a lymphopenic environment are not required for this severe immunopathology. (Blood. 2015;126(14):1658-1669).
AB - Omenn syndrome (OS) is a severe immunodeficiency associated with erythroderma, lymphoproliferation, elevated IgE, and hyperactive oligoclonal T cells. A restricted T-cell repertoire caused by defective thymic T-cell development and selection, lymphopeniawith homeostatic proliferation, and lack of regulatory T cells are considered key factors inOS pathogenesis.Wereport 2 siblings presentingwith cytomegalovirus (CMV) and Pneumocystis jirovecii infections and recurrent sepsis; one developed all clinical features of OS. Both carried homozygous germline mutations in CARD11 (p.Cys150∗), impairing NF-κB signaling and IL-2 production. A somatic second-site mutation reverting the stop codon to a missense mutation (p.Cys150Leu) was detected in tissue-infiltrating T cells of the OS patient. Expression of p.Cys150Leu in CARD11-deficient T cells largely reconstituted NF-κB signaling. The reversion likely occurred in a prethymic T-cell precursor, leading to a chimeric T-cell repertoire. We speculate that in our patient the functional advantage of the revertant T cells in the context of persistent CMV infection, combined with lack of regulatory T cells, may have been sufficient to favor OS. This first observation of OS in a patient with a T-cell activation defect suggests that severely defective T-cell development or homeostatic proliferation in a lymphopenic environment are not required for this severe immunopathology. (Blood. 2015;126(14):1658-1669).
UR - http://www.scopus.com/inward/record.url?scp=84947998118&partnerID=8YFLogxK
U2 - 10.1182/blood-2015-03-631374
DO - 10.1182/blood-2015-03-631374
M3 - Article
SN - 0006-4971
VL - 126
SP - 1658
EP - 1669
JO - Blood
JF - Blood
IS - 14
ER -