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.
Lee, Y.N., Frugoni, F., Dobbs, K., Tirosh, I., Du, L., Ververs, F.A., et al. (2016). Characterization of T and B cell repertoire diversity in patients with RAG deficiency. SCIENCE IMMUNOLOGY, 1(6), eaah6109-eaah6109.
|Tipologia:||Articolo su rivista|
|Citazione:||Lee, Y.N., Frugoni, F., Dobbs, K., Tirosh, I., Du, L., Ververs, F.A., et al. (2016). Characterization of T and B cell repertoire diversity in patients with RAG deficiency. SCIENCE IMMUNOLOGY, 1(6), eaah6109-eaah6109.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore MED/38|
|Revisione (peer review):||Esperti anonimi|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1126/sciimmunol.aah6109|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2016|
|Titolo:||Characterization of T and B cell repertoire diversity in patients with RAG deficiency|
|Autori:||Lee, YN; Frugoni, F; Dobbs, K; Tirosh, I; Du, L; Ververs, FA; Ru, H; De Bruin, LO; Adeli, M; Bleesing, JH; Buchbinder, D; Butte, MJ; Cancrini, C; Chen, K; Choo, S; Elfeky, RA; Finocchi, A; Fuleihan, RL; Gennery, AR; El-Ghoneimy, DH; Henderson, LA; Al-Herz, W; Hossny, E; Nelson, RP; Pai, S-; Patel, NC; Reda, SM; Soler-Palacin, P; Somech, R; Palma, P; Wu, H; Giliani, S; Walter, JE; Notarangelo, LD|
|Appare nelle tipologie:||01 - Articolo su rivista|