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 journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbereaah6109
JournalScience Immunology
Volume1
Issue number6
DOIs
StatePublished - Jan 1 2016

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Severe Combined Immunodeficiency
B-Lymphocytes
T-Lymphocytes
Granuloma
Autoimmunity
RAG-1 Genes
Genes
Phenotype
T-Cell Receptor Genes
Immunoglobulin Heavy Chains
Immunoglobulin Genes
Mutation
T-Cell Antigen Receptor
Genetic Recombination

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Lee, Y. N., Frugoni, F., Dobbs, K., Tirosh, I., Du, L., Ververs, F. A., ... Notarangelo, L. D. (2016). Characterization of T and B cell repertoire diversity in patients with RAG deficiency. Science Immunology, 1(6), [eaah6109]. https://doi.org/10.1126/sciimmunol.aah6109
Lee, Yu Nee ; Frugoni, Francesco ; Dobbs, Kerry ; Tirosh, Irit ; Du, Likun ; Ververs, Francesca A. ; Ru, Heng ; De Bruin, Lisa Ott ; 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. / Characterization of T and B cell repertoire diversity in patients with RAG deficiency. In: Science Immunology. 2016 ; Vol. 1, No. 6.
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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.",
author = "Lee, {Yu Nee} and Francesco Frugoni and Kerry Dobbs and Irit Tirosh and Likun Du and Ververs, {Francesca A.} and Heng Ru and {De Bruin}, {Lisa Ott} and Mehdi Adeli and Bleesing, {Jacob H.} and David Buchbinder and Butte, {Manish J.} and Caterina Cancrini and Karin Chen and Sharon Choo and Elfeky, {Reem A.} and Andrea Finocchi and Fuleihan, {Ramsay L.} and Gennery, {Andrew R.} and El-Ghoneimy, {Dalia H.} and Henderson, {Lauren A.} and Waleed Al-Herz and Elham Hossny and Nelson, {Robert P.} and Pai, {Sung Yun} and Patel, {Niraj C.} and Reda, {Shereen M.} and Pere Soler-Palacin and Raz Somech and Paolo Palma and Hao Wu and Silvia Giliani and Walter, {Jolan E.} and Notarangelo, {Luigi D.}",
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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, SY, Patel, NC, Reda, SM, Soler-Palacin, P, Somech, R, Palma, P, Wu, H, Giliani, S, Walter, JE & Notarangelo, LD 2016, 'Characterization of T and B cell repertoire diversity in patients with RAG deficiency', Science Immunology, vol. 1, no. 6, eaah6109. https://doi.org/10.1126/sciimmunol.aah6109

Characterization of T and B cell repertoire diversity in patients with RAG deficiency. / Lee, Yu Nee; Frugoni, Francesco; Dobbs, Kerry; Tirosh, Irit; Du, Likun; Ververs, Francesca A.; Ru, Heng; De Bruin, Lisa Ott; 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.

In: Science Immunology, Vol. 1, No. 6, eaah6109, 01.01.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Characterization of T and B cell repertoire diversity in patients with RAG deficiency

AU - Lee, Yu Nee

AU - Frugoni, Francesco

AU - Dobbs, Kerry

AU - Tirosh, Irit

AU - Du, Likun

AU - Ververs, Francesca A.

AU - Ru, Heng

AU - De Bruin, Lisa Ott

AU - Adeli, Mehdi

AU - Bleesing, Jacob H.

AU - Buchbinder, David

AU - Butte, Manish J.

AU - Cancrini, Caterina

AU - Chen, Karin

AU - Choo, Sharon

AU - Elfeky, Reem A.

AU - Finocchi, Andrea

AU - Fuleihan, Ramsay L.

AU - Gennery, Andrew R.

AU - El-Ghoneimy, Dalia H.

AU - Henderson, Lauren A.

AU - Al-Herz, Waleed

AU - Hossny, Elham

AU - Nelson, Robert P.

AU - Pai, Sung Yun

AU - Patel, Niraj C.

AU - Reda, Shereen M.

AU - Soler-Palacin, Pere

AU - Somech, Raz

AU - Palma, Paolo

AU - Wu, Hao

AU - Giliani, Silvia

AU - Walter, Jolan E.

AU - Notarangelo, Luigi D.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

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