Sevgi Kostel Bal, Austria
Ludwig Boltzmann Institute Rare and Undiagnosed DiseasesPresenter of 1 Presentation
IDENTIFICATION OF AN INBORN ERROR OF IMMUNITY WITH ATOPY AND ABNORMAL INFLAMMATORY RESPONSES
Abstract
Background and Aims
IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and it is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R. While the consequences of excessive IL-6 signaling in humans have been well established, the effects of impairment of IL-6R have not yet been described. Here we studied two unrelated patients with homozygous mutations in IL6R, presenting with recurrent infections, abnormal acute phase responses, elevated IgE, eczema and eosinophilia.
Methods
Peripheral blood mononuclear cells were assessed for their responsiveness to IL-6, IL-21, IL-27 through downstream STAT3 phosphorylation by flow cytometry. PBMCs from both patients were also used to assess the composition of differentiated T-helper cell subsets as well as cytokine release upon stimulation by flow cytometry. Single cell RNA sequencing was performed to for granular assessment of the immune cell phenotype
Results
Our results reveal the role of IL6 signaling on the differentiation of T helper subsets, indicated by diminished but present Th17 and Th1 populations. Similar to STAT3 deficient patients, B cell development was also impaired reflected by reduced percentage of memory B cells. In addition, pathological effector Th2 cells associated with chronic eosinophilic inflammation were elevated in both patients, in concordance with severe atopy and elevated IgE.
Conclusions
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 targeting the IL-6R.