Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD)

Mrinmoy Sanyal; Marie Morimoto; Alireza Baradaran-Heravi; Kunho Choi; Neeraja Kambham; Kent Jensen; Suparna Dutt; Kira Y. Dionis-Petersen; Lan Xiang Liu; Katie Felix; Christy Mayfield; Benjamin Dekel; Arend Bokenkamp; Helen Fryssira; Encarna Guillen-Navarro; Giuliana Lama; Milena Brugnara; Thomas Lücke; Ann Haskins Olney; Tracy E. Hunley; Ayse Ipek Polat; Uluc Yis; Radovan Bogdanovic; Katarina Mitrovic; Susan Berry; Lydia Najera; Behzad Najafian; Mattia Gentile; C. Nur Semerci; Michel Tsimaratos; David B. Lewis; Cornelius F. Boerkoel

doi:10.1016/j.clim.2015.10.005

Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD)

Mrinmoy Sanyal, Marie Morimoto, Alireza Baradaran-Heravi, Kunho Choi, Neeraja Kambham, Kent Jensen, Suparna Dutt, Kira Y. Dionis-Petersen, Lan Xiang Liu, Katie Felix, Christy Mayfield, Benjamin Dekel, Arend Bokenkamp, Helen Fryssira, Encarna Guillen-Navarro, Giuliana Lama, Milena Brugnara, Thomas Lücke, Ann Haskins Olney, Tracy E. HunleyAyse Ipek Polat, Uluc Yis, Radovan Bogdanovic, Katarina Mitrovic, Susan Berry, Lydia Najera, Behzad Najafian, Mattia Gentile, C. Nur Semerci, Michel Tsimaratos, David B. Lewis, Cornelius F. Boerkoel

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Abstract

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.

Original language	English (US)
Pages (from-to)	355-365
Number of pages	11
Journal	Clinical Immunology
Volume	161
Issue number	2
DOIs	https://doi.org/10.1016/j.clim.2015.10.005
State	Published - Dec 1 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Inc.

Keywords

CD127
CpG
IL7Rα
Promoter DNA methylation
SIOD
T-cell immunodeficiency

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Sanyal, M., Morimoto, M., Baradaran-Heravi, A., Choi, K., Kambham, N., Jensen, K., Dutt, S., Dionis-Petersen, K. Y., Liu, L. X., Felix, K., Mayfield, C., Dekel, B., Bokenkamp, A., Fryssira, H., Guillen-Navarro, E., Lama, G., Brugnara, M., Lücke, T., Olney, A. H., ... Boerkoel, C. F. (2015). Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD). Clinical Immunology, 161(2), 355-365. https://doi.org/10.1016/j.clim.2015.10.005

Sanyal, M, Morimoto, M, Baradaran-Heravi, A, Choi, K, Kambham, N, Jensen, K, Dutt, S, Dionis-Petersen, KY, Liu, LX, Felix, K, Mayfield, C, Dekel, B, Bokenkamp, A, Fryssira, H, Guillen-Navarro, E, Lama, G, Brugnara, M, Lücke, T, Olney, AH, Hunley, TE, Polat, AI, Yis, U, Bogdanovic, R, Mitrovic, K, Berry, S , Najera, L, Najafian, B, Gentile, M, Nur Semerci, C, Tsimaratos, M, Lewis, DB & Boerkoel, CF 2015, 'Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD)', Clinical Immunology, vol. 161, no. 2, pp. 355-365. https://doi.org/10.1016/j.clim.2015.10.005

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title = "Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD)",

abstract = "Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.",

keywords = "CD127, CpG, IL7Rα, Promoter DNA methylation, SIOD, T-cell immunodeficiency",

author = "Mrinmoy Sanyal and Marie Morimoto and Alireza Baradaran-Heravi and Kunho Choi and Neeraja Kambham and Kent Jensen and Suparna Dutt and Dionis-Petersen, {Kira Y.} and Liu, {Lan Xiang} and Katie Felix and Christy Mayfield and Benjamin Dekel and Arend Bokenkamp and Helen Fryssira and Encarna Guillen-Navarro and Giuliana Lama and Milena Brugnara and Thomas L{\"u}cke and Olney, {Ann Haskins} and Hunley, {Tracy E.} and Polat, {Ayse Ipek} and Uluc Yis and Radovan Bogdanovic and Katarina Mitrovic and Susan Berry and Lydia Najera and Behzad Najafian and Mattia Gentile and {Nur Semerci}, C. and Michel Tsimaratos and Lewis, {David B.} and Boerkoel, {Cornelius F.}",

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AU - Sanyal, Mrinmoy

AU - Morimoto, Marie

AU - Baradaran-Heravi, Alireza

AU - Choi, Kunho

AU - Kambham, Neeraja

AU - Jensen, Kent

AU - Dutt, Suparna

AU - Dionis-Petersen, Kira Y.

AU - Liu, Lan Xiang

AU - Felix, Katie

AU - Mayfield, Christy

AU - Dekel, Benjamin

AU - Bokenkamp, Arend

AU - Fryssira, Helen

AU - Guillen-Navarro, Encarna

AU - Lama, Giuliana

AU - Brugnara, Milena

AU - Lücke, Thomas

AU - Olney, Ann Haskins

AU - Hunley, Tracy E.

AU - Polat, Ayse Ipek

AU - Yis, Uluc

AU - Bogdanovic, Radovan

AU - Mitrovic, Katarina

AU - Berry, Susan

AU - Najera, Lydia

AU - Najafian, Behzad

AU - Gentile, Mattia

AU - Nur Semerci, C.

AU - Tsimaratos, Michel

AU - Lewis, David B.

AU - Boerkoel, Cornelius F.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.

AB - Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.

KW - CD127

KW - CpG

KW - IL7Rα

KW - Promoter DNA methylation

KW - SIOD

KW - T-cell immunodeficiency

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AN - SCOPUS:84945308414

SN - 1521-6616

VL - 161

SP - 355

EP - 365

JO - Clinical Immunology

JF - Clinical Immunology

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ER -

Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD)

Abstract

Bibliographical note

Keywords

UN SDGs

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