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Journal of Clinical Immunology

, Volume 38, Issue 4, pp 513–526 | Cite as

Lethal Influenza in Two Related Adults with Inherited GATA2 Deficiency

  • Ithaisa Sologuren
  • María Teresa Martínez-Saavedra
  • Jordi Solé-Violán
  • Edgar de Borges de Oliveira Jr
  • Eva Betancor
  • Inmaculada Casas
  • Carmen Oleaga-Quintas
  • Mónica Martínez-Gallo
  • Shen-Ying Zhang
  • Jose Pestano
  • Roger Colobran
  • Estefanía Herrera-Ramos
  • Carmen Pérez
  • Marta López-Rodríguez
  • José Juan Ruiz-Hernández
  • Nieves Franco
  • José María Ferrer
  • Cristina Bilbao
  • Miguel Andújar-Sánchez
  • Mercedes Álvarez Fernández
  • Michael J. Ciancanelli
  • Felipe Rodríguez de Castro
  • Jean-Laurent Casanova
  • Jacinta Bustamante
  • Carlos Rodríguez-Gallego
Original Article

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

Immunodeficiency GATA2 influenza A virus H1N1 immunological memory 

Notes

Acknowledgments

We would like to thank the patients and their families for their trust. We are highly indebted to Judith Noda, Juantxo Aróstegui, Yanira Florido, Nereida González-Quevedo, Ana Domínguez, Rafael Camacho, Mónica González-Esguevillas, and Teresa Molero for technical assistance.

Author Contributions

I.S., M.T.M.-S., E.B.O.-J., E.B., I.C, C.O.-Q., M.M.-G., S.-Y. A., J.P., R.C., E. H.-R., C.P., M. L.-R., J.J.R.-H., C.B., M.A.-A.., M.A.F, M.J.C., J.-L.C., J.B., and C.R.-G. performed the research and analyzed and interpreted the data. J.S.V., J.M.F., F.R.C, and NF were responsible for the clinical evaluation of the patients and also collected and interpreted the data. C.R.-G. designed the research. C.R.G. and J-L.C. wrote the manuscript, and JB collaborated in writing the manuscript.

Funding

This work was supported by grants from the Instituto de Salud Carlos III, Ministry of Health [FIS PI13/01456 and FIS PI16/00759, with the funding of European Regional Development Fund-European Social Fund, FEDER-FSE] to [C.R-G.]; National Center for Research Resources and the National Center for Advancing Sciences (NCATS) [grant 8UL1TR000043]; National Institutes of Health [grant 5R01NS072381] to [J-L.C.]; the St. Giles Foundation, the French National Research Agency under the “Investments for the Future” program [grant ANR-10-IAHU-01]; the Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases [ANR-10-LABX-62-IBEID], ANR grants [ANR2014-IEIHSEER] to [S-Y.Z.]; [ANR2016-GENMSMD] to [J.B.]; INSERM, Paris Descartes University; Universidad de Las Palmas de Gran Canaria (fellowship to [E.H.R.]); and Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (fellowship [FI 11/00593] to [M.L-R.]). The sponsors of the study had no role in designing the study, collecting, analyzing, and interpreting the data, or writing of the paper.

Compliance with Ethical Standards

This research has been performed in accordance with the Declaration of Helsinki. The protocols were approved by Clinical Research Ethics Committees of hospitals involved. Written informed consent for the study was obtained from their legal representative.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Supplementary material

10875_2018_512_MOESM1_ESM.doc (534 kb)
ESM 1 (DOC 533 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ithaisa Sologuren
    • 1
  • María Teresa Martínez-Saavedra
    • 1
  • Jordi Solé-Violán
    • 2
    • 3
  • Edgar de Borges de Oliveira Jr
    • 4
    • 5
  • Eva Betancor
    • 6
  • Inmaculada Casas
    • 7
  • Carmen Oleaga-Quintas
    • 4
    • 5
  • Mónica Martínez-Gallo
    • 8
  • Shen-Ying Zhang
    • 4
    • 5
    • 9
  • Jose Pestano
    • 6
  • Roger Colobran
    • 8
    • 10
  • Estefanía Herrera-Ramos
    • 1
  • Carmen Pérez
    • 11
  • Marta López-Rodríguez
    • 1
  • José Juan Ruiz-Hernández
    • 12
  • Nieves Franco
    • 13
  • José María Ferrer
    • 2
    • 3
  • Cristina Bilbao
    • 14
  • Miguel Andújar-Sánchez
    • 15
  • Mercedes Álvarez Fernández
    • 13
  • Michael J. Ciancanelli
    • 9
  • Felipe Rodríguez de Castro
    • 16
  • Jean-Laurent Casanova
    • 4
    • 5
    • 9
    • 17
    • 18
  • Jacinta Bustamante
    • 4
    • 5
    • 9
    • 19
    • 20
  • Carlos Rodríguez-Gallego
    • 1
    • 20
  1. 1.Department of ImmunologyGran Canaria Dr. Negrín University HospitalLas Palmas de Gran CanariaSpain
  2. 2.Intensive Care UnitGran Canaria Dr. Negrín University HospitalLas Palmas de Gran CanariaSpain
  3. 3.CIBER de Enfermedades RespiratoriasInstituto de Salud Carlos IIIMadridSpain
  4. 4.Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine InstituteNecker Hospital for Sick ChildrenParisFrance
  5. 5.Paris Descartes UniversityParisFrance
  6. 6.Department of Biochemistry, Molecular Biology, Physiology, Genetics and Immunology, School of MedicineUniversity of Las Palmas de Gran CanariaLas Palmas de Gran CanariaSpain
  7. 7.National Influenza Center-Madrid, National Center of MicrobiologyInstituto de Salud Carlos IIIMadridSpain
  8. 8.Department of ImmunologyVall d’Hebrón University HospitalBarcelonaSpain
  9. 9.St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchThe Rockefeller UniversityNew YorkUSA
  10. 10.Department of Cell Biology, Physiology and ImmunologyUniversitat Autónoma de Barcelona (UAB)BarcelonaSpain
  11. 11.Department of MicrobiologyGran Canaria Dr. Negrín University HospitalLas Palmas de Gran CanariaSpain
  12. 12.Department of Internal MedicineGran Canaria Dr. Negrín University HospitalLas Palmas de Gran CanariaSpain
  13. 13.Intensive Care UnitMostoles University HospitalMadridSpain
  14. 14.Department of HematologyGran Canaria Dr. Negrín University HospitalLas Palmas de Gran CanariaSpain
  15. 15.Department of PathologyComplejo Hospitalario Universitario Insular Materno InfantilLas Palmas de Gran CanariaSpain
  16. 16.Department of Respiratory DiseasesGran Canaria Dr. Negrín University HospitalLas Palmas de Gran CanariaSpain
  17. 17.Howard Hughes Medical InstituteNew YorkUSA
  18. 18.Pediatric Hematology-Immunology UnitNecker Hospital for Sick ChildrenParisFrance
  19. 19.Center for the Study of Primary ImmunodeficienciesNecker Hospital for Sick ChildrenParisFrance
  20. 20.Department of ImmunologyHospital Universitario de Gran Canaria Dr. NegrínLas Palmas de Gran CanariaSpain

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