Journal article

Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome

Yin-Huai Chen, Diane B Zastrow, Riley D Metcalfe, Lisa Gartner, Freia Krause, Craig J Morton, Shruti Marwaha, Laure Fresard, Yong Huang, Chunli Zhao, Colleen McCormack, David Bick, Elizabeth A Worthey, Christine M Eng, Jessica Gold, Stephen B Montgomery, Paul G Fisher, Euan A Ashley, Matthew T Wheeler, Michael W Parker Show all

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | MOSBY-ELSEVIER | Published : 2021

Abstract

BACKGROUND: Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling. OBJECTIVE: Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants. METHODS: We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OS..

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Grants

Awarded by Biomedical Research Centre for the Oxford GI Biobank


Awarded by National Institutes of Health Common Fund through the Office of Strategic Coordination/Office of the National Institutes of Health Director


Awarded by Stanford Clinical and Translational Science Award


Awarded by Australian National Health and Medical Research Council Independent Research Institutes


Awarded by National Health and Medical Research Council


Awarded by Australian Research Council


Awarded by Victorian Cancer Agency Fellowship


Awarded by Deutsche Forschungsgemeinschaft


Funding Acknowledgements

Supported by the Biomedical Research Centre for the Oxford GI Biobank (grants 11/YH/0020 and 16/YH/0247) and by the National Institute for Health Research, Oxford Biomedical Research Centre, University of Oxford. H.H.U. is supported by the Health Research Oxford Biomedical Research Centre and the Leona M. and Harry B. Helmsley Charitable Trust. Part of the work is funded by Celgene/BMS via a Celgene Oxford fellowship program that supports H.H.U., A.L., and Y.-H.C. Research reported in this article was supported in part by the National Institutes of Health Common Fund through the Office of Strategic Coordination/Office of the National Institutes of Health Director (under awards U01 HG007708, U01 HG007530, U01 HG007942, U01 HG007943, and U01 HG010218). This work was also supported by the Stanford Clinical and Translational Science Award to Spectrum (UL1 TR001085). We gratefully acknowledge infrastructure support from the Australian National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme (grant 9000587) and the Victorian State Government Operational Infrastructure Support Program, with additional support from the National Health and Medical Research Council (project grants APP1147621 and APP1080498). This research was undertaken using the Linkage Infrastructure, Equipment and Facilities High-Performance Computing General-Purpose Computing on Graphics Processing Units Facility, which is hosted at the University of Melbourne and was established with the assistance of an Australian Research Council Linkage Infrastructure, Equipment and Facilities grant (LE170100200). M.D.W.G. is the recipient of an Australian Research Council Future Fellowship (FT140100544), M.W.P. is a National Health and Medical Research Council Senior Principal Fellow (APP1117183), and T.L.P. is supported by a Victorian Cancer Agency Fellowship (MCRF16009). D.S.-A. was supported by the Deutsche Forschungsgemeinschaft (project grant SFB841 C1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.