Autosomal recessive OSMRβ deficiency: Connecting OSM and/or IL-31 with atopy

Hyper-IgE syndrome (HIES) is characterized by recurrent infections, severe eczema, impaired inflammation, and extrahematopoietic manifestations. Most patients carry dominant-negative STAT3 variants, which impair IL-6 family cytokine signaling. In this News & Views, we discuss two studies reporting autosomal recessive (AR) OSMRβ deficiency as a new inborn error of immunity. All 11 patients had severe atopy, hyper-IgE, and eosinophilia; one also had HIES-like infections and extrahematopoietic features. OSMRβ (encoded by OSMR) and gp130 form the OSM receptor II (LIFR and gp130 form OSMR I), while OSMRβ and IL-31RA form the IL-31 receptor. Patients' OSMR variants impair OSM-induced STAT activation; IL-31 signaling was not tested. It was reported that AR OSM deficiency causes bone marrow failure, while an IL-31RA-blocking antibody improves atopic dermatitis. The respective contributions of altered OSM and IL-31 signaling to atopy in AR OSMRβ deficiency remain unresolved. These findings expand the genetic dissection of the STAT3-HIES spectrum. AR OSMRβ deficiency should be considered in patients with one or more HIES-like features.