Human TYK2 deficiency

Mycobacterial and viral infections without hyper-IgE syndrome

Alexandra Y. Kreins, Michael J. Ciancanelli, Satoshi Okada, Xiao Fei Kong, Noé Ramírez-Alejo, Sara Sebnem Kilic, Jamila El Baghdadi, Shigeaki Nonoyama, Seyed Alireza Mahdaviani, Fatima Ailal, Aziz Bousfiha, Davood Mansouri, Elma Nievas, Cindy S. Ma, Geetha Rao, Andrea Bernasconi, Hye Sun Kuehn, Julie Niemela, Jennifer Stoddard, Paul Deveau & 34 others Aurelie Cobat, Safa El Azbaoui, Ayoub Sabri, Che Kang Lim, Mikael Sundin, Danielle T. Avery, Rabih Halwani, Audrey V. Grant, Bertrand Boisson, Dusan Bogunovic, Yuval Itan, Marcela Moncada-Velez, Ruben Martinez-Barricarte, Melanie Migaud, Caroline Deswarte, Laia Alsina, Daniel Kotlarz, Christoph Klein, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Valerie Cormier-Daire, Stefan Rose-John, Capucine Picard, Lennart Hammarstrom, Anne Puel, Saleh Al-Muhsen, Laurent Abel, Damien J. Chaussabel, Sergio D. Rosenzweig, Yoshiyuki Minegishi, Stuart G. Tangye, Jacinta Bustamante, Jean Laurent Casanova, Stéphanie Boisson-Dupuis

Research output: Contribution to journalArticle

92 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)1641-1662
Number of pages22
JournalJournal of Experimental Medicine
Volume212
Issue number10
DOIs
Publication statusPublished - 2015
Externally publishedYes

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Job Syndrome
Virus Diseases
Interleukin-6
Interleukin-12
Interleukin-27
Interleukin-23
Phenotype
Leukemia Inhibitory Factor
Interleukin-17
Candidiasis
Atopic Dermatitis
Inflammatory Bowel Diseases
Ethnic Groups
Bacterial Infections
Interleukin-10
Abscess
Immunoglobulin E
Tyrosine Kinase 2 Deficiency
Leukocytes
Fibroblasts

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Kreins, A. Y., Ciancanelli, M. J., Okada, S., Kong, X. F., Ramírez-Alejo, N., Kilic, S. S., ... Boisson-Dupuis, S. (2015). Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. Journal of Experimental Medicine, 212(10), 1641-1662. https://doi.org/10.1084/jem.20140280

Human TYK2 deficiency : Mycobacterial and viral infections without hyper-IgE syndrome. / Kreins, Alexandra Y.; Ciancanelli, Michael J.; Okada, Satoshi; Kong, Xiao Fei; Ramírez-Alejo, Noé; Kilic, Sara Sebnem; El Baghdadi, Jamila; Nonoyama, Shigeaki; Mahdaviani, Seyed Alireza; Ailal, Fatima; Bousfiha, Aziz; Mansouri, Davood; Nievas, Elma; Ma, Cindy S.; Rao, Geetha; Bernasconi, Andrea; Kuehn, Hye Sun; Niemela, Julie; Stoddard, Jennifer; Deveau, Paul; Cobat, Aurelie; Azbaoui, Safa El; Sabri, Ayoub; Lim, Che Kang; Sundin, Mikael; Avery, Danielle T.; Halwani, Rabih; Grant, Audrey V.; Boisson, Bertrand; Bogunovic, Dusan; Itan, Yuval; Moncada-Velez, Marcela; Martinez-Barricarte, Ruben; Migaud, Melanie; Deswarte, Caroline; Alsina, Laia; Kotlarz, Daniel; Klein, Christoph; Muller-Fleckenstein, Ingrid; Fleckenstein, Bernhard; Cormier-Daire, Valerie; Rose-John, Stefan; Picard, Capucine; Hammarstrom, Lennart; Puel, Anne; Al-Muhsen, Saleh; Abel, Laurent; Chaussabel, Damien J.; Rosenzweig, Sergio D.; Minegishi, Yoshiyuki; Tangye, Stuart G.; Bustamante, Jacinta; Casanova, Jean Laurent; Boisson-Dupuis, Stéphanie.

In: Journal of Experimental Medicine, Vol. 212, No. 10, 2015, p. 1641-1662.

Research output: Contribution to journalArticle

Kreins, AY, Ciancanelli, MJ, Okada, S, Kong, XF, Ramírez-Alejo, N, Kilic, SS, El Baghdadi, J, Nonoyama, S, Mahdaviani, SA, Ailal, F, Bousfiha, A, Mansouri, D, Nievas, E, Ma, CS, Rao, G, Bernasconi, A, Kuehn, HS, Niemela, J, Stoddard, J, Deveau, P, Cobat, A, Azbaoui, SE, 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, Alsina, L, Kotlarz, D, Klein, C, Muller-Fleckenstein, I, Fleckenstein, B, Cormier-Daire, V, Rose-John, S, Picard, C, Hammarstrom, L, Puel, A, Al-Muhsen, S, Abel, L, Chaussabel, DJ, Rosenzweig, SD, Minegishi, Y, Tangye, SG, Bustamante, J, Casanova, JL & Boisson-Dupuis, S 2015, 'Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome', Journal of Experimental Medicine, vol. 212, no. 10, pp. 1641-1662. https://doi.org/10.1084/jem.20140280
Kreins AY, Ciancanelli MJ, Okada S, Kong XF, Ramírez-Alejo N, Kilic SS et al. Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. Journal of Experimental Medicine. 2015;212(10):1641-1662. https://doi.org/10.1084/jem.20140280
Kreins, Alexandra Y. ; Ciancanelli, Michael J. ; Okada, Satoshi ; Kong, Xiao Fei ; Ramírez-Alejo, Noé ; Kilic, Sara Sebnem ; El Baghdadi, Jamila ; Nonoyama, Shigeaki ; Mahdaviani, Seyed Alireza ; Ailal, Fatima ; Bousfiha, Aziz ; Mansouri, Davood ; Nievas, Elma ; Ma, Cindy S. ; Rao, Geetha ; Bernasconi, Andrea ; Kuehn, Hye Sun ; Niemela, Julie ; Stoddard, Jennifer ; Deveau, Paul ; Cobat, Aurelie ; Azbaoui, Safa El ; Sabri, Ayoub ; Lim, Che Kang ; Sundin, Mikael ; Avery, Danielle T. ; Halwani, Rabih ; Grant, Audrey V. ; Boisson, Bertrand ; Bogunovic, Dusan ; Itan, Yuval ; Moncada-Velez, Marcela ; Martinez-Barricarte, Ruben ; Migaud, Melanie ; Deswarte, Caroline ; Alsina, Laia ; Kotlarz, Daniel ; Klein, Christoph ; Muller-Fleckenstein, Ingrid ; Fleckenstein, Bernhard ; Cormier-Daire, Valerie ; Rose-John, Stefan ; Picard, Capucine ; Hammarstrom, Lennart ; Puel, Anne ; Al-Muhsen, Saleh ; Abel, Laurent ; Chaussabel, Damien J. ; Rosenzweig, Sergio D. ; Minegishi, Yoshiyuki ; Tangye, Stuart G. ; Bustamante, Jacinta ; Casanova, Jean Laurent ; Boisson-Dupuis, Stéphanie. / Human TYK2 deficiency : Mycobacterial and viral infections without hyper-IgE syndrome. In: Journal of Experimental Medicine. 2015 ; Vol. 212, No. 10. pp. 1641-1662.
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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-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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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 J.

AU - Rosenzweig, Sergio D.

AU - Minegishi, Yoshiyuki

AU - Tangye, Stuart G.

AU - Bustamante, Jacinta

AU - Casanova, Jean Laurent

AU - Boisson-Dupuis, Stéphanie

PY - 2015

Y1 - 2015

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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