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- Oikonomou, Vasileios, et al.
(författare)
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The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.
- 2024
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Ingår i: The New England journal of medicine. - 1533-4406. ; 390:20, s. 1873-1884
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Tidskriftsartikel (refereegranskat)abstract
- 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.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.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.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.).
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| 2. |
- Sitas, Nadia, et al.
(författare)
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Exploring the usefulness of scenario archetypes in science-policy processes : experience across IPBES assessments
- 2019
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Ingår i: Ecology and Society. - 1708-3087. ; 24:3
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Tidskriftsartikel (refereegranskat)abstract
- Scenario analyses have been used in multiple science-policy assessments to better understand complex plausible futures. Scenario archetype approaches are based on the fact that many future scenarios have similar underlying storylines, assumptions, and trends in drivers of change, which allows for grouping of scenarios into typologies, or archetypes, facilitating comparisons between a large range of studies. The use of scenario archetypes in environmental assessments foregrounds important policy questions and can be used to codesign interventions tackling future sustainability issues. Recently, scenario archetypes were used in four regional assessments and one ongoing global assessment within the Intergovernmental Science-Policy Platform for Biodiversity and Ecosystem Services (IPBES). The aim of these assessments was to provide decision makers with policy-relevant knowledge about the state of biodiversity, ecosystems, and the contributions they provide to people. This paper reflects on the usefulness of the scenario archetype approach within science-policy processes, drawing on the experience from the IPBES assessments. Using a thematic analysis of (a) survey data collected from experts involved in the archetype analyses across IPBES assessments, (b) notes from IPBES workshops, and (c) regional assessment chapter texts, we synthesize the benefits, challenges, and frontiers of applying the scenario archetype approach in a science-policy process. Scenario archetypes were perceived to allow syntheses of large amounts of information for scientific, practice-, and policy-related purposes, streamline key messages from multiple scenario studies, and facilitate communication of them to end users. In terms of challenges, they were perceived as subjective in their interpretation, oversimplifying information, having a limited applicability across scales, and concealing contextual information and novel narratives. Finally, our results highlight what methodologies, applications, and frontiers in archetype-based research should be explored in the future. These advances can assist the design of future large-scale sustainability-related assessment processes, aiming to better support decisions and interventions for equitable and sustainable futures.
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