Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency,Nature

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Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency
Nature ( IF 50.5 ) Pub Date : 2023-11-08 , DOI: 10.1038/s41586-023-06717-x
Tom Le Voyer _{1,

2} , Audrey V Parent ₃ , Xian Liu ₃ , Axel Cederholm ₄ , Adrian Gervais _{1,

2} , Jérémie Rosain _{1,

2,

5} , Tina Nguyen _{6,

7} , Malena Perez Lorenzo _{1,

2} , Elze Rackaityte ₈ , Darawan Rinchai ₉ , Peng Zhang ₉ , Lucy Bizien _{1,

2} , Gonca Hancioglu ₁₀ , Pascale Ghillani-Dalbin ₁₁ , Jean-Luc Charuel ₁₁ , Quentin Philippot _{1,

2} , Mame Sokhna Gueye _{1,

2} , Majistor Raj Luxman Maglorius Renkilaraj _{1,

2} , Masato Ogishi ₉ , Camille Soudée _{1,

2} , Mélanie Migaud _{1,

2} , Flore Rozenberg ₁₂ , Mana Momenilandi _{1,

2} , Quentin Riller ₁₃ , Luisa Imberti ₁₄ , Ottavia M Delmonte ₁₅ , Gabriele Müller _{16,

17} , Baerbel Keller _{17,

18} , Julio Orrego ₁₉ , William Alexander Franco Gallego ₁₉ , Tamar Rubin ₂₀ , Melike Emiroglu ₂₁ , Nima Parvaneh ₂₂ , Daniel Eriksson _{23,

24,

25} , Maribel Aranda-Guillen ₂₅ , David I Berrios ₃ , Linda Vong _{26,

27} , Constance H Katelaris ₂₈ , Peter Mustillo ₂₉ , Johannes Raedler ₃₀ , Jonathan Bohlen _{1,

2} , Jale Bengi Celik ₃₁ , Camila Astudillo _{32,

33} , Sarah Winter ₃₄ , , , Catriona McLean ₃₅ , Aurélien Guffroy ₃₆ , Joseph L DeRisi _{8,

37} , David Yu ₃ , Corey Miller ₃ , Yi Feng ₉ , Audrey Guichard ₃₈ , Vivien Béziat _{1,

2,

9} , Jacinta Bustamante _{1,

2,

5,

9} , Qiang Pan-Hammarström _{39,

40} , Yu Zhang _{15,

41} , Lindsey B Rosen ₁₅ , Steve M Holland ₁₅ , Marita Bosticardo ₁₅ , Heather Kenney ₁₅ , Riccardo Castagnoli _{42,

43} , Charlotte A Slade _{44,

45,

46} , Kaan Boztuğ _{47,

48,

49,

50} , Nizar Mahlaoui _{51,

52} , Sylvain Latour ₃₄ , Roshini S Abraham ₅₃ , Vassilios Lougaris ₅₄ , Fabian Hauck ₃₀ , Anna Sediva ₅₅ , Faranaz Atschekzei ₅₆ , Georgios Sogkas ₅₆ , M Cecilia Poli _{32,

33} , Mary A Slatter ₅₇ , Boaz Palterer ₅₈ , Michael D Keller ₅₉ , Alberto Pinzon-Charry _{60,

61} , Anna Sullivan _{60,

61} , Luke Droney _{60,

61} , Daniel Suan _{60,

62} , Melanie Wong _{60,

62,

63} , Alisa Kane _{7,

60,

64,

65} , Hannah Hu _{60,

64,

65} , Cindy Ma _{6,

7,

60} , Hana Grombiříková ₆₆ , Peter Ciznar ₆₇ , Ilan Dalal ₆₈ , Nathalie Aladjidi ₆₉ , Miguel Hie ₇₀ , Estibaliz Lazaro ₇₁ , Jose Franco ₁₉ , Sevgi Keles ₇₂ , Marion Malphettes ₇₃ , Marlene Pasquet ₇₄ , Maria Elena Maccari _{16,

75} , Andrea Meinhardt ₇₆ , Aydan Ikinciogullari ₇₇ , Mohammad Shahrooei _{78,

79} , Fatih Celmeli ₈₀ , Patrick Frosk ₈₁ , Christopher C Goodnow _{6,

7,

60} , Paul E Gray _{60,

82} , Alexandre Belot _{83,

84,

85} , Hye Sun Kuehn ₈₆ , Sergio D Rosenzweig ₈₆ , Makoto Miyara _{11,

87} , Francesco Licciardi ₈₈ , Amélie Servettaz _{89,

90} , Vincent Barlogis ₉₁ , Guillaume Le Guenno ₉₂ , Vera-Maria Herrmann ₉₃ , Taco Kuijpers ₉₄ , Grégoire Ducoux ₉₅ , Françoise Sarrot-Reynauld ₉₆ , Catharina Schuetz ₉₇ , Charlotte Cunningham-Rundles ₉₈ , Frédéric Rieux-Laucat ₁₃ , Stuart G Tangye _{6,

7,

60} , Cristina Sobacchi _{99,

100} , Rainer Doffinger ₁₀₁ , Klaus Warnatz _{17,

18} , Bodo Grimbacher _{16,

17} , Claire Fieschi _{73,

102} , Laureline Berteloot ₁₀₃ , Vanessa L Bryant _{44,

45,

46} , Sophie Trouillet Assant _{38,

104} , Helen Su _{15,

41} , Benedicte Neven ₅₂ , Laurent Abel _{1,

2,

9} , Qian Zhang _{1,

2,

9} , Bertrand Boisson _{1,

2,

9} , Aurélie Cobat _{1,

2,

9} , Emmanuelle Jouanguy _{1,

2,

9} , Olle Kampe ₁₀₅ , Paul Bastard _{1,

2,

9,

52} , Chaim M Roifman _{26,

27} , Nils Landegren _{4,

25} , Luigi D Notarangelo ₁₅ , Mark S Anderson _{3,

106} , Jean-Laurent Casanova _{1,

2,

9,

107,

108} , Anne Puel _{1,

2,

9}

Affiliation

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.
Paris Cité University, Imagine Institute, Paris, France.
Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Study Center for Immunodeficiencies, Necker Hospital for Sick Children, Paris, France.
Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
School of Clinical Medicine, UNSW Medicine & Health, Darlinghurst, New South Wales, Australia.
Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
Division of Pediatric Allergy and Immunology, Ondokuz Mayıs University Faculty of Medicine, Samsun, Turkey.
Department of Immunology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
Virology, Cochin-Saint-Vincent de Paul Hospital, University of Paris, Paris, France.
Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Paris Cité University, Imagine Institute, INSERM UMR1163, Paris, France.
Section of Microbiology, University of Brescia, Brescia, Italy.
Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Institute for Immunodeficiency, Center for Chronic Immunodeficiencies, Medical Center-University Hospital Freiburg, and Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany.
Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia.
Division of Pediatric Clinical Immunology and Allergy, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
Department of Pediatric Infectious Diseases, Faculty of Medicine, Selcuk University, Konya, Turkey.
Division of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.
Department of Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden.
Department of Immunology, Genetics and Pathology, Section of Clinical Genetics, Uppsala University and University Hospital, Uppsala, Sweden.
Center for Molecular Medicine, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden.
Division of Immunology and Allergy, Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
The Canadian Centre for Primary Immunodeficiency and The Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, The Hospital for Sick Children, Toronto, Ontario, Canada.
Immunology and Allergy, University of Western Sydney and Campbelltown Hospital, Campbelltown, New South Wales, Australia.
Division of Allergy and Immunology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA.
Division of Pediatric Immunology and Rheumatology, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
Department of Anesthesiology and Reanimation, Selcuk University Faculty of Medicine, Konya, Turkey.
Hospital de Niños Roberto del Río, Santiago, Chile.
Department of Pediatrics, Facultad de Medicina Clinica Alemana Universidad del Desarrollo, Santiago, Chile.
Laboratory of Lymphocyte Activation and Susceptibility to EBV, Paris Cité University, Imagine Institute, Inserm UMR1163, Paris, France.
Department of Anatomical Pathology, The Alfred Hospital, Prahran, Victoria, Australia.
Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune Diseases, Strasbourg University Hospital, Strasbourg, France.
Chan Zuckerberg Biohub, San Francisco, CA, USA.
Joint Unit Hospices Civils de Lyon-BioMérieux, Lyon, France.
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
NIAID Clinical Genomics Program, NIH, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, Italy.
Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Immunology Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.
Dept Medical Biology, University of Melbourne, Victoria, Parkville, Australia.
Dept Clinical Immunology and Allergy, The Royal Melbourne Hospital, Parkville, Australia.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Anna Children's Cancer Research Institute, Vienna, Austria.
Anna Children's Hospital, Vienna, Austria.
French National Reference Center for Primary Immunodeficiencies (CEREDIH), Necker-Enfants University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
Department of Clinical and Experimental Sciences, Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, University of Brescia ASST-Spedali Civili di Brescia, Brescia, Italy.
Department of Immunology, Second Faculty of Medicine Charles University and Motol University Hospital, Prague, Czech Republic.
Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany.
Children's Haemopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle-upon-Tyne Hospital NHS Foundation Trust, Newcastle upon Tyne, UK.
Allergy and Clinical Immunology, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Division of Allergy and Immunology, Children's National Medical Center, Washington, DC, USA.
Clinical Immunogenomics Research Consortium Australasia (CIRCA), Darlinghurst, New South Wales, Australia.
Immunology and Allergy, Queensland Children's Hospital, South Brisbane, Queensland, Australia.
Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia.
Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia.
South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
Department of Immunology, Allergy and HIV, St Vincent's Hospital, Sydney, New South Wales, Australia.
Centre for Cardiovascular Surgery and Transplantation, Medical Faculty, Masaryk University, Brno, Czech Republic.
Department of Paediatrics, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia.
Pediatric Department, E. Wolfson Medical Center, Tel Aviv University, Tel Aviv, Israel.
Pediatric Oncology Hematology Unit, University Hospital, Plurithématique CIC (CICP), Centre d'Investigation Clinique (CIC) 1401, Bordeaux, France.
Internal Medicine Department, Pitié-Salpêtrière Hospital, Paris, France.
Department of Internal Medicine & Infectious Diseases, Bordeaux Hospital University, Bordeaux, France.
Division of Pediatric Allergy and Immunology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey.
Clinical Immunology Department, Saint Louis Hospital, Paris, France.
Department of Pediatric Hematology, Toulouse University Hospital, Toulouse, France.
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Department of Pediatric Hematology, Oncology and Immunodeficiencies, University Children's Hospital Gießen, Giessen, Germany.
Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.
Dr. Shahrooei Lab, Tehran, Iran.
Clinical and Diagnostic Immunology, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium.
Department of Allergy and Immunology, University of Medical Science, Antalya Education and Research Hospital, Antalya, Turkey.
Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Immunology and Infectious Diseases, Sydney Children's Hospital Randwick, Western Sydney University, Campbelltown, New South Wales, Australia.
CNRS UMR 5308, ENS, UCBL, Lyon, France.
National Reference Center for Rheumatic, Autoimmune and Systemic Diseases in Children (RAISE), Lyon, France.
Immunopathology Federation LIFE, Hospices Civils de Lyon, Lyon, France.
Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Centre d'Immunologie et des Maladies Infectieuses (CIMI), Sorbonne Université, INSERM U1135, Paris, France.
Department of Pediatrics and Public Health, Università degli Studi di Torino, Turin, Italy.
Internal Medicine, Clinical Immunology and Infectious Diseases Department, University Hospital Center, Reims, France.
IRMAIC EA 7509, URCA, Reims, France.
CHU Marseille, Hôpital La Timone, Service d'Hémato-oncologie Pédiatrique, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France.
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Internal Medicine, Edouard Herriot Hospital, Lyon, France.
Department of Internal Medicine, Hôpital Michallon, CHU de Grenoble Alpes, Grenoble, France.
Department of Pediatrics, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY, USA.
IRCCS Humanitas Research Hospital, Rozzano, Italy.
CNR-IRGB, Milan Unit, Milan, Italy.
Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, UK.
Paris Cité University, Paris, France.
Pediatric Radiology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, France.
CIRI (Centre International de Recherche en Infectiologie), Université de Lyon, Université Claude Bernard Lyon 1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Howard Hughes Medical Institute, New York, NY, USA.
Department of Pediatrics, Necker Hospital for Sick Children, Paris, France.

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)^1,2, conferring a predisposition to life-threatening COVID-19 pneumonia³. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52^LOF/IκBδ^GOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52^LOF/IκBδ^LOF) or gain-of-function of p52 (hereafter, p52^GOF/IκBδ^LOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

中文翻译：

具有替代 NF-κB 通路缺陷的人类体内针对 I 型干扰素的自身抗体

由常染色体隐性遗传 AIRE 缺陷引起的 1 型自身免疫性多内分泌病综合征 (APS-1) 患者会产生中和 I 型干扰素 (IFN) 的自身抗体^1,2 ，从而容易患上危及生命的 COVID-19 肺炎³ 。在此我们报告，患有常染色体隐性遗传 NIK 或 RELB 缺陷或特定类型的常染色体显性 NF-κB2 缺陷的患者也具有针对 I 型 IFN 的中和自身抗体，并且患危及生命的 COVID-19 肺炎的风险较高。在患有常染色体显性 NF-κB2 缺陷的患者中，这些自身抗体仅存在于与转录（p52 活性）由于 p100 生成 p52 的加工受损而导致的功能丧失 (LOF) 和调节性（IκBδ）相关变异杂合的个体中。活性）由于未加工的 p100 的积累而导致功能获得（GOF），因此增加了 IκBδ 的抑制活性（以下称为 p52 ^LOF /IκBδ ^GOF ）。相比之下，在导致 p100 和p52单倍体不足（以下称为 p52 ^LOF /IκBδ ^LOF ）或 p52 功能获得（以下称为 p52 ^GOF /IκBδ^洛夫）。与 APS-1 患者相比，患有 NIK、RELB 或 NF-κB2 疾病的患者几乎没有组织特异性自身抗体。然而，它们的胸腺结构异常，表达 AIRE 的髓质胸腺上皮细胞很少。人类先天性 NF-κB 通路缺陷会损害表达 AIRE 的髓质胸腺上皮细胞的发育，从而导致 I 型 IFN 自身抗体的产生和病毒性疾病的易感性。

更新日期：2023-11-08

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