Immunodeficiency: primary or acquired
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.