2. Academic Validation
  3. Selective loss of function variants in IL6ST cause Hyper-IgE syndrome with distinct impairments of T-cell phenotype and function

Selective loss of function variants in IL6ST cause Hyper-IgE syndrome with distinct impairments of T-cell phenotype and function

  • Haematologica. 2019 Mar;104(3):609-621. doi: 10.3324/haematol.2018.194233.
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 Uhlig 10 11,  Kaan Boztug 12 2 13 14
Affiliations

Affiliations

  • 1 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
  • 2 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 3 Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, UK.
  • 4 Section of Pediatric Immunology, Ihsan Doğramacı Children's Hospital, Hacettepe University, Ankara, Turkey.
  • 5 Institute of Child Health, Hacettepe University, Ankara, Turkey.
  • 6 Department of Pediatric Allergy and Immunology, Ankara University School of Medicine, Cebeci, Turkey.
  • 7 Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Germany.
  • 8 Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, UK.
  • 9 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  • 10 Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, UK [email protected] [email protected].
  • 11 Department of Paediatrics, University of Oxford, UK.
  • 12 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria [email protected] [email protected].
  • 13 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria.
  • 14 St. Anna Kinderspital and Children's Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Austria.
PMID: 30309848 DOI: 10.3324/haematol.2018.194233
Abstract

Hyper-IgE syndromes comprise a group of inborn errors of immunity. 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-deficient 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 differentiation of T-cell subsets.

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