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

• Published in: The New England journal of medicine Vol. 390; no. 20; pp. 1873 - 1884
• Main Authors: Oikonomou, Vasileios, Smith, Grace, Constantine, Gregory, Schmitt, Monica, Ferré, Elise M.N., Alejo, Julie, Riley, Deanna, Kumar, Dhaneshwar, dos Santos Dias, Lucas, Pechacek, Joseph, Hadjiyannis, Yannis, Webb, Taura, Seifert, Bryce, Ghosh, Rajarshi, Walkiewicz, Magdalena, Martin, Daniel, Besnard, Marine, Snarr, Brendan, Deljookorani, Shiva, Lee, Chyi-Chia, Dimaggio, Tom, Barber, Princess, Rosen, Lindsey, Cheng, Aristine, Rastegar, Andre, de Jesus, Adriana, Stoddard, Jennifer, Kuehn, Hye Sun, Break, Timothy, Kong, Heidi, Castelo-Soccio, Leslie, Colton, Ben, Warner, Blake, Kleiner, David, Quezado, Martha, Davis, Jeremy, Fennelly, Kevin, Olivier, Kenneth, Rosenzweig, Sergio, Suffredini, Anthony, Anderson, Mark, Swidergall, Marc, Guillonneau, Carole, Notarangelo, Luigi, Goldbach-Mansky, Raphaela, Neth, Olaf, Monserrat-Garcia, Maria Teresa, Valverde-Fernandez, Justo, Lucena, Jose Manuel, Gomez-Gila, Ana Lucia, Garcia Rojas, Angela, Seppänen, Mikko, Lohi, Jouko, Hero, Matti, Laakso, Saila, Klemetti, Paula, Lundberg, Vanja, Ekwall, Olov, Olbrich, Peter, Winer, Karen, Afzali, Behdad, Moutsopoulos, Niki, Holland, Steven, Heller, Theo, Pittaluga, Stefania, Lionakis, Michail
• Format: Journal Article
• Language: English
• Published: Massachusetts Medical Society 30.05.2024
• Subjects: Adolescent; Adult; AIRE Protein / deficiency; AIRE Protein / genetics; AIRE Protein / immunology; Animals; Autoantibodies / blood; Autoantibodies / immunology; Chemokine CXCL9 / genetics; Child; Disease Models, Animal; Female; Humans; Interferon-gamma / genetics; Interferon-gamma / immunology; Janus Kinase Inhibitors / therapeutic use; Life Sciences; Male; Mice; Mice, Knockout; Middle Aged; Nitriles / therapeutic use; Pilot Projects; Polyendocrinopathies, Autoimmune / drug therapy; Polyendocrinopathies, Autoimmune / genetics; Polyendocrinopathies, Autoimmune / immunology; Pyrazoles / pharmacology; Pyrazoles / therapeutic use; Pyrimidines / therapeutic use; T-Lymphocytes / immunology; Transcription Factors / genetics; Transcription Factors / immunology
• ISSN: 0028-4793; 1533-4406
• DOI: 10.1056/NEJMoa2312665

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.).