Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 212, Issue 10, Pages 1641-1662Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20140280
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Funding
- French National Agency for Research (ANR)
- EU-grant HOMITB [HEALTH-F3-2008-200732]
- European Research Council (ERC) [ERC-2010-AdG-268777]
- Bill and Melinda Gates Foundation
- St. Giles Foundation
- Jeffrey Modell Foundation
- Talecris Biotherapeutics
- National Center for Research Resources
- National Institutes of Health [8UL1TR000043]
- National Institute of Allergy and Infectious Diseases (NIAID) [5R01AI089970, 5R37AI095983, 5U01AI088685]
- Rockefeller University
- Fondation Medicale Medische Stichting Mathilde E. Horlait-Dapsens
- Helmsley Fellowship for Basic and Translational Research on Disorders of the Digestive System
- NIAID [1K99AI106942]
- Stony Wold-Herbert Fund
- European Molecular Biology Organization (EMBO)
- National Health and Medical Research Council of Australia
- Deutsche Forschungsgemeinschaft (DFG), Bonn [SFB841, C1, SFB877, A1]
- Cluster of Excellence Inflammation at interfaces
- National Center for Advancing Sciences (NCATS)
- Grants-in-Aid for Scientific Research [25293232, 25713039] Funding Source: KAKEN
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Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-alpha/beta, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-gamma, IL-28/29 (IFN-lambda), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-alpha/beta. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
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