Article Dans Une Revue New England Journal of Medicine Année : 2024

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

Vasileios Oikonomou (1) , Grace Smith (1) , Gregory Constantine (1) , Monica Schmitt (1) , Elise M.N. Ferré (1) , Julie Alejo (1) , Deanna Riley (1) , Dhaneshwar Kumar (1) , Lucas dos Santos Dias (1) , Joseph Pechacek (1) , Yannis Hadjiyannis (1) , Taura Webb (1) , Bryce Seifert (1) , Rajarshi Ghosh (1) , Magdalena Walkiewicz (1) , Daniel Martin (1) , Marine Besnard (2, 3) , Brendan Snarr (1) , Shiva Deljookorani (1) , Chyi-Chia Lee (1) , Tom Dimaggio (1) , Princess Barber (1) , Lindsey Rosen (1) , Aristine Cheng (1) , Andre Rastegar (1) , Adriana de Jesus (1) , Jennifer Stoddard (1) , Hye Sun Kuehn (1) , Timothy Break (1) , Heidi Kong (1) , Leslie Castelo-Soccio (1) , Ben Colton (1) , Blake Warner (1) , David Kleiner (1) , Martha Quezado (1) , Jeremy Davis (1) , Kevin Fennelly (1) , Kenneth Olivier (1) , Sergio Rosenzweig (1) , Anthony Suffredini (1) , Mark Anderson (4) , Marc Swidergall (5, 6) , Carole Guillonneau (2, 3) , Luigi Notarangelo (1) , Raphaela Goldbach-Mansky (1) , Olaf Neth (7, 8) , Maria Teresa Monserrat-Garcia (7, 8) , Justo Valverde-Fernandez (8, 7) , Jose Manuel Lucena (8, 7) , Ana Lucia Gomez-Gila (8, 7) , Angela Garcia Rojas (7, 8) , Mikko Seppänen (9, 10) , Jouko Lohi (9, 10) , Matti Hero (10, 9) , Saila Laakso (10, 9) , Paula Klemetti (9, 10) , Vanja Lundberg (11) , Olov Ekwall (11) , Peter Olbrich (7, 8) , Karen Winer (1) , Behdad Afzali (1) , Niki Moutsopoulos (1) , Steven Holland (1) , Theo Heller (1) , Stefania Pittaluga (1) , Michail Lionakis (1)

Résumé

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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inserm-04676012 , version 1 (23-08-2024)

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Vasileios Oikonomou, Grace Smith, Gregory Constantine, Monica Schmitt, Elise M.N. Ferré, et al.. The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1. New England Journal of Medicine, 2024, 390 (20), pp.1873-1884. ⟨10.1056/NEJMoa2312665⟩. ⟨inserm-04676012⟩
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