The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.
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Oikonomou Vasileios, Smith Grace, Constantine Gregory M, Schmitt Monica M, Ferré Elise M N, Alejo Julie C, Riley Deanna, Kumar Dhaneshwar, Dos Santos Dias Lucas, Pechacek Joseph, Hadjiyannis Yannis, Webb Taura, Seifert Bryce A, Ghosh Rajarshi, Walkiewicz Magdalena, Martin Daniel, Besnard Marine, Snarr Brendan D, Deljookorani Shiva, Lee Chyi-Chia R, DiMaggio Tom, Barber Princess, Rosen Lindsey B, Cheng Aristine, Rastegar Andre, de Jesus Adriana A, Stoddard Jennifer, Kuehn Hye Sun, Break Timothy J, Kong Heidi H, Castelo-Soccio Leslie, Colton Ben, Warner Blake M, Kleiner David E, Quezado Martha M, Davis Jeremy L, Fennelly Kevin P, Olivier Kenneth N, Rosenzweig Sergio D, Suffredini Anthony F, Anderson Mark S, Swidergall Marc, Guillonneau Carole, Notarangelo Luigi D, Goldbach-Mansky Raphaela, Neth Olaf, Monserrat-Garcia Maria Teresa, Valverde-Fernandez Justo, Lucena Jose Manuel, Gomez-Gila Ana Lucia, Garcia Rojas Angela, Seppänen Mikko R J, Lohi Jouko, Hero Matti, Laakso Saila, Klemetti Paula, Lundberg Vanja, Ekwall Olov, Olbrich Peter, Winer Karen K, Afzali Behdad, Moutsopoulos Niki M, Holland Steven M, Heller Theo, Pittaluga Stefania, Lionakis Michail S
Аннотация
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-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.
RESULTS: Patients 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.
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.).