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
  • 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.