The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.

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Oikonomou, Vasileios (author)

The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.

Article/chapterEnglish2024

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2024

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LIBRIS-ID:oai:gup.ub.gu.se/338274
https://gup.ub.gu.se/publication/338274URI
https://doi.org/10.1056/NEJMoa2312665DOI

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Language:English

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SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood.We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses.Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients.Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Pediatrik hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Pediatrics hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Immunologi inom det medicinska området hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Immunology in the medical area hsv//eng
Polyendocrinopathies
Autoimmune
genetics
drug therapy
immunology
Interferon-gamma
metabolism
genetics
Humans
Animals
Nitriles
therapeutic use
Mice
Pyrazoles
therapeutic use
pharmacology
Pyrimidines
therapeutic use
Transcription Factors
genetics
AIRE Protein
Female
Male
Mice
Knockout
Adult
Chemokine CXCL9
genetics
Autoantibodies
blood
T-Lymphocytes
immunology
Janus Kinase Inhibitors
therapeutic use

Added entries (persons, corporate bodies, meetings, titles ...)

Smith, Grace (author)
Constantine, Gregory M (author)
Schmitt, Monica M (author)
Ferré, Elise M N (author)
Alejo, Julie C (author)
Riley, Deanna (author)
Kumar, Dhaneshwar (author)
Dos Santos Dias, Lucas (author)
Pechacek, Joseph (author)
Hadjiyannis, Yannis (author)
Webb, Taura (author)
Seifert, Bryce A (author)
Ghosh, Rajarshi (author)
Walkiewicz, Magdalena (author)
Martin, Daniel (author)
Besnard, Marine (author)
Snarr, Brendan D (author)
Deljookorani, Shiva (author)
Lee, Chyi-Chia R (author)
DiMaggio, Tom (author)
Barber, Princess (author)
Rosen, Lindsey B (author)
Cheng, Aristine (author)
Rastegar, Andre (author)
de Jesus, Adriana A (author)
Stoddard, Jennifer (author)
Kuehn, Hye Sun (author)
Break, Timothy J (author)
Kong, Heidi H (author)
Castelo-Soccio, Leslie (author)
Colton, Ben (author)
Warner, Blake M (author)
Kleiner, David E (author)
Quezado, Martha M (author)
Davis, Jeremy L (author)
Fennelly, Kevin P (author)
Olivier, Kenneth N (author)
Rosenzweig, Sergio D (author)
Suffredini, Anthony F (author)
Anderson, Mark S (author)
Swidergall, Marc (author)
Guillonneau, Carole (author)
Notarangelo, Luigi D (author)
Goldbach-Mansky, Raphaela (author)
Neth, Olaf (author)
Monserrat-Garcia, Maria Teresa (author)
Valverde-Fernandez, Justo (author)
Lucena, Jose Manuel (author)
Gomez-Gila, Ana Lucia (author)
Garcia Rojas, Angela (author)
Seppänen, Mikko R J (author)
Lohi, Jouko (author)
Hero, Matti (author)
Laakso, Saila (author)
Klemetti, Paula (author)
Lundberg, VanjaGothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Clinical Sciences, Department of Pediatrics,Institute of Medicine, Department of Rheumatology and Inflammation Research(Swepub:gu)xlunva (author)
Ekwall, Olov,1968Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institute of Medicine, Department of Rheumatology and Inflammation Research,Institute of Clinical Sciences, Department of Pediatrics(Swepub:gu)xekwol (author)
Olbrich, Peter (author)
Winer, Karen K (author)
Afzali, Behdad (author)
Moutsopoulos, Niki M (author)
Holland, Steven M (author)
Heller, Theo (author)
Pittaluga, Stefania (author)
Lionakis, Michail S (author)
Göteborgs universitetInstitutionen för kliniska vetenskaper, Avdelningen för pediatrik (creator_code:org_t)

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In:The New England journal of medicine390:20, s. 1873-18841533-4406

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By the author/editor: Oikonomou, Vasil ...; Smith, Grace; Constantine, Gre ...; Schmitt, Monica ...; Ferré, Elise M N; Alejo, Julie C; show more...; Riley, Deanna; Kumar, Dhaneshwa ...; Dos Santos Dias, ...; Pechacek, Joseph; Hadjiyannis, Yan ...; Webb, Taura; Seifert, Bryce A; Ghosh, Rajarshi; Walkiewicz, Magd ...; Martin, Daniel; Besnard, Marine; Snarr, Brendan D; Deljookorani, Sh ...; Lee, Chyi-Chia R; DiMaggio, Tom; Barber, Princess; Rosen, Lindsey B; Cheng, Aristine; Rastegar, Andre; de Jesus, Adrian ...; Stoddard, Jennif ...; Kuehn, Hye Sun; Break, Timothy J; Kong, Heidi H; Castelo-Soccio, ...; Colton, Ben; Warner, Blake M; Kleiner, David E; Quezado, Martha ...; Davis, Jeremy L; Fennelly, Kevin ...; Olivier, Kenneth ...; Rosenzweig, Serg ...; Suffredini, Anth ...; Anderson, Mark S; Swidergall, Marc; Guillonneau, Car ...; Notarangelo, Lui ...; Goldbach-Mansky, ...; Neth, Olaf; Monserrat-Garcia ...; Valverde-Fernand ...; Lucena, Jose Man ...; Gomez-Gila, Ana ...; Garcia Rojas, An ...; Seppänen, Mikko ...; Lohi, Jouko; Hero, Matti; Laakso, Saila; Klemetti, Paula; Lundberg, Vanja; Ekwall, Olov, 19 ...; Olbrich, Peter; Winer, Karen K; Afzali, Behdad; Moutsopoulos, Ni ...; Holland, Steven ...; Heller, Theo; Pittaluga, Stefa ...; Lionakis, Michai ...; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Pediatrics

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Immunology in th ...

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