The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1
Vasileios Oikonomou
(1)
,
Grace Smith
(1)
,
Gregory Constantine
(1)
,
Monica Schmitt
(1)
,
Elise M.N. Ferré
(1)
,
Julie Alejo
(1)
,
Deanna Riley
(1)
,
Dhaneshwar Kumar
(1)
,
Lucas dos Santos Dias
(1)
,
Joseph Pechacek
(1)
,
Yannis Hadjiyannis
(1)
,
Taura Webb
(1)
,
Bryce Seifert
(1)
,
Rajarshi Ghosh
(1)
,
Magdalena Walkiewicz
(1)
,
Daniel Martin
(1)
,
Marine Besnard
(2, 3)
,
Brendan Snarr
(1)
,
Shiva Deljookorani
(1)
,
Chyi-Chia Lee
(1)
,
Tom Dimaggio
(1)
,
Princess Barber
(1)
,
Lindsey Rosen
(1)
,
Aristine Cheng
(1)
,
Andre Rastegar
(1)
,
Adriana de Jesus
(1)
,
Jennifer Stoddard
(1)
,
Hye Sun Kuehn
(1)
,
Timothy Break
(1)
,
Heidi Kong
(1)
,
Leslie Castelo-Soccio
(1)
,
Ben Colton
(1)
,
Blake Warner
(1)
,
David Kleiner
(1)
,
Martha Quezado
(1)
,
Jeremy Davis
(1)
,
Kevin Fennelly
(1)
,
Kenneth Olivier
(1)
,
Sergio Rosenzweig
(1)
,
Anthony Suffredini
(1)
,
Mark Anderson
(4)
,
Marc Swidergall
(5, 6)
,
Carole Guillonneau
(2, 3)
,
Luigi Notarangelo
(1)
,
Raphaela Goldbach-Mansky
(1)
,
Olaf Neth
(7, 8)
,
Maria Teresa Monserrat-Garcia
(7, 8)
,
Justo Valverde-Fernandez
(8, 7)
,
Jose Manuel Lucena
(8, 7)
,
Ana Lucia Gomez-Gila
(8, 7)
,
Angela Garcia Rojas
(7, 8)
,
Mikko Seppänen
(9, 10)
,
Jouko Lohi
(9, 10)
,
Matti Hero
(10, 9)
,
Saila Laakso
(10, 9)
,
Paula Klemetti
(9, 10)
,
Vanja Lundberg
(11)
,
Olov Ekwall
(11)
,
Peter Olbrich
(7, 8)
,
Karen Winer
(1)
,
Behdad Afzali
(1)
,
Niki Moutsopoulos
(1)
,
Steven Holland
(1)
,
Theo Heller
(1)
,
Stefania Pittaluga
(1)
,
Michail Lionakis
(1)
1
NIH -
National Institutes of Health [Bethesda, MD, USA]
2 U1064 Inserm - CR2TI - Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology
3 Team 2 - U1064 Inserm - CR2TI - Team 2 : Cell and gene engineering in tolerance, fertility and regenerative medicine
4 UC San Francisco - University of California [San Francisco]
5 UC - University of California
6 David Geffen School of Medicine [Los Angeles]
7 Hospital Universitario Virgen del Rocío [Sevilla]
8 Universidad de Sevilla = University of Seville
9 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
10 HUS - Helsinki University Hospital [Finland]
11 Sahlgrenska Academy at University of Gothenburg [Göteborg]
2 U1064 Inserm - CR2TI - Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology
3 Team 2 - U1064 Inserm - CR2TI - Team 2 : Cell and gene engineering in tolerance, fertility and regenerative medicine
4 UC San Francisco - University of California [San Francisco]
5 UC - University of California
6 David Geffen School of Medicine [Los Angeles]
7 Hospital Universitario Virgen del Rocío [Sevilla]
8 Universidad de Sevilla = University of Seville
9 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
10 HUS - Helsinki University Hospital [Finland]
11 Sahlgrenska Academy at University of Gothenburg [Göteborg]
Elise M.N. Ferré
- Fonction : Auteur
- PersonId : 1409011
- ORCID : 0000-0002-3285-7768
Yannis Hadjiyannis
- Fonction : Auteur
- PersonId : 1409012
- ORCID : 0000-0001-6723-4299
Marine Besnard
- Fonction : Auteur
- PersonId : 1158661
- ORCID : 0000-0002-3009-5528
- IdRef : 261222295
Blake Warner
- Fonction : Auteur
- PersonId : 1346959
- ORCID : 0000-0002-4961-018X
Carole Guillonneau
- Fonction : Auteur
- PersonId : 1048248
- IdHAL : carole-guillonneau
- ORCID : 0000-0002-7195-0631
- IdRef : 09534084X
Raphaela Goldbach-Mansky
- Fonction : Auteur
- PersonId : 1248371
- ORCID : 0000-0001-7865-5769
Mikko Seppänen
- Fonction : Auteur
- PersonId : 795581
- ORCID : 0000-0001-9733-3650
Michail Lionakis
- Fonction : Auteur
- PersonId : 1409013
- ORCID : 0000-0003-4994-9500
Résumé
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-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.).
Domaines
Sciences du Vivant [q-bio]
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