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.

• Autores: Moncada Vélez, Marcela; Kreins, Alexandra Yema; Ciancanelli, Michael; Okada, Satoshi; Kong, Xiao-Fei; Ramírez Alejo, Noé; Sebnem Kilic, Sara; 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; El Azbaoui, Safa; Sabri, Ayoub; Lim, Che Kang; Sundin, Mikael; Avery, Danielle T.; Halwani, Rabih; Grant, Audrey V.; Boisson, Bertrand; Bogunovic, Dusan; Itan, Yuval; Martínez Barricarte, Rubén; Migaud, Melanie; Deswarte, Caroline; Alsina, Laia; Kotlarz, Daniel; Klein, Christoph; Fleckenstein, Ingrid Muller; Fleckenstein, Bernhard; Cormier Daire, Valerie; Rose John, Stefan; Picard, Capucine; Hammarstrom, Lennart; Puel, Anne; Al Muhsen, Saleh; Abel, Laurent; Chaussabel, Damien; Rosenzweig, Sergio D.; Minegishi, Yoshiyuki; Tangye, Stuart G.; Bustamante, Jacinta; Casanova, Jean Laurent; Boisson Dupuis, Stéphanie
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2015
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/35110
• Acceso en línea: https://hdl.handle.net/10495/35110
• Palabra clave: TYK2 Kinase; TYK2 Quinasa; Bacterial Infections; Infecciones Bacterianas; Job Syndrome; Síndrome de Job; Immunoglobulin E; Inmunoglobulina E; Loss of Function Mutation; Mutación con Pérdida de Función
• Rights: openAccess
• License: http://creativecommons.org/licenses/by/2.5/co/