Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome

Abstract

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic manifestations and susceptibility to infections with extracellular pathogens, typically Staphylococcus aureus, which preferentially affect the skin and lung. Previous studies reported the defective differentiation of T helper 17 (Th17) cells in HIES patients caused by hypomorphic STAT3 mutations. However, the apparent contradiction between the systemic Th17 deficiency and the skin/lung-restricted susceptibility to staphylococcal infections remains puzzling. We present a possible molecular explanation for this enigmatic contradiction. HIES T cells showed impaired production of Th17 cytokines but normal production of classical proinflammatory cytokines including interleukin 1β. Normal human keratinocytes and bronchial epithelial cells were deeply dependent on the synergistic action of Th17 cytokines and classical proinflammatory cytokines for their production of antistaphylococcal factors, including neutrophil-recruiting chemokines and antimicrobial peptides. In contrast, other cell types were efficiently stimulated with the classical proinflammatory cytokines alone to produce such factors. Accordingly, keratinocytes and bronchial epithelial cells, unlike other cell types, failed to produce antistaphylococcal factors in response to HIES T cell–derived cytokines. These results appear to explain, at least in part, why HIES patients suffer from recurrent staphylococcal infections confined to the skin and lung in contrast to more systemic infections in neutrophil-deficient patients.

Eight-color immunophenotyping of T-, B-, and NK-cell subpopulations for characterization of chronic immunodeficiencies

“…TH17-like cells, also detected in panel (iv), require TGF-b in combination with IL-2 and IL-21 or IL-23 for differentiation. While those cells were characterized as proinflammatory effectors, which produce large amounts of not only IL-17 but also IL-21 and IL-22, abnormalities and adysregulation in TH17 cell differentiation has been described in inflammatory skin diseases, rheumatoid arthritis, and multiple sclerosis, as well as in PID such as in autosomaldominant Hyper-IgE-syndrome (STAT3 mutations) or in chronic mucocutaneous candidiasis due to defects in STAT1 (46)(47)(48)(49)(50)(51).…”

Mendelian Genetics of Human Susceptibility to Fungal Infection

“…As a result of impaired IL-17/IL-22 secretion, AD-HIES T cells fail to prime keratinocytes to produce IL-17-dependent b-defensins and neutrophil-recruiting chemoattractants ( Fig. 2) (Minegishi et al 2009). Moreover, AD-HIES patient saliva has diminished candidacidal activity associated with decreased levels of b-defensin-2 and histatin (Conti et al 2011), implying that STAT3 is critical for the orchestration of mucosal immune responses for Candidaclearance.…”

Mechanisms of NDV-3 vaccine efficacy in MRSA skin versus invasive infection

“…For example, patients with Chronic Granulomatous Disease (CGD; deficient Th1 and oxidative burst response) have increased risk of disseminated S. aureus infection. In contrast, patients with Job's Syndrome (deficient Th17 response) typically have increased risk to SSSI and lung infections, but less so for systemic S. aureus bacteremia (35,36). This pattern contrasts that observed in neutropenic or CGD patients (37).…”