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

免疫学 医学
作者
Vasileios Oikonomou,Grace Smith,Gregory 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,Chyi-Chia R Lee,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 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,Michail S. Lionakis
出处
期刊:The New England Journal of Medicine [New England Journal of Medicine]
卷期号:390 (20): 1873-1884 被引量:15
标识
DOI:10.1056/nejmoa2312665
摘要

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.)
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