학술논문
Characterization of T and B cell repertoire diversity in patients with RAG deficiency
Document Type
article
Author
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
Source
Science Immunology. 1(6)
Subject
Language
Abstract
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.