Correction: ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans

Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses

“…While an expansion of such proatopic T cells is consistent with the clinical phenotype, this result appears initially surprising because of data implicating IL-6 in generating Th2 cells (Rincón et al, 1997) and promoting IgE class switching (Vercelli et al, 1989; Jabara et al, 1990). However, STAT3 activation leads to the expression of and physical binding to ERBIN, encoded by the gene ERBB2IP , which limits TGF-β signaling by cytoplasmic sequestering of the SMAD2/3 components and normally prevents expression of IL-4Rα on naive CD4 + T cells and B cells, restraining Th2 responses (Lyons et al, 2017). Corroborating this was the observation that P1’s IL4R expression was elevated in these cell types in the single-cell RNA-seq analysis (Fig.…”

PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients

“…Although vascular anomalies have not been described in patients with inherited mutations in IL17F, IL17RA, or IL17RC, the numbers of these patients reported is low and this could account for the lack of observed vascular issues (Puel et al, 2011;Ling et al, 2015). Alternatively, deregulated TGF-β signaling, which has been reported in STAT3 LOF, could underlie these vascular defects (Lyons et al, 2017).…”

Inborn errors of IL-6 family cytokine responses

“…Key for understanding might be the intersection with non-canonical STAT3 signalling pathways. Patients with ERBIN deficiency and Loeys–Dietz-syndrome due to TGF-β receptor defects show elevated IgE (ERBIN-deficient patients show only slightly elevated serum IgE), eosinophilic inflammation, joint hypermobility and vascular abnormalities [ 42 , 43 ]. Patients with mutations in ERBB2IP demonstrated reduced expression of ERBIN, impaired formation of the STAT3–ERBIN–SMAD2/3 complex and failure to constrain TGF-β signaling.…”

“…Patients with mutations in ERBB2IP demonstrated reduced expression of ERBIN, impaired formation of the STAT3–ERBIN–SMAD2/3 complex and failure to constrain TGF-β signaling. This deregulated TGF-β signaling is associated with increased functional IL-4Rα expression on naive lymphocytes, and increased activation of the IL-4-GATA3 axis in vitro [ 42 ]. This is corroborated by the detection of increased IL4R expression in naïve lymphocytes in IL6R deficiency [ 5 •• ].…”