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Lookup NU author(s): Professor Mary Slatter
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, The Author(s). 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.
Author(s): Le Voyer T, Parent AV, Liu X, Cederholm A, Gervais A, Rosain J, Nguyen T, Perez Lorenzo M, Rackaityte E, Rinchai D, Zhang P, Bizien L, Hancioglu G, Ghillani-Dalbin P, Charuel J-L, Philippot Q, Gueye MS, Maglorius Renkilaraj MRL, Ogishi M, Soudee C, Migaud M, Rozenberg F, Momenilandi M, Riller Q, Imberti L, Delmonte OM, Muller G, Keller B, Orrego J, Franco Gallego WA, Rubin T, Emiroglu M, Parvaneh N, Eriksson D, Aranda-Guillen M, Berrios DI, Vong L, Katelaris CH, Mustillo P, Raedler J, Bohlen J, Bengi Celik J, Astudillo C, Winter S, Boisson-Dupuis S, Oksenhendler E, Okada S, Caluseriu O, Ursini MV, Ballot E, Lafarge G, Freiberger T, Arango-Franco CA, Levy R, McLean C, Guffroy A, DeRisi JL, Yu D, Miller C, Feng Y, Guichard A, Beziat V, Bustamante J, Pan-Hammarstrom Q, Zhang Y, Rosen LB, Holland SM, Bosticardo M, Kenney H, Castagnoli R, Slade CA, Boztug K, Mahlaoui N, Latour S, Abraham RS, Lougaris V, Hauck F, Sediva A, Atschekzei F, Sogkas G, Poli MC, Slatter MA, Palterer B, Keller MD, Pinzon-Charry A, Sullivan A, Droney L, Suan D, Wong M, Kane A, Hu H, Ma C, Grombirikova H, Ciznar P, Dalal I, Aladjidi N, Hie M, Lazaro E, Franco J, Keles S, Malphettes M, Pasquet M, Maccari ME, Meinhardt A, Ikinciogullari A, Shahrooei M, Celmeli F, Frosk P, Goodnow CC, Gray PE, Belot A, Kuehn HS, Rosenzweig SD, Miyara M, Licciardi F, Servettaz A, Barlogis V, Le Guenno G, Herrmann V-M, Kuijpers T, Ducoux G, Sarrot-Reynauld F, Schuetz C, Cunningham-Rundles C, Rieux-Laucat F, Tangye SG, Sobacchi C, Doffinger R, Warnatz K, Grimbacher B, Fieschi C, Berteloot L, Bryant VL, Trouillet Assant S, Su H, Neven B, Abel L, Zhang Q, Boisson B, Cobat A, Jouanguy E, Kampe O, Bastard P, Roifman CM, Landegren N, Notarangelo LD, Anderson MS, Casanova J-L, Puel A
Publication type: Article
Publication status: Published
Journal: Nature
Year: 2023
Volume: 623
Pages: 803-813
Print publication date: 23/11/2023
Online publication date: 08/11/2023
Acceptance date: 04/10/2023
Date deposited: 22/11/2023
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Research
URL: https://doi.org/10.1038/s41586-023-06717-x
DOI: 10.1038/s41586-023-06717-x
Data Access Statement: All the data supporting the findings of this study are available within the Article and its Supplementary Information. The gel source data are shown in Supplementary Fig. 1. The RNA-seq data generated in this study have been deposited in the NCBI database under NCBI-SRA project PRJNA989123. All the other data and material supporting the findings of this study are available under a data transfer agreement from the corresponding authors on reasonable request. Source data are provided with this paper.
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