Characterization of T and B cell repertoire diversity in patients with RAG deficiency

Yu Nee Lee; Francesco Frugoni; Kerry Dobbs; Irit Tirosh; Likun Du; Francesca A. Ververs; Heng Ru; Lisa Ott de Bruin; Mehdi Adeli; Jacob H. Bleesing; David Buchbinder; Manish J. Butte; Caterina Cancrini; Karin Chen; Sharon Choo; Reem A. Elfeky; Andrea Finocchi; Ramsay L. Fuleihan; Andrew R. Gennery; Dalia H. El-Ghoneimy; Lauren A. Henderson; Waleed Al-Herz; Elham Hossny; Robert P. Nelson; Sung-Yun Pai; Niraj C. Patel; Shereen M. Reda; Pere Soler-Palacin; Raz Somech; Paolo Palma; Hao Wu; Silvia Giliani; Jolan E. Walter; Luigi D. Notarangelo

doi:10.1126/sciimmunol.aah6109

Research ResourcesIMMUNODEFICIENCY

Characterization of T and B cell repertoire diversity in patients with RAG deficiency

Yu Nee Lee¹,²,
Francesco Frugoni¹,
Kerry Dobbs³,
Irit Tirosh¹,
Likun Du¹,
Francesca A. Ververs¹,
Heng Ru⁴,⁵,
Lisa Ott de Bruin¹,
Mehdi Adeli⁶,
Jacob H. Bleesing⁷,
David Buchbinder⁸,
Manish J. Butte⁹,
Caterina Cancrini¹⁰,
Karin Chen¹¹,
Sharon Choo¹²,
Reem A. Elfeky¹³,
Andrea Finocchi¹⁰,
Ramsay L. Fuleihan¹⁴,
Andrew R. Gennery¹⁵,¹⁶,
Dalia H. El-Ghoneimy¹³,
Lauren A. Henderson¹,
Waleed Al-Herz¹⁷,
Elham Hossny¹³,
Robert P. Nelson¹⁸,
Sung-Yun Pai¹⁹,
Niraj C. Patel²⁰,
Shereen M. Reda¹³,
Pere Soler-Palacin²¹,
Raz Somech²,
Paolo Palma¹⁰,
Hao Wu⁴,⁵,
Silvia Giliani²²,²³,
Jolan E. Walter¹,²⁴ and
Luigi D. Notarangelo³,*

¹Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
²Pediatric Department A and the Immunology Service, “Edmond and Lily Safra” Children’s Hospital, Jeffrey Modell Foundation Center, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁴Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
⁵Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA.
⁶Pediatrics Department, Weill Cornell Medical College, Hamad Medical Corporation, Doha, Qatar.
⁷Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
⁸Division of Hematology, Children’s Hospital Orange County, Orange County, CA 92868, USA.
⁹Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
¹⁰DPUO, University Department of Pediatrics, Bambino Gesù Children’s Hospital and University of Tor Vergata School of Medicine, Rome, Italy.
¹¹Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
¹²Department of Immunology, Royal Children’s Hospital, Melbourne, Victoria, Australia.
¹³Department of Pediatric Allergy and Immunology, Children’s Hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
¹⁴Division of Allergy and Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
¹⁵Department of Paediatric Immunology, Great North Children’s Hospital, Newcastle Upon Tyne, U.K.
¹⁶Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, U.K.
¹⁷Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
¹⁸Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
¹⁹Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA.
²⁰Division of Infectious Disease and Immunology, Department of Pediatrics, Levine Children’s Hospital, Carolinas Medical Center, Charlotte, NC 28203, USA.
²¹Paediatric Infectious Diseases and Immunodeficiencies Unit, Vall d’Hebron University Hospital, Barcelona, Spain.
²²A. Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
²³Section of Medical Genetics, Department of Pathology, Spedali Civili di Bresia, Brescia, Italy.
²⁴Division of Pediatric Allergy/Immunology, University of South Florida, and Johns Hopkins All Children’s Hospital, St. Petersburg, FL 33701, USA.

↵*Corresponding author. Email: luigi.notarangelo2{at}nih.gov

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Science Immunology 16 Dec 2016:
Vol. 1, Issue 6, eaah6109
DOI: 10.1126/sciimmunol.aah6109

Yu Nee Lee

1Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

2Pediatric Department A and the Immunology Service, “Edmond and Lily Safra” Children’s Hospital, Jeffrey Modell Foundation Center, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

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Francesco Frugoni

1Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

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Kerry Dobbs

3Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

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Irit Tirosh

1Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

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Likun Du

1Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

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Francesca A. Ververs

1Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

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Heng Ru

4Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

5Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA.

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Lisa Ott de Bruin

1Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

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Mehdi Adeli

6Pediatrics Department, Weill Cornell Medical College, Hamad Medical Corporation, Doha, Qatar.

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Jacob H. Bleesing

7Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.

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David Buchbinder

8Division of Hematology, Children’s Hospital Orange County, Orange County, CA 92868, USA.

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Manish J. Butte

9Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.

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Caterina Cancrini

10DPUO, University Department of Pediatrics, Bambino Gesù Children’s Hospital and University of Tor Vergata School of Medicine, Rome, Italy.

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Karin Chen

11Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.

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Sharon Choo

12Department of Immunology, Royal Children’s Hospital, Melbourne, Victoria, Australia.

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Reem A. Elfeky

13Department of Pediatric Allergy and Immunology, Children’s Hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

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Andrea Finocchi

10DPUO, University Department of Pediatrics, Bambino Gesù Children’s Hospital and University of Tor Vergata School of Medicine, Rome, Italy.

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Ramsay L. Fuleihan

14Division of Allergy and Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

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Andrew R. Gennery

15Department of Paediatric Immunology, Great North Children’s Hospital, Newcastle Upon Tyne, U.K.

16Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, U.K.

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Dalia H. El-Ghoneimy

13Department of Pediatric Allergy and Immunology, Children’s Hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

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Lauren A. Henderson

1Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

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Waleed Al-Herz

17Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.

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Elham Hossny

13Department of Pediatric Allergy and Immunology, Children’s Hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

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Robert P. Nelson

18Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

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Sung-Yun Pai

19Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA.

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Niraj C. Patel

20Division of Infectious Disease and Immunology, Department of Pediatrics, Levine Children’s Hospital, Carolinas Medical Center, Charlotte, NC 28203, USA.

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Shereen M. Reda

13Department of Pediatric Allergy and Immunology, Children’s Hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

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Pere Soler-Palacin

21Paediatric Infectious Diseases and Immunodeficiencies Unit, Vall d’Hebron University Hospital, Barcelona, Spain.

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Raz Somech

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Paolo Palma

10DPUO, University Department of Pediatrics, Bambino Gesù Children’s Hospital and University of Tor Vergata School of Medicine, Rome, Italy.

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Hao Wu

4Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

5Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA.

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Silvia Giliani

22A. Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

23Section of Medical Genetics, Department of Pathology, Spedali Civili di Bresia, Brescia, Italy.

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Jolan E. Walter

1Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

24Division of Pediatric Allergy/Immunology, University of South Florida, and Johns Hopkins All Children’s Hospital, St. Petersburg, FL 33701, USA.

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Luigi D. Notarangelo

3Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

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For correspondence: luigi.notarangelo2@nih.gov

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Taking SCID genetics to the clinic

Mutations that lead to deficiencies in the recombination-activating genes RAG1 and RAG2 result in a spectrum of immunodeficiencies ranging from loss of T and/or B cell repertoire diversity to a complete lack of T and B cells—severe combined immunodeficiency (SCID). Here, Lee et al. perform next-generation B and T cell repertoire sequencing on 12 patients with RAG mutations who have immunodeficiencies of varying severity. They found that the level of repertoire skewing was associated with the severity of disease and that specific repertoire deficiencies were associated with particular phenotypes. These data support a genotype-phenotype connection for primary immunodeficiencies.

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Characterization of T and B cell repertoire diversity in patients with RAG deficiency

Taking SCID genetics to the clinic

Science Immunology

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