TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome

Author:

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, Doug

Kieh, Mark D

Saleem, Arhum

Welch, Pamela A

Darnell, Dirk A

Gallin, John I

Freeman, Alexandra F

Holland, Steven M

Datta, Sandip K
Author Address

Laboratory of Clinical Immunology and Microbiology, and., Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA., Infectious Disease and Pathogenesis Section, Comparative Medicine Branch, NIAID, NIH, Rockville, Maryland, USA., Biological Imaging Section, Research Technology Branch, NIAID, NIH, Bethesda, Maryland, USA., Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom., Applied Developmental Research Directorate, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.,

Abstract:

Autosomal dominant hyper IgE syndrome (AD-HIES), or Job 39;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-a 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-a 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.

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Author Address