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