• Vasileios Oikonomou, Grace Smith, Gregory M Constantine, Monica M Schmitt, Elise M N Ferré, Julie C Alejo, Deanna Riley, Dhaneshwar Kumar, Lucas Dos Santos Dias, Joseph Pechacek, Yannis Hadjiyannis, Taura Webb, Bryce A Seifert, Rajarshi Ghosh, Magdalena Walkiewicz, Daniel Martin, Marine Besnard, Brendan D Snarr, Shiva Deljookorani, LeeChyi-Chia RCRFrom the Fungal Pathogenesis (V.O., G.M.C., M.M.S., E.M.N.F., L.D.S.D., J.P., Y.H., T.W., B.D.S., S.D., T.D., P.B., T.J.B., M.S.L.), the Immunopathogenesis (L.B.R., A.C., S.M.H.), and Immune Deficiency Genetics (L.D.N.) Sections, Laborator, Tom DiMaggio, Princess Barber, Lindsey B Rosen, Aristine Cheng, Andre Rastegar, Adriana A de Jesus, Jennifer Stoddard, Hye Sun Kuehn, Timothy J Break, Heidi H Kong, Leslie Castelo-Soccio, Ben Colton, Blake M Warner, David E Kleiner, Martha M Quezado, Jeremy L Davis, Kevin P Fennelly, Kenneth N Olivier, Sergio D Rosenzweig, Anthony F Suffredini, Mark S Anderson, Marc Swidergall, Carole Guillonneau, Luigi D Notarangelo, Raphaela Goldbach-Mansky, Olaf Neth, Maria Teresa Monserrat-Garcia, Justo Valverde-Fernandez, Jose Manuel Lucena, Ana Lucia Gomez-Gila, Angela Garcia Rojas, Mikko R J Seppänen, Jouko Lohi, Matti Hero, Saila Laakso, Paula Klemetti, Vanja Lundberg, Olov Ekwall, Peter Olbrich, Karen K Winer, Behdad Afzali, Niki M Moutsopoulos, Steven M Holland, Theo Heller, Stefania Pittaluga, and Michail S Lionakis.
• From the Fungal Pathogenesis (V.O., G.M.C., M.M.S., E.M.N.F., L.D.S.D., J.P., Y.H., T.W., B.D.S., S.D., T.D., P.B., T.J.B., M.S.L.), the Immunopathogenesis (L.B.R., A.C., S.M.H.), and Immune Deficiency Genetics (L.D.N.) Sections, Laboratory of Clinical Immunology and Microbiology, the Centralized Sequencing Program, Division of Intramural Research (B.A.S., R.G., M.W.), and the Translational Autoinflammatory Disease Section (A.R., A.A.J., R.G.-M.), National Institute of Allergy and Infectious Diseases, the Laboratory of Pathology, Center for Cancer Research (J.L.D.), National Cancer Institute (G.S., J.C.A., D.R., C.R.L., D.E.K., M.M.Q., S.P.), the Immunoregulation Section, Kidney Diseases Branch (D.K., B.A.), and the Translational Hepatology Section, Liver Diseases Branch (T.H.), National Institute of Diabetes and Digestive and Kidney Diseases, the Genomics and Computational Biology Core (D.M.), the Salivary Disorders Unit (B.M.W.), and the Oral Immunity and Inflammation Section (N.M.M.), National Institute of Dental and Craniofacial Research, the Immunology Service, Department of Laboratory Medicine (J.S., H.S.K., S.D.R.), the Pharmacy Department (B.C.), and the Critical Care Medicine Department (A.F.S.), Clinical Center, the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., L.C.-S.), the Pulmonary Branch, National Heart, Lung, and Blood Institute (K.P.F., K.N.O.), and Eunice Kennedy Shriver National Institute of Child Health and Human Development (K.K.W.) - all at the National Institutes of Health, Bethesda, MD; Nantes Université, Centre Hospitalier Universitaire Nantes, INSERM, Centre de Recherche en Transplantation et Immunologie, Unité Mixte de Recherche 1064, Institut de Transplantation Urologie-Néphrologie, Nantes, France (M.B., C.G.); the Diabetes Center, University of California at San Francisco, San Francisco (M.S.A.), the Division of Infectious Diseases and the Lundquist Institute for Biomedical Innovation, Harbor-University of California, Los Angeles (UCLA), Medical Center, Torrance (M.S.), and the David Geffen School of Medicine, UCLA, Los Angeles (M.S.); Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla/Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Red de Investigación Translacional en Infectología Pediátrica (O.N., P.O.), and Departamento de Dermatología (M.T.M.-G.), Sección de Gastroenterología, Hepatología y Nutrición Pediatrica (J.V.-F.), Sección de Inmunología (J.M.L.), Sección de Endocrinología Pediátrica (A.L.G.-G.), and Sección de Nefrología Pediátrica (A.G.R.), Hospital Infantil Universitario Virgen del Rocío, and Departamento de Farmacología, Pediatría, y Radiología, Facultad de Medicina, Universidad de Sevilla (P.O.) - all in Seville, Spain; the University of Helsinki and Helsinki University Hospital, New Children's Hospital, Pediatric Research Center, Helsinki (M.R.J.S., J.L., M.H., S.L., P.K.); and the Department of Pediatrics, Institute of Clinical Sciences, and the Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (V.L., O.E.).
• N. Engl. J. Med. 2024 May 30; 390 (20): 187318841873-1884.

BackgroundAutoimmune 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.MethodsWe 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.ResultsPatients 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.ConclusionsOur 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.).Copyright © 2024 Massachusetts Medical Society.

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