The Role of Interferon-γin Autoimmune Polyendocrine Syndrome Type 1

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, Chyi Chia R. LeeTom 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, Michail S. Lionakis

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review


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-γusing 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-γresponses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γproduction 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-γresponses 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-γand 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.

TidskriftNew England Journal of Medicine
Sidor (från-till)1873-1884
Antal sidor12
StatusPublicerad - 30 maj 2024
MoE-publikationstypA1 Tidskriftsartikel-refererad

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© 2024 Massachusetts Medical Society.


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