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J Clin Immunol. 2018 Jun 7. doi: 10.1007/s10875-018-0512-0. [Epub ahead of print]
Lethal Influenza in Two Related Adults with Inherited GATA2 Deficiency.
Sologuren I1, Mart?nez-Saavedra MT1, Sol?-Viol?n J2,3, de Borges de Oliveira E Jr4,5, Betancor E6, Casas I7, Oleaga-Quintas C4,5, Mart?nez-Gallo M8, Zhang SY4,5,9, Pestano J6, Colobran R8,10, Herrera-Ramos E1, P?rez C11, L?pez-Rodr?guez M1, Ruiz-Hern?ndez JJ12, Franco N13, Ferrer JM2,3, Bilbao C14, And?jar-S?nchez M15, ?lvarez Fern?ndez M13, Ciancanelli MJ9, Rodr?guez de Castro F16, Casanova JL4,5,9,17,18, Bustamante J4,5,9,19,20, Rodr?guez-Gallego C21,22.
Author information
Abstract
The pathogenesis of life-threatening influenza A virus (IAV) disease remains elusive, as infection is benign in most individuals. We studied two relatives who died from influenza. We Sanger sequenced GATA2 and evaluated the mutation by gene transfer, measured serum cytokine levels, and analyzed circulating T- and B-cells. Both patients (father and son, P1 and P2) died in 2011 of H1N1pdm IAV infection at the ages of 54 and 31 years, respectively. They had not suffered from severe or moderately severe infections in the last 17 (P1) and 15 years (P2). A daughter of P1 had died at 20 years from infectious complications. Low B-cell, NK- cell, and monocyte numbers and myelodysplastic syndrome led to sequence GATA2. Patients were heterozygous for a novel, hypomorphic, R396L mutation leading to haplo-insufficiency. B- and T-cell rearrangement in peripheral blood from P1 during the influenza episode showed expansion of one major clone. No T-cell receptor excision circles were detected in P1 and P3 since they were 35 and 18 years, respectively. Both patients presented an exuberant, interferon (IFN)-γ-mediated hypercytokinemia during H1N1pdm infection. No data about patients with viremia was available. Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood. However, a role of other genetic variants involved in immune responses cannot be ruled out. Patients with GATA2 deficiency can reach young adulthood without severe infections, including influenza, despite long-lasting complete B-cell and natural killer (NK) cell deficiency, as well as profoundly diminished T-cell thymic output.
KEYWORDS:
GATA2; H1N1; Immunodeficiency; immunological memory; influenza A virus
PMID: 29882021 DOI: 10.1007/s10875-018-0512-0
Lethal Influenza in Two Related Adults with Inherited GATA2 Deficiency.
Sologuren I1, Mart?nez-Saavedra MT1, Sol?-Viol?n J2,3, de Borges de Oliveira E Jr4,5, Betancor E6, Casas I7, Oleaga-Quintas C4,5, Mart?nez-Gallo M8, Zhang SY4,5,9, Pestano J6, Colobran R8,10, Herrera-Ramos E1, P?rez C11, L?pez-Rodr?guez M1, Ruiz-Hern?ndez JJ12, Franco N13, Ferrer JM2,3, Bilbao C14, And?jar-S?nchez M15, ?lvarez Fern?ndez M13, Ciancanelli MJ9, Rodr?guez de Castro F16, Casanova JL4,5,9,17,18, Bustamante J4,5,9,19,20, Rodr?guez-Gallego C21,22.
Author information
Abstract
The pathogenesis of life-threatening influenza A virus (IAV) disease remains elusive, as infection is benign in most individuals. We studied two relatives who died from influenza. We Sanger sequenced GATA2 and evaluated the mutation by gene transfer, measured serum cytokine levels, and analyzed circulating T- and B-cells. Both patients (father and son, P1 and P2) died in 2011 of H1N1pdm IAV infection at the ages of 54 and 31 years, respectively. They had not suffered from severe or moderately severe infections in the last 17 (P1) and 15 years (P2). A daughter of P1 had died at 20 years from infectious complications. Low B-cell, NK- cell, and monocyte numbers and myelodysplastic syndrome led to sequence GATA2. Patients were heterozygous for a novel, hypomorphic, R396L mutation leading to haplo-insufficiency. B- and T-cell rearrangement in peripheral blood from P1 during the influenza episode showed expansion of one major clone. No T-cell receptor excision circles were detected in P1 and P3 since they were 35 and 18 years, respectively. Both patients presented an exuberant, interferon (IFN)-γ-mediated hypercytokinemia during H1N1pdm infection. No data about patients with viremia was available. Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood. However, a role of other genetic variants involved in immune responses cannot be ruled out. Patients with GATA2 deficiency can reach young adulthood without severe infections, including influenza, despite long-lasting complete B-cell and natural killer (NK) cell deficiency, as well as profoundly diminished T-cell thymic output.
KEYWORDS:
GATA2; H1N1; Immunodeficiency; immunological memory; influenza A virus
PMID: 29882021 DOI: 10.1007/s10875-018-0512-0