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Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome

Abstract

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-α/β, 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-γ, IL-28/29 (IFN-λ), 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-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.

Type Journal
Authors Kreins, AY; Ciancanelli, MJ; Okada, S; Kong, XF; RamArez-Alejo, N; Sebnem Kilic, S; El Baghdadi, J; Nonoyama, S; Alireza Mahdaviani, S; Ailal, F; Bousfiha,A; Mansouri, D; Nievas, E; Ma, C; Rao, G; Bernasconi, A; Kuehn, HS; Niemela, J; Stoddard,J; Deveau, P; Cobat, A; El Azbaoui, S; Sabri, A; Lim, CK; Sundin, M; Avery, DT; Halwani, R; Grant, AV; Boisson, B; Bogunovic, D; Itan, Y; Moncada-Velez, M; Martinez-Barricarte, R; Migaud, M; Deswarte, C; lsina, L; Kotlarz, D; Klein, C; Muller-Flecken
Responsible Garvan Author A/Prof Cindy Ma
Publisher Name JOURNAL OF EXPERIMENTAL MEDICINE
Published Date 2015-09-21
Published Volume 212
Published Issue 10
Published Pages 1641-62
Status Published in-print
URL link to publisher's version http://www.ncbi.nlm.nih.gov/pubmed/26304966
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/12940