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, p52LOF/IκBδGOF). 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, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). 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.

Allergy and Clinical Immunology Department of Experimental and Clinical Medicine University of Florence Florence Italy

Anna Children's Cancer Research Institute Vienna Austria

Anna Children's Hospital Vienna Austria

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria

Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Center for Molecular Medicine Department of Medicine Karolinska Institute Stockholm Sweden

Centre d'Immunologie et des Maladies Infectieuses Sorbonne Université INSERM U1135 Paris France

Centre for Cardiovascular Surgery and Transplantation Medical Faculty Masaryk University Brno Czech Republic

Centre Hospitalier Universitaire Estaing Clermont Ferrand France

Chan Zuckerberg Biohub San Francisco CA USA

Children's Haemopoietic Stem Cell Transplant Unit Great North Children's Hospital Newcastle upon Tyne Hospital NHS Foundation Trust Newcastle upon Tyne UK

CHU Marseille Hôpital La Timone Service d'Hémato oncologie Pédiatrique Assistance Publique Hôpitaux de Marseille Marseille France

CIRI Université de Lyon Université Claude Bernard Lyon 1 INSERM U1111 CNRS UMR5308 ENS Lyon Université Jean Monnet de Saint Etienne Lyon France

Clinical and Diagnostic Immunology Department of Microbiology Immunology and Transplantation KU Leuven Leuven Belgium

Clinical Immunogenomics Research Consortium Australasia Darlinghurst New South Wales Australia

Clinical Immunology Department Saint Louis Hospital Paris France

CNR IRGB Milan Unit Milan Italy

CNRS UMR 5308 ENS UCBL Lyon France

Department of Allergy and Immunology University of Medical Science Antalya Education and Research Hospital Antalya Turkey

Department of Anatomical Pathology The Alfred Hospital Prahran Victoria Australia

Department of Anesthesiology and Reanimation Selcuk University Faculty of Medicine Konya Turkey

Department of Biochemistry and Biophysics University of California San Francisco San Francisco CA USA

Department of Biochemistry and Medical Genetics Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba Canada

Department of Biosciences and Nutrition Karolinska Institutet Stockholm Sweden

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 Clinical Biochemistry and Immunology Addenbrooke's Hospital Cambridge UK

Department of Clinical Genetics Uppsala University Hospital Uppsala Sweden

Department of Clinical Immunology and Internal Medicine National Reference Center for Autoimmune Diseases Strasbourg University Hospital Strasbourg France

Department of Endocrinology Metabolism and Diabetes Karolinska University Hospital Stockholm Sweden

Department of Immunology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Immunology Allergy and HIV St Vincent's Hospital Sydney New South Wales Australia

Department of Immunology AP HP Pitié Salpêtrière Hospital Paris France

Department of Immunology Genetics and Pathology Section of Clinical Genetics Uppsala University and University Hospital Uppsala Sweden

Department of Internal Medicine and Infectious Diseases Bordeaux Hospital University Bordeaux France

Department of Internal Medicine Edouard Herriot Hospital Lyon France

Department of Internal Medicine Hôpital Michallon CHU de Grenoble Alpes Grenoble France

Department of Medicine University of California San Francisco San Francisco CA USA

Department of Paediatrics Faculty of Medicine Comenius University Bratislava Bratislava Slovakia

Department of Pathology and Laboratory Medicine Nationwide Children's Hospital Columbus OH USA

Department of Pediatric Hematology Oncology and Immunodeficiencies University Children's Hospital Gießen Giessen Germany

Department of Pediatric Hematology Toulouse University Hospital Toulouse France

Department of Pediatric Immunology and Allergy Ankara University School of Medicine Ankara Turkey

Department of Pediatric Immunology Hematology and Rheumatology Necker Enfants Malades Hospital AP HP Paris France

Department of Pediatric Immunology Rheumatology and Infectious Diseases Emma Children's Hospital Amsterdam University Medical Center University of Amsterdam Amsterdam The Netherlands

Department of Pediatric Infectious Diseases Faculty of Medicine Selcuk University Konya Turkey

Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

Department of Pediatrics and Public Health Università degli Studi di Torino Turin Italy

Department of Pediatrics Facultad de Medicina Clinica Alemana Universidad del Desarrollo Santiago Chile

Department of Pediatrics Necker Hospital for Sick Children Paris France

Department of Pediatrics Universitätsklinikum Carl Gustav Carus Technische Universität Dresden Dresden Germany

Department of Rheumatology and Clinical Immunology Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Department of Rheumatology and Immunology Hannover Medical School Hannover Germany

Departments of Medicine and Pediatrics Mount Sinai School of Medicine New York NY USA

Dept Clinical Immunology and Allergy The Royal Melbourne Hospital Parkville Australia

Dept Medical Biology University of Melbourne Victoria Parkville Australia

Diabetes Center University of California San Francisco San Francisco CA USA

Division of Allergy and Clinical Immunology Department of Pediatrics Tehran University of Medical Sciences Tehran Iran

Division of Allergy and Immunology Children's National Medical Center Washington DC USA

Division of Allergy and Immunology Nationwide Children's Hospital The Ohio State University College of Medicine Columbus OH USA

Division of Immunology and Allergy Department of Paediatrics Hospital for Sick Children and University of Toronto Toronto Ontario Canada

Division of Immunology Department of Medical Biochemistry and Biophysics Karolinska Institutet Stockholm Sweden

Division of Pediatric Allergy and Immunology Meram Medical Faculty Necmettin Erbakan University Konya Turkey

Division of Pediatric Allergy and Immunology Ondokuz Mayıs University Faculty of Medicine Samsun Turkey

Division of Pediatric Clinical Immunology and Allergy Department of Pediatrics and Child Health University of Manitoba Winnipeg Manitoba Canada

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

Division of Pediatric Immunology and Rheumatology Department of Pediatrics Dr von Hauner Children's Hospital University Hospital Ludwig Maximilians Universität München Munich Germany

Dr Shahrooei Lab Tehran Iran

Faculty of Medicine University of Sydney Sydney New South Wales Australia

French National Reference Center for Primary Immunodeficiencies Paris France

Garvan Institute of Medical Research Sydney New South Wales Australia

Hospital de Niños Roberto del Río Santiago Chile

Howard Hughes Medical Institute New York NY USA

Immunology and Allergy Queensland Children's Hospital South Brisbane Queensland Australia

Immunology and Allergy University of Western Sydney and Campbelltown Hospital Campbelltown New South Wales Australia

Immunology and Infectious Diseases Sydney Children's Hospital Randwick Western Sydney University Campbelltown New South Wales Australia

Immunology Division Walter and Eliza Hall Institute Melbourne Victoria Australia

Immunology Service Department of Laboratory Medicine Clinical Center National Institutes of Health Bethesda MD USA

Immunopathology Federation LIFE Hospices Civils de Lyon Lyon France

Institute for Immunodeficiency Center for Chronic Immunodeficiencies Medical Center University Hospital Freiburg and Faculty of Medicine Albert Ludwigs University Freiburg Germany

Institute of Human Genetics University of Leipzig Medical Center Leipzig Germany

Internal Medicine Clinical Immunology and Infectious Diseases Department University Hospital Center Reims France

Internal Medicine Department Pitié Salpêtrière Hospital Paris France

IRCCS Humanitas Research Hospital Rozzano Italy

IRMAIC EA 7509 URCA Reims France

Joint Unit Hospices Civils de Lyon BioMérieux Lyon France

Laboratory of Clinical Immunology and Microbiology Division of Intramural Research National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD USA

Laboratory of Human Genetics of Infectious Diseases Necker Branch INSERM UMR1163 Paris France

Laboratory of Immunogenetics of Pediatric Autoimmune Diseases Paris Cité University Imagine Institute INSERM UMR1163 Paris France

Laboratory of Lymphocyte Activation and Susceptibility to EBV Paris Cité University Imagine Institute Inserm UMR1163 Paris France

National Reference Center for Rheumatic Autoimmune and Systemic Diseases in Children Lyon France

NIAID Clinical Genomics Program NIH Laboratory of Clinical Immunology and Microbiology Division of Intramural Research NIAID NIH Bethesda MD USA

Paris Cité University Imagine Institute Paris France

Paris Cité University Paris France

Pediatric Clinic Fondazione IRCCS Policlinico San Matteo Pavia Italy

Pediatric Department E Wolfson Medical Center Tel Aviv University Tel Aviv Israel

Pediatric Oncology Hematology Unit University Hospital Plurithématique CIC 1401 Bordeaux France

Pediatric Radiology Department Assistance Publique Hôpitaux de Paris Necker Hospital for Sick Children Paris France

Pediatric Unit Department of Clinical Surgical Diagnostic and Pediatric Sciences University of Pavia Pavia Italy

Primary Immunodeficiencies Group Department of Microbiology and Parasitology School of Medicine University of Antioquia Medellín Colombia

School of Clinical Medicine UNSW Medicine and Health Darlinghurst New South Wales Australia

Science for Life Laboratory Department of Medical Biochemistry and Microbiology Uppsala University Uppsala Sweden

Section of Microbiology University of Brescia Brescia Italy

South Western Sydney Clinical School Faculty of Medicine and Health UNSW Sydney Sydney New South Wales Australia

St Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch The Rockefeller University New York NY USA

Study Center for Immunodeficiencies Necker Hospital for Sick Children Paris France

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

Virology Cochin Saint Vincent de Paul Hospital University of Paris Paris France

Westmead Clinical School University of Sydney Sydney New South Wales Australia

See more in PubMed

Levin M. Anti-interferon auto-antibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 2006;3:e292. doi: 10.1371/journal.pmed.0030292. PubMed DOI PMC

Meager A, et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 2006;3:e289. doi: 10.1371/journal.pmed.0030289. PubMed DOI PMC

Bastard P, et al. Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1. J. Exp. Med. 2021;218:e20210554. doi: 10.1084/jem.20210554. PubMed DOI PMC

Puel A, Bastard P, Bustamante J, Casanova J-L. Human autoantibodies underlying infectious diseases. J. Exp. Med. 2022;219:e20211387. doi: 10.1084/jem.20211387. PubMed DOI PMC

Mogensen KE, Daubas P, Gresser I, Sereni D, Varet B. Patient with circulating antibodies to alpha-interferon. Lancet. 1981;318:1227–1228. doi: 10.1016/S0140-6736(81)91460-4. PubMed DOI

Pozzetto, B., Mogensen, K. E., Tovey, M. G. & Gresser, I. Characteristics of autoantibodies to human interferon in a patient with varicella-zoster disease. J. Infect. Dis.150, 707–713 (1984). PubMed

Bastard, P. et al. Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths. Sci. Immunol. 10.1126/sciimmunol.abl4340 (2021). PubMed PMC

Bastard, P. et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science10.1126/science.abd4585 (2020). PubMed PMC

Zhang Q, Bastard P, COVID Human Genetic Effort, Cobat A, Casanova J-L. Human genetic and immunological determinants of critical COVID-19 pneumonia. Nature. 2022;603:587–598. doi: 10.1038/s41586-022-04447-0. PubMed DOI PMC

Manry J, et al. The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies. Proc. Natl Acad. Sci. USA. 2022;119:e2200413119. doi: 10.1073/pnas.2200413119. PubMed DOI PMC

Casanova, J. L. & Abel, L. Mechanisms of viral inflammation and disease in humans. Science374, 1080–1086 (2021). PubMed PMC

Bastard P, et al. Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine. J. Exp. Med. 2021;218:e20202486. doi: 10.1084/jem.20202486. PubMed DOI PMC

Zhang Q, et al. Autoantibodies against type I IFNs in patients with critical influenza pneumonia. J. Exp. Med. 2022;219:e20220514. doi: 10.1084/jem.20220514. PubMed DOI PMC

Alotaibi F, et al. Type I interferon autoantibodies in hospitalized patients with Middle East respiratory syndrome and association with outcomes and treatment effect of interferon beta‐1b in MIRACLE clinical trial. Influenza Other Respir. Viruses. 2023;17:e13116. doi: 10.1111/irv.13116. PubMed DOI PMC

Gervais A, et al. Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in ∼40% of patients. J. Exp. Med. 2023;220:e20230661. doi: 10.1084/jem.20230661. PubMed DOI PMC

van der Wijst MGP, et al. Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19. Sci. Transl. Med. 2021;13:eabh2624. doi: 10.1126/scitranslmed.abh2624. PubMed DOI PMC

Lopez J, et al. Early nasal type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs. J. Exp. Med. 2021;218:e20211211. doi: 10.1084/jem.20211211. PubMed DOI PMC

Cheng M, Anderson MS. Thymic tolerance as a key brake on autoimmunity. Nat. Immunol. 2018;19:659–664. doi: 10.1038/s41590-018-0128-9. PubMed DOI PMC

Anderson MS, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002;298:1395–1401. doi: 10.1126/science.1075958. PubMed DOI

Cavadini P, et al. AIRE deficiency in thymus of 2 patients with Omenn syndrome. J. Clin. Invest. 2005;115:728–732. doi: 10.1172/JCI200523087. PubMed DOI PMC

Poliani PL, et al. Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome. Blood. 2009;114:105–108. doi: 10.1182/blood-2009-03-211029. PubMed DOI PMC

De Ravin SS, et al. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood. 2010;116:1263–1271. doi: 10.1182/blood-2010-02-267583. PubMed DOI PMC

Hetemäki I, et al. Patients with autoimmune polyendocrine syndrome type 1 have an increased susceptibility to severe herpesvirus infections. Clin. Immunol. 2021;231:108851. doi: 10.1016/j.clim.2021.108851. PubMed DOI PMC

Rossi SW, et al. RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 2007;204:1267–1272. doi: 10.1084/jem.20062497. PubMed DOI PMC

White AJ, et al. Sequential phases in the development of Aire-expressing medullary thymic epithelial cells involve distinct cellular input. Eur. J. Immunol. 2008;38:942–947. doi: 10.1002/eji.200738052. PubMed DOI

Akiyama T, et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity. 2008;29:423–437. doi: 10.1016/j.immuni.2008.06.015. PubMed DOI

Sun S-C. The non-canonical NF-κB pathway in immunity and inflammation. Nat. Rev. Immunol. 2017;17:545–558. doi: 10.1038/nri.2017.52. PubMed DOI PMC

Fusco AJ, et al. The NF-κB subunit RelB controls p100 processing by competing with the kinases NIK and IKK1 for binding to p100. Sci. Signal. 2016;9:ra96. doi: 10.1126/scisignal.aad9413. PubMed DOI

Hogquist KA, Baldwin TA, Jameson SC. Central tolerance: learning self-control in the thymus. Nat. Rev. Immunol. 2005;5:772–782. doi: 10.1038/nri1707. PubMed DOI

Burkly L, et al. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature. 1995;373:531–536. doi: 10.1038/373531a0. PubMed DOI

Wirasinha RC, et al. Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility. J. Exp. Med. 2021;218:e20200476. doi: 10.1084/jem.20200476. PubMed DOI PMC

Bautista JL, et al. Single-cell transcriptional profiling of human thymic stroma uncovers novel cellular heterogeneity in the thymic medulla. Nat. Commun. 2021;12:1096. doi: 10.1038/s41467-021-21346-6. PubMed DOI PMC

Tucker E, et al. A novel mutation in the Nfkb2 gene generates an NF-κB2 “super repressor”. J. Immunol. 2007;179:7514–7522. doi: 10.4049/jimmunol.179.11.7514. PubMed DOI

Jiang W, Anderson MS, Bronson R, Mathis D, Benoist C. Modifier loci condition autoimmunity provoked by Aire deficiency. J. Exp. Med. 2005;202:805–815. doi: 10.1084/jem.20050693. PubMed DOI PMC

Michelson DA, Hase K, Kaisho T, Benoist C, Mathis D. Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells. Cell. 2022;185:2542–2558. doi: 10.1016/j.cell.2022.05.018. PubMed DOI PMC

Michelson DA, Mathis D. Thymic mimetic cells: tolerogenic masqueraders. Trends Immunol. 2022;43:782–791. doi: 10.1016/j.it.2022.07.010. PubMed DOI PMC

Yano M, et al. Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. J. Exp. Med. 2008;205:2827–2838. doi: 10.1084/jem.20080046. PubMed DOI PMC

Bornstein C, et al. Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells. Nature. 2018;559:622–626. doi: 10.1038/s41586-018-0346-1. PubMed DOI

Kinoshita D, et al. Essential role of IκB kinase α in thymic organogenesis required for the establishment of self-tolerance1. J. Immunol. 2006;176:3995–4002. doi: 10.4049/jimmunol.176.7.3995. PubMed DOI

Kajiura F, et al. NF-κB-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J. Immunol. 2004;172:2067–2075. doi: 10.4049/jimmunol.172.4.2067. PubMed DOI

LaFlam TN, et al. Identification of a novel cis-regulatory element essential for immune tolerance. J. Exp. Med. 2015;212:1993–2002. doi: 10.1084/jem.20151069. PubMed DOI PMC

Koh AS, et al. Rapid chromatin repression by Aire provides precise control of immune tolerance. Nat. Immunol. 2018;19:162–172. doi: 10.1038/s41590-017-0032-8. PubMed DOI PMC

Kisand K, et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 2010;207:299–308. doi: 10.1084/jem.20091669. PubMed DOI PMC

Puel A, et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 2010;207:291–297. doi: 10.1084/jem.20091983. PubMed DOI PMC

Meyer S, et al. AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell. 2016;166:582–595. doi: 10.1016/j.cell.2016.06.024. PubMed DOI PMC

Landegren N, et al. Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1. Sci. Rep. 2016;6:20104. doi: 10.1038/srep20104. PubMed DOI PMC

Wang EY, et al. High-throughput identification of autoantibodies that target the human exoproteome. Cell Rep. Methods. 2022;2:100172. PubMed PMC

Bruserud Ø, et al. A longitudinal follow-up of autoimmune polyendocrine syndrome type 1. J. Clin. Endocrinol. Metab. 2016;101:2975–2983. doi: 10.1210/jc.2016-1821. PubMed DOI PMC

Ströbel P, et al. Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1) J. Pathol. 2007;211:563–571. doi: 10.1002/path.2141. PubMed DOI

Givony, T. et al. Thymic mimetic cells function beyond self-tolerance. Nature622, 164–172 (2023). PubMed

Weih F, Caamaño J. Regulation of secondary lymphoid organ development by the nuclear factor-κB signal transduction pathway. Immunol. Rev. 2003;195:91–105. doi: 10.1034/j.1600-065X.2003.00064.x. PubMed DOI

Perry JSA, et al. Distinct contributions of aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity. 2014;41:414–426. doi: 10.1016/j.immuni.2014.08.007. PubMed DOI PMC

Malchow S, et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science. 2013;339:1219–1224. doi: 10.1126/science.1233913. PubMed DOI PMC

Mathian, A. et al. Lower disease activity but higher risk of severe COVID-19 and herpes zoster in patients with systemic lupus erythematosus with pre-existing autoantibodies neutralising IFN-α. Ann. Rheum. Dis.10.1136/ard-2022-222549 (2022). PubMed

Meisel C, et al. Mild COVID-19 despite autoantibodies against type I IFNs in autoimmune polyendocrine syndrome type 1. J. Clin. Invest. 2021;131:e150867. doi: 10.1172/JCI150867. PubMed DOI PMC

Kuehn HS, et al. Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype. Blood. 2017;130:1553–1564. doi: 10.1182/blood-2017-05-782177. PubMed DOI PMC

Willmann KL, et al. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nat. Commun. 2014;5:5360. doi: 10.1038/ncomms6360. PubMed DOI PMC

Warnatz K, et al. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc. Natl Acad. Sci. USA. 2009;106:13945–13950. doi: 10.1073/pnas.0903543106. PubMed DOI PMC

Sharfe N, et al. The effects of RelB deficiency on lymphocyte development and function. J. Autoimmun. 2015;65:90–100. doi: 10.1016/j.jaut.2015.09.001. PubMed DOI

Merico D, Sharfe N, Hu P, Herbrick J-A, Roifman CM. RelB deficiency causes combined immunodeficiency. LymphoSign J. 2015;2:147–155. doi: 10.14785/lpsn-2015-0005. DOI

Sharfe, N. et al. NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity. J. Autoimmun.10.1016/j.jaut.2022.102946 (2022). PubMed PMC

Tangye, S. G. et al. Human inborn errors of immunity: 2022 update on the classification from the international union of immunological societies expert committee. J. Clin. Immunol.10.1007/s10875-022-01289-3 (2022). PubMed PMC

Zhang, Q. et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science10.1126/science.abd4570 (2020). PubMed PMC

Li J, et al. Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency. J. Exp. Med. 2021;218:e20210566. doi: 10.1084/jem.20210566. PubMed DOI PMC

Vazquez SE, et al. Identification of novel, clinically correlated autoantigens in the monogenic autoimmune syndrome APS1 by proteome-wide PhIP-Seq. eLife. 2020;9:e55053. doi: 10.7554/eLife.55053. PubMed DOI PMC

Abolhassani H, et al. X-linked TLR7 deficiency underlies critical COVID-19 pneumonia in a male patient with ataxia-telangiectasia. J. Clin. Immunol. 2022;42:1–9. doi: 10.1007/s10875-021-01151-y. PubMed DOI PMC

Pescarmona R, et al. Comparison of RT-qPCR and Nanostring in the measurement of blood interferon response for the diagnosis of type I interferonopathies. Cytokine. 2019;113:446–452. doi: 10.1016/j.cyto.2018.10.023. PubMed DOI

Slade CA, et al. Fatal enteroviral encephalitis in a patient with common variable immunodeficiency harbouring a novel mutation in NFKB2. J. Clin. Immunol. 2019;39:324–335. doi: 10.1007/s10875-019-00602-x. PubMed DOI

Miller CN, et al. Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. Nature. 2018;559:627–631. doi: 10.1038/s41586-018-0345-2. PubMed DOI PMC

Rackaityte, E. et al. Validation of a murine proteome-wide phage display library for the identification of autoantibody specificities. Preprint at bioRxiv10.1101/2023.04.07.535899 (2023). PubMed PMC

Altman MC, et al. Development of a fixed module repertoire for the analysis and interpretation of blood transcriptome data. Nat. Commun. 2021;12:4385. doi: 10.1038/s41467-021-24584-w. PubMed DOI PMC

Autoantibodies neutralizing type I IFNs underlie severe tick-borne encephalitis in ∼10% of patients