@article{Tala Shahin_Dominik Aschenbrenner_Deniz Cagdas_Sevgi Köstel Bal_Cecilia Domínguez Conde_Wojciech Garncarz_David Medgyesi_Tobias Schwerd_Betül Karaatmaca_Pınar Gur Cetinkaya_Saliha Esenboga_Stephen R. F. Twigg_Andrew Cant_Andrew O. M. Wilkie_Ilhan Tezcan_Holm H. Uhlig_Kaan Boztug_2019, place={Pavia, Italy}, title={Selective loss of function variants in IL6ST cause Hyper-IgE syndrome with distinct impairments of T-cell phenotype and function}, volume={104}, url={https://haematologica.org/article/view/8818}, DOI={10.3324/haematol.2018.194233}, abstractNote={Hyper-IgE syndromes comprise a group of inborn errors of immunity. STAT3-deficient hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections and eczema, and characteristic skeletal anomalies. A loss-of-function biallelic mutation in <em>IL6ST</em> encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as P<sup>N404Y</sup>) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in <em>IL6ST</em> (p.P498L; patient herein referred to as P<sup>P498L</sup>) leading to abrogated GP130 signaling after stimulation with IL-6 and IL-27 in peripheral blood mononuclear cells as well as IL-6 and IL-11 in fibroblasts. Extending the initial identification of selective GP130 deficiency, we aimed to dissect the effects of aberrant cytokine signaling on T-helper cell differentiation in both patients. Our results reveal the importance of IL-6 signaling for the development of CCR6-expressing memory CD4<sup>+</sup> T cells (including T-helper 17-enriched subsets) and non-conventional CD8<sup>+</sup>T cells which were reduced in both patients. Downstream functional analysis of the GP130 mutants (p.N404Y and p.P498L) have shown differences in response to IL-27, with the p.P498L mutation having a more severe effect that is reflected by reduced T-helper 1 cells in this patient (P<sup>P498L</sup&gt;) only. Collectively, our data suggest that characteristic features of GP130-deficient hyper-IgE syndrome phenotype are IL-6 and IL-11 dominated, and indicate selective roles of aberrant IL-6 and IL-27 signaling on the differentiation of T-cell subsets.}, number={3}, journal={Haematologica}, author={Tala Shahin and Dominik Aschenbrenner and Deniz Cagdas and Sevgi Köstel Bal and Cecilia Domínguez Conde and Wojciech Garncarz and David Medgyesi and Tobias Schwerd and Betül Karaatmaca and Pınar Gur Cetinkaya and Saliha Esenboga and Stephen R. F. Twigg and Andrew Cant and Andrew O. M. Wilkie and Ilhan Tezcan and Holm H. Uhlig and Kaan Boztug}, year={2019}, month={Feb.}, pages={609-621} }