Hyper-IgE syndrome, 2021 update.

Clinically and pathologically, the patients with hyper-IgE syndrome present similar skin manifestations to common atopic dermatitis. The original hyper-IgE syndrome is characterized by diminished inflammatory response, in combination with Staphylococcus aureus skin abscess and pneumonia followed by pneumatocele formation. These immunological manifestations are frequently associated with skeletal and connective tissue abnormalities. We previously identified that major causal variants of the hyper-IgE syndrome are dominant negative variants in the STAT3. In addition to the identification of new causative variants for the disorders similar to the original hyper-IgE syndrome, causative variants for new types of hyper-IgE syndrome centered only on atopy, high serum IgE levels, and susceptibility to infection, but not associated with diminished inflammatory response, pneumatocele formation, and connective tissue manifestations, have been identified. Recent discovery identified a novel zinc finger protein that regulates STAT3 transcription. Investigation of IL6ST variants disclosed that IL6ST/IL6R cytokine receptor plays a crucial role for the signal transduction upstream of STAT3 in the pathogenesis of the original hyper-IgE syndrome. Even if the same IL6ST variants are used for the signal transduction of IL-6 family cytokines, the signaling defect is more severe in IL-6/IL-11 and milder in LIF. The fact that the non-immune manifestations of the gain-of-function mutations of TGFBR1 and TGFBR2 are similar to the those of dominant negative mutations of STAT3 provide a clue to elucidate molecular mechanisms of non-immune manifestations of hyper-IgE syndrome. Research on this hereditary atopic syndrome is being actively conducted to elucidate the molecular mechanisms and to develop new therapeutic approaches.