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)

Clin Immunol. 2015 Dec;161(2):355-65. doi: 10.1016/j.clim.2015.10.005. Epub 2015 Oct 21.

Authors

Mrinmoy Sanyal¹, Marie Morimoto², Alireza Baradaran-Heravi³, Kunho Choi², Neeraja Kambham⁴, Kent Jensen⁵, Suparna Dutt⁵, Kira Y Dionis-Petersen⁶, Lan Xiang Liu⁶, Katie Felix⁷, Christy Mayfield⁸, Benjamin Dekel⁹, Arend Bokenkamp¹⁰, Helen Fryssira¹¹, Encarna Guillen-Navarro¹², Giuliana Lama¹³, Milena Brugnara¹⁴, Thomas Lücke¹⁵, Ann Haskins Olney¹⁶, Tracy E Hunley¹⁷, Ayse Ipek Polat¹⁸, Uluc Yis¹⁸, Radovan Bogdanovic¹⁹, Katarina Mitrovic¹⁹, Susan Berry²⁰, Lydia Najera²⁰, Behzad Najafian²¹, Mattia Gentile²², C Nur Semerci²³, Michel Tsimaratos²⁴, David B Lewis⁶, Cornelius F Boerkoel²⁵

Affiliations

¹ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: msanyal@stanford.edu.
² Department of Medical Genetics and Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
³ Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
⁴ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Medicine, Division of Rheumatology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Department of Cardiothoracic Surgery, Division of Pediatric Cardiothoracic Surgery, Lucile Packard Children's Hospital at Stanford, Stanford, CA, USA.
⁸ Warren Clinic, Tulsa, OK, USA.
⁹ Pediatric Stem Cell Research Institute, Safra Children's Hospital, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel.
¹⁰ Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
¹¹ Department of Medical Genetics, "Aghia Sophia" Children's Hospital, Athens University Medical School, Athens, Greece.
¹² Sección de Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain; UCAM-Universidad Católica de Murcia, Spain; CIBERER-ISCIII, Madrid, Spain.
¹³ Department of Pediatrics, University of Naples, Naples, Italy.
¹⁴ Department of Pediatrics, University of Verona, Verona, Italy.
¹⁵ Department of Neuropediatrics, Children's Hospital, Ruhr-University Bochum, Bochum, Germany.
¹⁶ Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁷ Division of Pediatric Nephrology, Vanderbilt Children's Hospital, Nashville, TN, USA.
¹⁸ Department of Pediatrics, Dokuz Eylul University, Izmir, Turkey.
¹⁹ Institute of Mother and Child Health Care of Serbia and Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
²⁰ Department of Pediatrics, University of Minnesota Health System, Minneapolis, MN, USA.
²¹ Department of Pathology, University of Washington, Seattle, WA, USA.
²² Department of Medical Genetics, Hospital Di Venere - ASL Bari, Bari, Italy.
²³ Department of Medical Genetics, School of Medicine, Pamukkale University, Denizli, Turkey.
²⁴ Pediatric Multidisciplinary Unit, AP-HM Timone Enfant, Aix-Marseille University, Marseille, France.
²⁵ Department of Medical Genetics and Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada. Electronic address: boerkoel@interchange.ubc.ca.

PMID: 26499378
DOI: 10.1016/j.clim.2015.10.005

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Arteriosclerosis / genetics*
Arteriosclerosis / metabolism
Arteriosclerosis / pathology
Cells, Cultured
Child
Child, Preschool
DNA Helicases / genetics
DNA Methylation
Flow Cytometry
Gene Expression
Humans
Immunohistochemistry
Immunologic Deficiency Syndromes / genetics*
Immunologic Deficiency Syndromes / metabolism
Immunologic Deficiency Syndromes / pathology
Interleukin-17 / pharmacology
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / metabolism
Mutation
Nephrotic Syndrome / genetics*
Nephrotic Syndrome / metabolism
Nephrotic Syndrome / pathology
Osteochondrodysplasias / genetics*
Osteochondrodysplasias / metabolism
Osteochondrodysplasias / pathology
Primary Immunodeficiency Diseases
Promoter Regions, Genetic / genetics
Pulmonary Embolism / genetics*
Pulmonary Embolism / metabolism
Pulmonary Embolism / pathology
Receptors, Interleukin-7 / genetics*
Receptors, Interleukin-7 / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, DNA
T-Lymphocytes / metabolism*
Young Adult

Substances

Interleukin-17
Receptors, Interleukin-7
interleukin-7 receptor, alpha chain
SMARCAL1 protein, human
DNA Helicases

Supplementary concepts

Schimke immunoosseous dysplasia