TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome
Ian A. Myles, … , Steven M. Holland, Sandip K. Datta
Ian A. Myles, … , Steven M. Holland, Sandip K. Datta
Published July 23, 2018
Citation Information: J Clin Invest. 2018;128(8):3595-3604. https://doi.org/10.1172/JCI121486.
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Research Article Immunology Infectious disease

TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome

Abstract

Autosomal dominant hyper IgE syndrome (AD-HIES), or Job’s syndrome, is a primary immune deficiency caused by dominant-negative mutations in STAT3. Recurrent Staphylococcus aureus skin abscesses are a defining feature of this syndrome. A widely held hypothesis that defects in peripheral Th17 differentiation confer this susceptibility has never been directly evaluated. To assess the cutaneous immune response in AD-HIES, we induced suction blisters in healthy volunteers (HVs) and patients with AD-HIES and then challenged the wound with lethally irradiated bacteria. We show that cutaneous production of IL-17A and IL-17F was normal in patients with AD-HIES. Overproduction of TNF-α differentiated the responses in AD-HIES from HVs. This was associated with reduced IL-10 family signaling in blister-infiltrating cells and defective epithelial cell function. Mouse models of AD-HIES recapitulated these aberrant epithelial responses to S. aureus and involved defective epithelial-to-mesenchymal transition (EMT) rather than a failure of bacterial killing. Defective responses in mouse models of AD-HIES and primary keratinocyte cultures from patients with AD-HIES could be reversed by TNF-α blockade and by drugs with reported modulatory effects on EMT. Our results identify these as potential therapeutic approaches in patients with AD-HIES suffering S. aureus infections.

Authors

Ian A. Myles, Erik D. Anderson, Noah J. Earland, Kol A. Zarember, Inka Sastalla, Kelli W. Williams, Portia Gough, Ian N. Moore, Sundar Ganesan, Cedar J. Fowler, Arian Laurence, Mary Garofalo, Douglas B. Kuhns, Mark D. Kieh, Arhum Saleem, Pamela A. Welch, Dirk A. Darnell, John I. Gallin, Alexandra F. Freeman, Steven M. Holland, Sandip K. Datta

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Figure 1

Human STAT3 dysfunction is associated with overproduction of TNF-α.

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Human STAT3 dysfunction is associated with overproduction of TNF-α. (A–D...
(A–D) Twelve HVs and eight patients with AD-HIES underwent blister induction and challenge of the wounded area with lethally irradiated bacteria or diluent control. IL-17A, IL-17F (A and B), TNF-α (C), and IL-10 (D) concentrations in blister fluid after 20 hours of incubation with saline (A, C, and D) or irradiated MRSA (B–D). (E–G) Live blister-infiltrating neutrophils (1 × 105) from the blister well challenged with irradiated MRSA as in B–D (E) or peripheral neutrophils (F) were harvested from 4 HVs and 4 patients with AD-HIES. The cells were then incubated ex vivo for 48 hours with irradiated S. aureus (MOI of 10) and IL-10, IL-20, or diluent. (G) Approximately 1 × 106 primary KCs from 3 HVs or 3 with AD-HIES patients were incubated for 24 hours with irritated MRSA as in E and F. Shown is the supernatant TNF-α concentration from independent cell lines, which are indicated by individual dots. Data represent a combination of experiments involving individual patients (A–F) or are representative of 3 independent experiments (G) and are displayed as the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001, by ANOVA with Bonferroni’s correction versus HVs across 14 tested cytokines (A–D; see also Supplemental Figure 1 and Methods).