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

• Published in: Science immunology 2016-12, Vol.1 (6)
• Main Authors: Lee, Yu Nee, Frugoni, Francesco, Dobbs, Kerry, Tirosh, Irit, Du, Likun, Ververs, Francesca A, Ru, Heng, Ott de Bruin, Lisa, Adeli, Mehdi, Bleesing, Jacob H, Buchbinder, David, Butte, Manish J, Cancrini, Caterina, Chen, Karin, Choo, Sharon, Elfeky, Reem A, Finocchi, Andrea, Fuleihan, Ramsay L, Gennery, Andrew R, El-Ghoneimy, Dalia H, Henderson, Lauren A, Al-Herz, Waleed, Hossny, Elham, Nelson, Robert P, Pai, Sung-Yun, Patel, Niraj C, Reda, Shereen M, Soler-Palacin, Pere, Somech, Raz, Palma, Paolo, Wu, Hao, Giliani, Silvia, Walter, Jolan E, Notarangelo, Luigi D
• Format: Article
• Language: English
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.aah6109

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.