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 pneumonia 3 . Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-kappa B2 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-kappa B2 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 (I kappa B delta activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of I kappa B delta (hereafter, p52LOF/I kappa B delta 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, p52LOF/I kappa B delta LOF) or gain-of-function of p52 (hereafter, p52GOF/I kappa B delta LOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-kappa B2 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-kappa B 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.|Inborn errors of the alternative NF-kappa B pathway in humans 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
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Title
Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency
Grant
Howard Hughes Medical Institute Rockefeller University St Giles Foundation National Institutes of Health (NIH): R01AI088364 National Center for Advancing Translational Sciences (NCATS) NIH Clinical and Translational Science Award (CTSA) programme: UL1 TR001866 Fisher Center for Alzheimer's Research Foundation Meyer Foundation JBP Foundation French National Research Agency (ANR) under the 'Investments for the Future' programme: ANR-10-IAHU-01 Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence: ANR-10-LABX-62-IBEID French Foundation for Medical Research (FRM): EQU201903007798 ANRS-COV05 ANR GENVIR: ANR-20-CE93-003 ANR AABIFNCOV: ANR-20-CO11-0001 ANR AAILC: ANR-21-LIBA-0002 ANR AI2D: ANR-22-CE15-0046 ANR-RHU programme: ANR-21-RHUS-08-COVIFERON European Union: 824110 HORIZON-HLTH-2021-DISEASE-04 programme: 01057100 Square Foundation Grandir-Fonds de solidarite pour l'enfance, the Fondation du Souffle SCOR Corporate Foundation for Science Battersea & Bowery Advisory Group French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19) Institut National de la Sante et de la Recherche Medicale (INSERM) Paris Cite University MD-PhD programme of Imagine InstitutePoste CCA-INSERM-Bettencourt Assistance Publique Hopitaux de Paris INSERM David Rockefeller Graduate Program Funai Foundation for Information Technology (FFIT) Honjo International Scholarship Foundation (HISF) New York Hideyo Noguchi Memorial Society (HNMS) Swedish Research Council and the Goeran Gustafsson Foundation Bundesministerium fur Bildung und Forschung: GAIN 01GM1910A Swedish Research Council Knut and Alice Wallenberg Foundation Else Kroner-Fresenius Stiftung (EKFS): 2017_A110 German Federal Ministry of Education and Research (BMBF): 01GM1910C Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health National Health and Medical Research Council of Australia Jeffrey Modell Foundation John Brown Cook Foundation ANRS Maladies infectieuses emergentes: ECTZ173053 German Center for Infection Research: DZIF TTU 07.801