Abel L

Abraham RS

Aladjidi N

Anderson MS

Aranda-Guillen M

Arango-Franco CA

Astudillo C

Atschekzei F

Ballot E

Barlogis V

Bastard P

Belot A

Bengi Celik J

Berrios DI

Berteloot L

Beziat V

Bizien L

Bohlen J

Boisson B

Boisson-Dupuis S

Bosticardo M

Boztug K

Bryant VL

Bustamante J

Caluseriu O

Casanova J-L

Castagnoli R

Cederholm A

Celmeli F

Charuel J-L

Ciznar P

Cobat A

Cunningham-Rundles C

Dalal I

Delmonte OM

DeRisi JL

Doffinger R

Droney L

Ducoux G

Emiroglu M

Eriksson D

Feng Y

Fieschi C

Franco Gallego WA

Franco J

Freiberger T

Frosk P

Gervais A

Ghillani-Dalbin P

Goodnow CC

Gray PE

Grimbacher B

Grombirikova H

Gueye MS

Guffroy A

Guichard A

Hancioglu G

Hauck F

Herrmann V-M

Hie M

Holland SM

Hu H

Ikinciogullari A

Imberti L

Jouanguy E

Kampe O

Kane A

Katelaris CH

Keles S

Keller B

Keller MD

Kenney H

Kuehn HS

Kuijpers T

Lafarge G

Landegren N

Latour S

Lazaro E

Le Guenno G

Le Voyer T

Levy R

Licciardi F

Liu X

Lougaris V

Ma C

Maccari ME

Maglorius Renkilaraj MRL

Mahlaoui N

Malphettes M

McLean C

Meinhardt A

Migaud M

Miller C

Miyara M

Momenilandi M

Muller G

Mustillo P

Neven B

Nguyen T

Notarangelo LD

English

\ua9 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

Parent AV

Rosain J

Perez Lorenzo M

Rackaityte E

Rinchai D

Zhang P

Philippot Q

Ogishi M

Soudee C

Rozenberg F

Riller Q

Orrego J

Rubin T

Parvaneh N

Vong L

Raedler J

Winter S

Oksenhendler E

Okada S

Ursini MV

Yu D

Pan-Hammarstrom Q

Zhang Y

Rosen LB

Slade CA

Sediva A

Sogkas G

Poli MC

Slatter MA

Palterer B

Pinzon-Charry A

Sullivan A

Suan D

Wong M

Newcastle University E-Prints

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

https://eprints.ncl.ac.uk/file_store/production/294896/46F4D37B-D65C-4ECB-AAB3-F07D494EB1FD.pdf

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

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