1. TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome
- Author
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Myles, Ian A., Anderson, Erik D., Earland, Noah J., Zarember, Kol A., Sastalla, Inka, Williams, Kelli W., Gough, Portia, Moore, Ian N., Ganesan, Sundar, Fowler, Cedar J., Laurence, Arian, Garofalo, Mary, Kuhns, Douglas B., Kieh, Mark D., Saleem, Arhum, Welch, Pamela A., Darnell, Dirk A., Gallin, John I., Freeman, Alexandra F., Holland, Steven M., and Datta, Sandip K.
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Staphylococcus aureus -- Health aspects ,Epithelial cells -- Research ,Immune response -- Research ,Immunoglobulin E -- Health aspects ,Health care industry - 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- [alpha] differentiated the responses in ADHIES 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-[alpha] blockade and by drugs with reported modulatory effects on EMT. Our results identify these as potential therapeutic approaches in patients with ADHIES suffering S. aureus infections., Introduction Autosomal dominant hyper IgE syndrome (AD-HIES), also known as Job's syndrome, is a primary immune deficiency caused by dominant-negative loss-of-function mutations in the STAT3 gene. Recurrent Staphylococcus aureus skin [...]
- Published
- 2018
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