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Immunodeficiency: primary or acquired
Oral
Sarah Spencer, MBChB MSc MRCP
Academic Clinical Fellow in Immunology
Department of Medicine, University of Cambridge
William Egner, PhD
Sheffield Teaching Hospitals NHS Foundation Trust
Sevgi Kostel Bal, MD
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Hana Lango Allen, PhD
Department of Haematology, University of Cambridge
Irfan Raza Syed, PhD
Quaid-i-Azam University
Chi Adrian Ma, PhD
National Institute of Allergy and Infectious Diseases
Meltem Gurel, BSc
Cancer Research UK Cambridge Institute
Yuan Zhang, PhD
National Institute of Allergy and Infectious Diseases
Guanping Sun, PhD
National Institute of Allergy and Infectious Diseases
Ruth A Sabroe, MD
Department of Dermatology, Sheffield Teaching Hospitals NHS Trust
Daniel Greene, PhD
Department of Haematology, University of Cambridge
William Rae, MSc
Department of Medicine, University of Cambridge
Tala Shahin, MRes
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Katarzyna Kania, PhD
Cancer Research UK Cambridge Institute
Rico Chandra Ardy, MRes
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Annika Pecchia-Bekkum, MSc
Department of Medicine, University of Cambridge
William P.M. Worrall, BSc
Department of Medicine, University of Cambridge
Jonathan Stephens, PhD
Department of Haematology, University of Cambridge
Matthew Brown, BSc
Department of Haematology, University of Cambridge
Salih Tuna, PhD
Department of Haematology, University of Cambridge
Melanie York, MSc
Sheffield Teaching Hospitals NHS Foundation Trust
Fiona Shackley, MBChB
Sheffield Teaching Hospitals NHS Foundation Trust
Diarmuid Kerrin, BM
Barnsley Hospitals NHS Foundation Trust
Ravishakar Sargur, MD
Sheffield Teaching Hospitals NHS Foundation Trust
Alison Condliffe, PhD
Sheffield Teaching Hospitals NHS Foundation Trust
Hamid Nawaz Tipu, MBBS
Immunology Department, Armed Forces Institute of Pathology
Ernest Turro, PhD
Department of Haematology, University of Cambridge
Simon Tavare, PhD
Herbert and Florence Irving Institute for Cancer Dynamics
Adrian Thrasher, PhD
Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health
Duncan Jodrell, PhD
Cancer Research UK Cambridge Institute
Kenneth G.C. Smith, PhD
Department of Medicine, University of Cambridge
Kaan Boztug, PhD
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Joshua D. Milner, PhD
National Institute of Allergy and Infectious Diseases
James E.D. Thaventhiran, PhD
Cancer Research UK Cambridge Institute
The pleiotropic cytokine IL-6 plays a central role in the pathogenesis of multiple inflammatory diseases. In clinical practice it is targeted with the monoclonal antibody tocilizumab, which blocks the IL-6 receptor (IL-6R) encoded by IL6R. In classical IL-6 signalling, presentation of IL-6 to gp130 by IL-6R triggers a potent intracellular signal transduction cascade, mediated by the phosphorylation of STAT3. Loss of function mutations in gp130 and STAT3 cause multisystem disorders encompassing IgE elevation, host defence defects and connective tissue abnormalities, however the specific contribution of poor IL-6 signalling itself in those disorders is not yet established. We report here the first patient with a homozygous loss of function mutation in IL6R, who presented with recurrent infections, abolished acute phase response, eczema, atopy, elevated IgE and eosinophilia. For the first time we have used whole-genome sequencing to identify uniparental disomy of chromosome 1 as the mode of inheritance. T-cells isolated from our patient were found to have absent expression of IL-6R, and absent STAT3 phosphorylation despite stimulation with supraphysiological doses of IL-6, which was restored following transfection with wild-type IL6R. Patient T-cells demonstrated abnormal Th17 differentiation, and an increased population of pathological effector Th2 cells was found. This rare patient defines a novel immunodeficiency, helps us to understand the contribution of IL-6 signalling to the phenotypes of patients with mutations in IL6ST, STAT3 and ZNF341, genes encoding components of the IL-6 signalling pathway, and alerts us to the possible toxicities associated with therapies targeting IL-6R.