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. 2024 May 30;390(20):1873-1884.
doi: 10.1056/NEJMoa2312665.

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

Vasileios Oikonomou  1 Grace Smith  1 Gregory M Constantine  1 Monica M Schmitt  1 Elise M N Ferré  1 Julie C Alejo  1 Deanna Riley  1 Dhaneshwar Kumar  1 Lucas Dos Santos Dias  1 Joseph Pechacek  1 Yannis Hadjiyannis  1 Taura Webb  1 Bryce A Seifert  1 Rajarshi Ghosh  1 Magdalena Walkiewicz  1 Daniel Martin  1 Marine Besnard  1 Brendan D Snarr  1 Shiva Deljookorani  1 Chyi-Chia R Lee  1 Tom DiMaggio  1 Princess Barber  1 Lindsey B Rosen  1 Aristine Cheng  1 Andre Rastegar  1 Adriana A de Jesus  1 Jennifer Stoddard  1 Hye Sun Kuehn  1 Timothy J Break  1 Heidi H Kong  1 Leslie Castelo-Soccio  1 Ben Colton  1 Blake M Warner  1 David E Kleiner  1 Martha M Quezado  1 Jeremy L Davis  1 Kevin P Fennelly  1 Kenneth N Olivier  1 Sergio D Rosenzweig  1 Anthony F Suffredini  1 Mark S Anderson  1 Marc Swidergall  1 Carole Guillonneau  1 Luigi D Notarangelo  1 Raphaela Goldbach-Mansky  1 Olaf Neth  1 Maria Teresa Monserrat-Garcia  1 Justo Valverde-Fernandez  1 Jose Manuel Lucena  1 Ana Lucia Gomez-Gila  1 Angela Garcia Rojas  1 Mikko R J Seppänen  1 Jouko Lohi  1 Matti Hero  1 Saila Laakso  1 Paula Klemetti  1 Vanja Lundberg  1 Olov Ekwall  1 Peter Olbrich  1 Karen K Winer  1 Behdad Afzali  1 Niki M Moutsopoulos  1 Steven M Holland  1 Theo Heller  1 Stefania Pittaluga  1 Michail S Lionakis  1
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The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1

Vasileios Oikonomou et al. N Engl J Med. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.).

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