| First Author | Myles IA | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 8 | Pages | 3595-3604 |
| PubMed ID | 30035749 | Mgi Jnum | J:265479 |
| Mgi Id | MGI:6197670 | Doi | 10.1172/JCI121486 |
| Citation | Myles IA, et al. (2018) TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome. J Clin Invest 128(8):3595-3604 |
| abstractText | 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 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-alpha 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. |
