SH2 domain mutations of STAT3 gene result in impairment of IL-10 function in hyper-IgE syndrome patients

Autosomal-dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency caused by STAT3 mutations. This inherited condition is characterized by eczema, staphylococcal cold abscesses, and recurrent pulmonary infections. Because STAT3 is involved in IL-10 signaling, we examined the immunoregulatory role of IL-10 in inflammation by studying the effects of IL-10 on monocytes, neutrophils, and monocyte-derived dendritic cells (DC) from HIES subjects. Analysis of gene expression in PBMCs and neutrophils stimulated with LPS in the presence of IL-10 in HIES patients showed reduced expression of IL1RN, which encodes interleukin-1 receptor antagonist (IL-1ra), and SOCS3 mRNA but increased CXCL8 mRNA expression. Moreover, secretion of the anti-inflammatory protein IL-1ra was reduced in AD-HIES patients. DCs from HIES patients secreted higher levels of TNF-á, IL-6, and, to a lesser extent, IL-12 when cells were cultured in the presence of IL-10. These results suggest that IL-10 activity is affected in myeloid cells (e.g., monocytes, DCs) of HIES patients. Impairment of IL-10 signaling in patients with autosomal-dominant HIES might result in an altered balance between pro-inflammatory and anti-inflammatory signals and might lead to persistent inflammation and delayed healing after infections.