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Immunodeficiencies
Selective loss of function variants in IL6ST cause Hyper-IgE syndrome with distinct impairments of T-cell phenotype and function
Ferrata Storti Foundation
Haematologica 2019 Volume 104(3):609-621
Tala Shahin,1,2* Dominik Aschenbrenner,3* Deniz Cagdas,4,5*
Sevgi Köstel Bal,1,2,6 Cecilia Domínguez Conde,1,2 Wojciech Garncarz,1,2
David Medgyesi,1,2 Tobias Schwerd,3,7 Betül Karaatmaca,4
Pınar Gur Cetinkaya,4 Saliha Esenboga,4 Stephen R. F. Twigg,8 Andrew Cant,9 Andrew O. M. Wilkie,8 Ilhan Tezcan,4,5 Holm H. Uhlig3,10 and Kaan Boztug1,2,11,12
1Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria;
2CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,
Vienna, Austria; Translational Gastroenterology Unit, John Radcliffe Hospital, University 43
of Oxford, UK; Section of Pediatric Immunology, Ihsan Doğramacı Children’s Hospital, Hacettepe University, Ankara, Turkey; 5Institute of Child Health, Hacettepe University, Ankara, Turkey; 6Department of Pediatric Allergy and Immunology, Ankara University School of Medicine, Cebeci, Turkey; 7Dr. von Hauner Children's Hospital, Ludwig- Maximilians-University of Munich, Germany; 8Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, UK; 9Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; 10Department of Paediatrics, University of Oxford, UK; 11Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria and 12St. Anna Kinderspital and Children’s Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Austria
*TSh, DA and DC contributed equally to this work. #HHU and KB are co-senior authors.
ABSTRACT
Hyper-IgE syndromes comprise a group of inborn errors of immu- nity. STAT3-deficient hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections and eczema, and characteristic skeletal anomalies. A loss-of-function biallelic mutation in IL6ST encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as PN404Y) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in IL6ST (p.P498L; patient herein referred to as PP498L) leading to abrogated GP130 signaling after stimulation with IL-6 and IL-27 in peripheral blood mononuclear cells as well as IL-6 and IL-11 in fibroblasts. Extending the initial identification of selective GP130 deficiency, we aimed to dissect the effects of aberrant cytokine signaling on T-helper cell differentiation in both patients. Our results reveal the importance of IL-6 signaling for the development of CCR6-expressing memory CD4+ T cells (including T-helper 17-enriched subsets) and non-conventional CD8+ T cells which were reduced in both patients. Downstream functional analysis of the GP130 mutants (p.N404Y and p.P498L) have shown differences in response to IL-27, with the p.P498L mutation having a more severe effect that is reflected by reduced T-helper 1 cells in this patient (PP498L) only. Collectively, our data suggest that characteristic features of GP130-defi- cient hyper-IgE syndrome phenotype are IL-6 and IL-11 dominated, and indicate selective roles of aberrant IL-6 and IL-27 signaling on the differ- entiation of T-cell subsets.
Introduction
Hyper-IgE syndromes (HIES) comprise a group of primary immunodeficiencies (PIDs) associated with recurrent pulmonary infections, eczema and skin abscesses. As a subtype of HIES, autosomal-dominant STAT3 deficiency also involves skeletal abnormalities including scoliosis, craniosynostosis and retained dentition.1-4 We
Correspondence:
KAAN BOTZUG
kaan.boztug@rud.lbg.ac.at
HOLM H. UHLIG
holm.uhlig@ndm.ox.ac.uk
Received: March 26, 2018. Accepted: October 3, 2018. Pre-published: October 11, 2018.
doi:10.3324/haematol.2018.194233
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/609
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