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-GhoneimyLauren 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Recombination-activating genes 1 and 2 (RAG1 and RAG2) 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 RAG1 and RAG2 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 RAG mutations presenting with Omenn syndrome (n = 5), leaky SCID (n = 3), or CID-G/AI (n = 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.

Original languageEnglish
Article numbereaah6109
JournalScience immunology
Issue number6
StatePublished - 2016


FundersFunder number
National Institutes of Health2U54AI082973, 2R01AI100887, 1-FY13-500


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