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

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.

SUBMITTER: Lee YN

PROVIDER: S-EPMC5586490 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Lee Yu Nee YN Frugoni Francesco F Dobbs Kerry K Tirosh Irit I Du Likun L Ververs Francesca A FA Ru Heng H Ott de Bruin Lisa L Adeli Mehdi M Bleesing Jacob H JH Buchbinder David D Butte Manish J MJ Cancrini Caterina C Chen Karin K Choo Sharon S Elfeky Reem A RA Finocchi Andrea A Fuleihan Ramsay L RL Gennery Andrew R AR El-Ghoneimy Dalia H DH Henderson Lauren A LA Al-Herz Waleed W Hossny Elham E Nelson Robert P RP Pai Sung-Yun SY Patel Niraj C NC Reda Shereen M SM Soler-Palacin Pere P Somech Raz R Palma Paolo P Wu Hao H Giliani Silvia S Walter Jolan E JE Notarangelo Luigi D LD

Science immunology 20161216 6

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 autoimmu ...[more]

PMID: 28783691

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Project description:BackgroundThe importance of CD4⁺ and CD8⁺ T cells in protection against tuberculosis (TB) is well known, however, the association between changes to the T cell repertoire and disease presentation has never been analyzed. Characterization of T-cells in TB patients in previous study only analyzed the TCR β chain and omitted analysis of the Vα family even though α chain also contribute to antigen recognition. Furthermore, limited information is available regarding the heterogeneity compartment and overall function of the T cells in TB patients as well as the common TCR structural features of Mtb antigen specific T cells among the vast numbers of TB patients.Methodology/principal findingsCDR3 spectratypes of CD4⁺ and CD8⁺ T cells were analyzed from 86 patients with TB exhibiting differing degrees of disease severity, and CDR3 spectratype complexity scoring system was used to characterize TCR repertoire diversity. TB patients with history of other chronic disease and other bacterial or viral infections were excluded for the study to decrease the likely contribution of TCRs specific to non-TB antigens as far as possible. Each patient was age-matched with a healthy donor group to control for age variability. Results showed that healthy controls had a normally diversified TCR repertoire while TB patients represented with restricted TCR repertoire. Patients with mild disease had the highest diversity of TCR repertoire while severely infected patients had the lowest, which suggest TCR repertoire diversity inversely correlates with disease severity. In addition, TB patients showed preferred usage of certain TCR types and have a bias in the usage of variable (V) and joining (J) gene segments and N nucleotide insertions.Conclusions/significanceResults from this study promote a better knowledge about the public characteristics of T cells among TB patients and provides new insight into the TCR repertoire associated with clinic presentation in TB patients.

Dataset Information

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

Publications

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

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