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

Journal: Science immunology
Published Date: Dec 16, 2016

Abstract

Recombination-activating genes 1 and 2 ( and ) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the and genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with mutations presenting with Omenn syndrome ( = 5), leaky SCID ( = 3), or CID-G/AI ( = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency.

Authors

  • Yu Nee Lee
    Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Francesco Frugoni
    Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Kerry Dobbs
    Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • Irit Tirosh
    Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Likun Du
    Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Francesca A Ververs
    Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Heng Ru
    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • Lisa Ott de Bruin
    Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Mehdi Adeli
    Pediatrics Department, Weill Cornell Medical College, Hamad Medical Corporation, Doha, Qatar.
  • Jacob H Bleesing
    Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • David Buchbinder
    Division of Hematology, Children's Hospital Orange County, Orange County, CA 92868, USA.
  • Manish J Butte
    Department of Pediatrics and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States.
  • Caterina Cancrini
    DPUO, University Department of Pediatrics, Bambino Gesù Children's Hospital and University of Tor Vergata School of Medicine, Rome, Italy.
  • Karin Chen
    Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
  • Sharon Choo
    Department of Immunology, Royal Children's Hospital, Melbourne, Victoria, Australia.
  • Reem A Elfeky
    Department of Pediatric Allergy and Immunology, Children's Hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
  • Andrea Finocchi
    DPUO, University Department of Pediatrics, Bambino Gesù Children's Hospital and University of Tor Vergata School of Medicine, Rome, Italy.
  • Ramsay L Fuleihan
    Division of Allergy and Immunology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • Andrew R Gennery
    Department of Paediatric Immunology, Great North Children's Hospital, Newcastle Upon Tyne, U.K.
  • Dalia H El-Ghoneimy
    Department of Pediatric Allergy and Immunology, Children's Hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
  • Lauren A Henderson
    Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Waleed Al-Herz
    Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
  • Elham Hossny
    Department of Pediatric Allergy and Immunology, Children's Hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
  • Robert P Nelson
    Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Sung-Yun Pai
    Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
  • Niraj C Patel
    Division of Infectious Disease and Immunology, Department of Pediatrics, Levine Children's Hospital, Carolinas Medical Center, Charlotte, NC 28203, USA.
  • Shereen M Reda
    Department of Pediatric Allergy and Immunology, Children's Hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
  • Pere Soler-Palacin
    Paediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron University Hospital, Barcelona, Spain.
  • Raz Somech
    Pediatric 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.
  • Paolo Palma
    DPUO, University Department of Pediatrics, Bambino Gesù Children's Hospital and University of Tor Vergata School of Medicine, Rome, Italy.
  • Hao Wu
    Zhejiang Institute of Tianjin University (Shaoxing), Shaoxing, China.
  • Silvia Giliani
    A. Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
  • Jolan E Walter
    Department of Pediatric Allergy and Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States.
  • Luigi D Notarangelo
    Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. luigi.notarangelo2@nih.gov.

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