Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses PMID: 31235509

Target-related Cytokines

2026-09-23

Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses

J Exp Med. 2019 Sep 2;216(9):1986-1998. doi: 10.1084/jem.20190344.

Sarah Spencer ^# ¹ ² , Sevgi Köstel Bal ^# ³ ⁴ , William Egner ^# ⁵ ⁶ , Hana Lango Allen ^# ⁷ ⁸ , Syed I Raza ^# ⁹ , Chi A Ma ^# ¹⁰ , Meltem Gürel ^# ¹¹ , Yuan Zhang ^# ¹⁰ , Guangping Sun ^# ¹⁰ , Ruth A Sabroe ¹² , Daniel Greene ⁷ ⁸ ¹³ , William Rae ² , Tala Shahin ³ ⁴ , Katarzyna Kania ¹¹ , Rico Chandra Ardy ³ ⁴ , Marini Thian ³ ⁴ ¹⁴ ¹⁵ , Emily Staples ² , Annika Pecchia-Bekkum ² , William P M Worrall ² , Jonathan Stephens ⁷ ⁸ ¹⁶ , Matthew Brown ⁷ ⁸ ¹⁶ , Salih Tuna ⁷ ⁸ ¹⁶ , Melanie York ⁵ ⁶ , Fiona Shackley ⁵ ⁶ , Diarmuid Kerrin ¹⁷ , Ravishankar Sargur ⁵ ⁶ , Alison Condliffe ⁵ ⁶ , Hamid Nawaz Tipu ¹⁸ , Hye Sun Kuehn ¹⁹ , Sergio D Rosenzweig ¹⁹ , Ernest Turro ⁷ ⁸ ¹³ ¹⁶ , Simon Tavaré ¹¹ ²⁰ ²¹ , Adrian J Thrasher ²² , Duncan Ian Jodrell ²³ , Kenneth G C Smith ² , Kaan Boztug ^# ²⁴ ⁴ ¹⁴ ¹⁵ ²⁵ , Joshua D Milner ^# ²⁶ , James E D Thaventhiran ^# ²⁷ ² ¹¹

Affiliations

1. Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK.
2. Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
3. Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
4. CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria.
5. Sheffield Teaching Hospitals National Health Service Trust, Sheffield, UK.
6. Department of Infection Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
7. Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
8. National Institute for Health Research BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, UK.
9. Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
10. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
11. Cancer Research UK Cambridge Institute, Cambridge Biomedical Campus, Cambridge, UK.
12. Department of Dermatology, Sheffield Teaching Hospitals National Health Service Trust, Sheffield, UK.
13. Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge, UK.
14. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
15. St. Anna Kinderspital and Children's Cancer Research Institute, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
16. National Health Service Blood and Transplant Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
17. Barnsley Hospitals National Health Service Foundation Trust, Barnsley, UK.
18. Immunology Department, Armed Forces Institute of Pathology, Rawalpindi, Pakistan.
19. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
20. Herbert and Florence Irving Institute for Cancer Dynamics, Columbia University, New York, NY.
21. New York Genome Center, New York, NY.
22. Molecular and Cellular Immunology Section, University College London Great Ormond Street Institute of Child Health, Great Ormond Street Hospital National Health Service Trust, London, UK.
23. Department of Oncology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
24. Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria [email protected].
25. Vienna Center for Rare and Undiagnosed Diseases, Vienna, Austria.
26. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD [email protected].
27. Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK [email protected].
# Contributed equally.

Abstract

IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.