Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome
Alexandra Y. Kreins,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,Cindy S. Ma,Geetha Rao,Andrea Bernasconi,Hye Sun Kuehn,Julie E. Niemela,Jennifer Stoddard,Paul Deveau,Paul Deveau,Aurélie Cobat,Aurélie Cobat,Safa El Azbaoui,Ayoub Sabri,Che Kang Lim,Che Kang Lim,Mikael Sundin,Danielle T. Avery,Rabih Halwani,Audrey V. Grant,Audrey V. Grant,Bertrand Boisson,Dusan Bogunovic,Yuval Itan,Marcela Moncada-Vélez,Marcela Moncada-Vélez,Rubén Martínez-Barricarte,Mélanie Migaud,Mélanie Migaud,Caroline Deswarte,Caroline Deswarte,Laia Alsina,Laia Alsina,Daniel Kotlarz,Christoph Klein,Ingrid Müller-Fleckenstein,Bernhard Fleckenstein,Valérie Cormier-Daire,Stefan Rose-John,Capucine Picard,Lennart Hammarström,Anne Puel,Anne Puel,Saleh Al-Muhsen,Laurent Abel,Laurent Abel,Laurent Abel,Damien Chaussabel,Sergio D. Rosenzweig,Yoshiyuki Minegishi,Stuart G. Tangye,Stuart G. Tangye,Jacinta Bustamante,Jacinta Bustamante,Jean-Laurent Casanova,Stéphanie Boisson-Dupuis,Stéphanie Boisson-Dupuis,Stéphanie Boisson-Dupuis +70 more
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TLDR
The identification and immunological characterization of a group of TYK2-deficient patients is reported and they are described as having at least some of the hallmarks of central giant cell apoptosis.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.read more
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Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer
TL;DR: The key roles of the IL-6 cytokine family in regulating innate and adaptive immunity, as well as other physiological responses are considered, which highlight the potential of targeting IL- 6 family members to treat inflammatory diseases and cancer.
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Chelsea Gerada,Tessa Mollie Campbell,Jarrod J. Kennedy,Brian P. McSharry,Megan Steain,Barry Slobedman,Allison Abendroth +6 more
TL;DR: This review will focus on the current understanding of the innate anti-viral control mechanisms faced by VZV and the diverse array of strategies employed by VzV to regulate these innate immune responses and highlight new knowledge on the interactions between VZVs and human innate immune cells.
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From GWAS to Function: Using Functional Genomics to Identify the Mechanisms Underlying Complex Diseases.
Eddie Cano-Gamez,Gosia Trynka +1 more
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Canonical and Non-Canonical Aspects of JAK–STAT Signaling: Lessons from Interferons for Cytokine Responses
Andrea Majoros,Ekaterini Platanitis,Elisabeth Kernbauer-Hölzl,Felix Rosebrock,Mathias Müller,Thomas Decker +5 more
TL;DR: The contribution of non-canonical JAK-STAT signaling to the innate antimicrobial immunity imparted by interferon (IFN) is discussed in this paper. But, the contribution is limited to the activation of the JAK signal.
Journal ArticleDOI
Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity
Calliope A. Dendrou,Adrian Cortes,Adrian Cortes,Lydia Shipman,Hayley G. Evans,Kathrine E. Attfield,Luke Jostins,Thomas R Barber,Gurman Kaur,Subita Balaram Kuttikkatte,Oliver A. Leach,Christiane Desel,Soren L. Faergeman,Soren L. Faergeman,Jane Cheeseman,Matt J. Neville,Matt J. Neville,Stephen Sawcer,Alastair Compston,Adam R. Johnson,Christine Everett,John Bell,Fredrik Karpe,Fredrik Karpe,Mark Ultsch,Charles Eigenbrot,Gil McVean,Lars Fugger,Lars Fugger +28 more
TL;DR: A protective homozygous effect is revealed that defined a signaling optimum between autoimmunity and immunodeficiency and identified TYK2 as a potential drug target for certain common autoimmune disorders.
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