TY - JOUR
T1 - Human TYK2 deficiency
T2 - Mycobacterial and viral infections without hyper-IgE syndrome
AU - Kreins, Alexandra Y.
AU - Ciancanelli, Michael J.
AU - Okada, Satoshi
AU - Kong, Xiao Fei
AU - Ramírez-Alejo, Noé
AU - Kilic, Sara Sebnem
AU - El Baghdadi, Jamila
AU - Nonoyama, Shigeaki
AU - Mahdaviani, Seyed Alireza
AU - Ailal, Fatima
AU - Bousfiha, Aziz
AU - Mansouri, Davood
AU - Nievas, Elma
AU - Ma, Cindy S.
AU - Rao, Geetha
AU - Bernasconi, Andrea
AU - Kuehn, Hye Sun
AU - Niemela, Julie
AU - Stoddard, Jennifer
AU - Deveau, Paul
AU - Cobat, Aurelie
AU - Azbaoui, Safa El
AU - Sabri, Ayoub
AU - Lim, Che Kang
AU - Sundin, Mikael
AU - Avery, Danielle T.
AU - Halwani, Rabih
AU - Grant, Audrey V.
AU - Boisson, Bertrand
AU - Bogunovic, Dusan
AU - Itan, Yuval
AU - Moncada-Velez, Marcela
AU - Martinez-Barricarte, Ruben
AU - Migaud, Melanie
AU - Deswarte, Caroline
AU - Alsina, Laia
AU - Kotlarz, Daniel
AU - Klein, Christoph
AU - Muller-Fleckenstein, Ingrid
AU - Fleckenstein, Bernhard
AU - Cormier-Daire, Valerie
AU - Rose-John, Stefan
AU - Picard, Capucine
AU - Hammarstrom, Lennart
AU - Puel, Anne
AU - Al-Muhsen, Saleh
AU - Abel, Laurent
AU - Chaussabel, Damien
AU - Rosenzweig, Sergio D.
AU - Minegishi, Yoshiyuki
AU - Tangye, Stuart G.
AU - Bustamante, Jacinta
AU - Casanova, Jean Laurent
AU - Boisson-Dupuis, Stéphanie
N1 - Publisher Copyright:
© 2015 Tang et al.
PY - 2015/9/21
Y1 - 2015/9/21
N2 - 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-Υ, 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.
AB - 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-Υ, 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.
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U2 - 10.1084/jem.20140280
DO - 10.1084/jem.20140280
M3 - Article
C2 - 26304966
AN - SCOPUS:84944807941
SN - 0022-1007
VL - 212
SP - 1641
EP - 1662
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -