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

Abstract

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. Given that 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 DCs from HIES subjects. Analysis of gene expression in PBMCs and neutrophils isolated from HIES patients and stimulated with LPS in the presence of IL-10 showed reduced expression of IL1RN, which encodes IL-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-a, IL-6 and, to a lesser extent, IL-12 when these 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 AD-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.

A STATus report on DC development

“…In addition, E2-2 demonstrates instructive function because its overexpression in CD34 ϩ thymic progenitors promotes pDC generation in the presence of Flt3L and IL-7 [232]. Individuals with STAT3 mutations that abrogate transcriptional activity (e.g., mutations in the DNA binding, SH2, or transactivation domains) have an impaired ability to produce tolerogenic DCs in response to IL-10, consistent with the role for STAT3 in IL-10 signal transduction [233][234][235]. In contrast, congenital Id2 mutations have not been associated with DC deficiency to date, although overexpression of Id2 or the related factor Id3 in CD34 ϩ progenitors inhibits pDC development in agreement with the negative role for Id2 in murine pDCs [231,236].…”

Hyper IgE syndrome: anaphylaxis in a patient carrying the N567D STAT3 mutation

“…Despite a normal frequency of total CD4+ cells, we documented an increase in na€ ıve CD4+ T cells (71%) compared with normal donors (median 42%, range 35%-53%), as previously described in STAT3mut individuals (4); moreover, stimulation with IL-12 resulted in a reduction of IL-21 expression in na€ ıve CD4+ T cells (3.5%), compared with that observed in normal donors (median 32%, range (25%-39%)) (4). The addition of IL-10 to LPS-treated DC, contrary to what occurs in normal controls, did not affect their maturation, as indicated by the expression of maturation antigens CD1, CD80, and CD86 (5).…”

“…To confirm the pathologic relevance of this newly identified mutation, immunologic tests were performed, as previously described (3)(4)(5). Accordingly with diagnostic guidelines proposed for hyper-IgE syndrome (3), the induction of Th17 cells after stimulation with the superantigen SEB was strongly impaired in the patient (0.05%) compared with age-matched healthy controls (0.52-0.76%).…”

Phosphotyrosine recognition domains: the typical, the atypical and the versatile

“…Moreover, Hong et al demonstrated that the BTK SH2 domain binds to phospholipids and the XLA-causing mutations alter lipid binding selectivity [174]. In another example, multiple point mutations within the transcription factor STAT3 SH2 domain have been identified and linked to large granular lymphocytic leukemia and the hyper-IgE syndrome [175,176]. In conjunction with the identification and study of SH2 domain-related diseases, small molecule inhibitors of SH2 domains, SH2 domain-containing proteins or SH2 binding partners, are being developed with some success as therapeutic reagents, although the development of phosphomimetics faces hurdles due to the strong charge of the phosphate group [177,178].…”