Oikonomou, VasileiosVasileiosOikonomouSmith, GraceGraceSmithConstantine, Gregory MGregory MConstantineSchmitt, Monica MMonica MSchmittFerré, Elise M NElise M NFerréAlejo, Julie CJulie CAlejoRiley, DeannaDeannaRileyKumar, DhaneshwarDhaneshwarKumarDos Santos Dias, LucasLucasDos Santos DiasPechacek, JosephJosephPechacekHadjiyannis, YannisYannisHadjiyannisWebb, TauraTauraWebbSeifert, Bryce ABryce ASeifertGhosh, RajarshiRajarshiGhoshWalkiewicz, MagdalenaMagdalenaWalkiewiczMartin, DanielDanielMartinBesnard, MarineMarineBesnardSnarr, Brendan DBrendan DSnarrDeljookorani, ShivaShivaDeljookoraniLee, Chyi-Chia RChyi-Chia RLeeDiMaggio, TomTomDiMaggioBarber, PrincessPrincessBarberRosen, Lindsey BLindsey BRosenARISTINE CHENGRastegar, AndreAndreRastegarde Jesus, Adriana AAdriana Ade JesusStoddard, JenniferJenniferStoddardKuehn, Hye SunHye SunKuehnBreak, Timothy JTimothy JBreakKong, Heidi HHeidi HKongCastelo-Soccio, LeslieLeslieCastelo-SoccioColton, BenBenColtonWarner, Blake MBlake MWarnerKleiner, David EDavid EKleinerQuezado, Martha MMartha MQuezadoDavis, Jeremy LJeremy LDavisFennelly, Kevin PKevin PFennellyOlivier, Kenneth NKenneth NOlivierRosenzweig, Sergio DSergio DRosenzweigSuffredini, Anthony FAnthony FSuffrediniAnderson, Mark SMark SAndersonSwidergall, MarcMarcSwidergallGuillonneau, CaroleCaroleGuillonneauNotarangelo, Luigi DLuigi DNotarangeloGoldbach-Mansky, RaphaelaRaphaelaGoldbach-ManskyNeth, OlafOlafNethMonserrat-Garcia, Maria TeresaMaria TeresaMonserrat-GarciaValverde-Fernandez, JustoJustoValverde-FernandezLucena, Jose ManuelJose ManuelLucenaGomez-Gila, Ana LuciaAna LuciaGomez-GilaGarcia Rojas, AngelaAngelaGarcia RojasSeppänen, Mikko R JMikko R JSeppänenLohi, JoukoJoukoLohiHero, MattiMattiHeroLaakso, SailaSailaLaaksoKlemetti, PaulaPaulaKlemettiLundberg, VanjaVanjaLundbergEkwall, OlovOlovEkwallOlbrich, PeterPeterOlbrichWiner, Karen KKaren KWinerAfzali, BehdadBehdadAfzaliMoutsopoulos, Niki MNiki MMoutsopoulosHolland, Steven MSteven MHollandHeller, TheoTheoHellerPittaluga, StefaniaStefaniaPittalugaLionakis, Michail SMichail SLionakis2024-09-062024-09-062024-05-30https://scholars.lib.ntu.edu.tw/handle/123456789/720830Background 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. © 2024 Massachusetts Medical Society.enjournal article10.1056/NEJMoa231266538810185