2022年新着論文 32　免疫アレルギー学分野から論文が発表されました

Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency

J Exp Med. 2022 Oct 3;219(10):e20220094. doi: 10.1084/jem.20220094. Epub 2022 Sep 12.

Authors

Masato Ogishi^#¹, Andrés Augusto Arias^#^{1 2 3}, Rui Yang^#¹, Ji Eun Han^#¹, Peng Zhang¹, Darawan Rinchai¹, Joshua Halpern¹, Jeanette Mulwa¹, Narelle Keating^1 4, Maya Chrabieh^5 6, Candice Lainé^5 6, Yoann Seeleuthner^5 6, Noé Ramírez-Alejo¹, Nioosha Nekooie-Marnany⁷, Andrea Guennoun⁸, Ingrid Muller-Fleckenstein⁹, Bernhard Fleckenstein⁹, Sara S Kilic¹⁰, Yoshiyuki Minegishi¹¹, Stephan Ehl¹², Petra Kaiser-Labusch¹³, Yasemin Kendir-Demirkol¹⁴, Flore Rozenberg¹⁵, Abderrahmane Errami¹⁶, Shen-Ying Zhang^{1 5 6}, Qian Zhang^{1 5 6}, Jonathan Bohlen^5 6, Quentin Philippot^5 6, Anne Puel^{1 5 6}, Emmanuelle Jouanguy^{1 5 6}, Zahra Pourmoghaddas^#¹⁷, Shahrzad Bakhtiar^#¹⁸, Andre M Willasch^#¹⁸, Gerd Horneff^#^19 20, Genevieve Llanora^#²¹, Lynette P Shek^#^21 22, Louis Y A Chai^#^{23 24 25}, Sen Hee Tay^#^25 26, Hamid H Rahimi^#²⁷, Seyed Alireza Mahdaviani^#²⁸, Serdar Nepesov^#²⁹, Aziz A Bousfiha^#³⁰, Emine Hafize Erdeniz^#³¹, Adem Karbuz^#³², Nico Marr^#⁸, Carmen Navarrete^#³³, Mehdi Adeli^#³⁴, Lennart Hammarstrom^#^{35 36 37}, Hassan Abolhassani^#^35 37, Nima Parvaneh^#³⁷, Saleh Al Muhsen^#³⁸, Mohammed F Alosaimi^#³⁸, Fahad Alsohime^#^39 40, Maryam Nourizadeh^#^41 42, Mostafa Moin^#^41 42, Rand Arnaout^#^43 44, Saad Alshareef^#⁴³, Jamila El-Baghdadi^#⁴⁵, Ferah Genel^#⁴⁶, Roya Sherkat^#⁷, Ayça Kiykim^#⁴⁷, Esra Yücel^#⁴⁸, Sevgi Keles^#⁴⁹, Jacinta Bustamante^#^{1 5 50}, Laurent Abel^#^{1 5 6}, Jean-Laurent Casanova^#^{1 5 6 51 52}, Stéphanie Boisson-Dupuis^#^{1 5 6}

Affiliations

¹ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
² Primary Immunodeficiencies Group, University of Antioquia, Medellin, Colombia.
³ School of Microbiology, University of Antioquia, Medellin, Colombia.
⁴ Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, Australia.
⁵ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
⁶ Paris Cité University, Imagine Institute, Paris, France.
⁷ Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
⁸ Sidra Medicine, Doha, Qatar.
⁹ Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany.
¹⁰ Department of Pediatric Immunology and Rheumatology, Faculty of Medicine, Uludag University, Bursa, Turkey.
¹¹ Division of Molecular Medicine, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
¹² Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹³ Eltern- Kind -Zentrum Prof. Hess, Klinikum Bremen-Mitte, Bremen, Germany.
¹⁴ Department of Pediatric Genetics, Umraniye Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
¹⁵ Laboratory of Virology, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris, France.
¹⁶ Laboratory of Clinical Immunology, Inflammation and Allergy, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco.
¹⁷ Department of Pediatric Infectious Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
¹⁸ Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Child and Adolescent Medicine, University Hospital Frankfurt, Frankfurt, Germany.
¹⁹ Center for Pediatric Rheumatology, Department of Pediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin, Germany.
²⁰ Medical Faculty, University of Cologne, Cologne, Germany.
²¹ Division of Allergy and Immunology, Department of Paediatrics, Khoo Teck Puat – National University Children’s Medical Institute, National University Health System, Singapore.
²² Department of Pediatrics, National University of Singapore, Singapore.
²³ Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore.
²⁴ Synthetic Biology for Clinical and Technological Innovation, Life Sciences Institute; Synthetic Biology Translational Research Program, National University of Singapore.
²⁵ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
²⁶ Division of Rheumatology, Department of Medicine, National University Hospital, Singapore.
²⁷ Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran.
²⁸ Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
²⁹ Department of Pediatric Allergy and Immunology, Istanbul Medipol University, Istanbul, Turkey.
³⁰ Clinical Immunology Unit, Department of Pediatrics, King Hassan II University, Ibn-Rochd Hospital, Casablanca, Morocco.
³¹ Division of Pediatric Infectious Diseases, Ondokuz Mayıs University, Samsun, Turkey.
³² Division of Pediatric Infectious Diseases, Okmeydani Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
³³ Department of Immunology, Hospital de Niños Roberto del Río, Santiago de Chile, Chile.
³⁴ Division of Allergy and Immunology, Sidra Medicine/Hamad Medical Corp., Doha, Qatar.
³⁵ Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden.
³⁶ Beijing Genomics Institute, Shenzhen, China.
³⁷ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
³⁸ Immunology Research Laboratory, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
³⁹ Pediatric Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
⁴⁰ Pediatric Intensive Care Unit, King Saud University Medical City, Riyadh, Saudi Arabia.
⁴¹ Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
⁴² Children’s Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.
⁴³ Section of Allergy & Immunology, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
⁴⁴ Al Faisal University, Riyadh, Saudi Arabia.
⁴⁵ Genetics Unit, Mohamed V Military Hospital, Hay Riad, Rabat, Morocco.
⁴⁶ University of Health Sciences, Dr Behçet Uz Children’s Hospital, Division of Pediatric Immunology, Izmir, Turkey.
⁴⁷ Pediatric Allergy and Immunology, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.
⁴⁸ Division of Pediatric Allergy and Immunology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
⁴⁹ Division of Pediatric Allergy and Immunology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey.
⁵⁰ Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France.
⁵¹ Howard Hughes Medical Institute, New York, NY.
⁵² Deparment of Pediatrics, Necker Hospital for Sick Children, Paris, France.

^# Contributed equally.

Free PMC article

Abstract

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.

Conflict of interest statement

Disclosures: The authors declare no competing financial interests.

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