Selective loss of function variants in IL6ST cause Hyper-IgE syndrome with distinct impairments of T-cell phenotype and function

Abstract

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 IL6ST encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as P N404Y ) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in IL6ST (p.P498L; patient herein referred to as P P498L ) 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 + T cells (including T-helper 17-enriched subsets) and non-conventional CD8 + 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 P498L ) 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.

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

“…The terminal differentiation profile of the CD56 dim compartment was investigated by determining the distribution of NKG2A and KIR (Béziat et al, 2010;Björkström et al, 2010). P9 immunophenotyping was performed as previously described (Shahin et al, 2019).…”

“…A condition similar to SWS, with skeletal malformations, respiratory failure, and perinatal death, was recently reported in fetuses and patients homozygous for loss-of-function (LOF) mutations in IL6ST (Monies et al, 2019;Chen et al, 2020). By contrast, patients with AR partial, as opposed to complete, GP130 deficiency present recurrent lung infections, eczema, eosinophilia, high serum IgE levels, impaired acute-phase responses, craniosynostosis, scoliosis, and deciduous tooth retention (Schwerd et al, 2017;Shahin et al, 2019). The proximal cytoplasmic region of GP130 contains two boxes that constitutively bind JAKs (Lütticken et al, 1994).…”

Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome

“…Genetic ablation of either OSM (Sato et al, 2014) or OSM receptor (Tanaka et al, 2003) in mice is associated with thrombocytopenia, and a first-time-in-human study of an anti-OSM monoclonal antibody (GSK2330811) was associated with thrombocytopenia (Reid et al, 2018). Patient C-II-3 survived infancy and developed additional immunologic symptoms of eczematoid dermatitis reminiscent of defective IL-6/GP130/ STAT3 signaling, as observed in previous GP130 homozygous patients with missense variants in IL6ST (Schwerd et al, 2017;Shahin et al, 2019).…”

Spontaneous Gastrointestinal Perforations in STAT3-Deficient Hyper-IgE Syndrome

“…Given that IL-6 signaling is diminished in STAT3 LOF, it appears that impaired IL-6 signaling also plays a key role in increasing perforation risk in this cohort as well. Furthermore, a case of a fatal gastrointestinal perforation in a 3-year-old child suspected to have IL-6 signal transducer (IL6ST) deficiency (due to confirmed diagnosis in the sibling and consistent phenotype) provides additional evidence that impaired IL-6 signaling may lead to gastrointestinal perforations [10].…”