IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical studies are investigating whether ...tocilizumab (anti-IL-6 receptor) can help preserve beta cell function in patients recently diagnosed with T1D. However, in some rodent models and isolated human islets, IL-6 has been found to have a protective role for beta cells by reducing oxidative stress. Hence, we systematically investigated local tissue expression of IL-6 in human pancreas from non-diabetic, auto-antibody positive donors and donors with T1D and T2D. IL-6 was constitutively expressed by beta and alpha cells regardless of the disease state. However, expression of IL-6 was highly reduced in insulin-deficient islets of donors with T1D, and the expression was then mostly restricted to alpha cells. Our findings suggest that the implication of IL-6 in T1D pathogenesis might be more complex than previously assumed.
•IL-6 is expressed on human pancreatic beta and alpha cells.•Beta cells are the source of majority of IL-6 in pancreatic islets.•IL-6 expression is reduced in islets of donors with type 1 diabetes, particularly in insulin-deficient islets.•IL-6 is secreted by live human islet cultures and increased upon metabolic and immune stress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aims/hypothesis
We aimed to characterise and quantify the expression of HLA class II (HLA-II) in human pancreatic tissue sections and to analyse its induction in human islets.
Methods
We ...immunostained human pancreatic tissue sections from non-diabetic (
n
= 5), autoantibody positive (Aab+;
n
= 5), and type 1 diabetic (
n
= 5) donors, obtained from the Network of Pancreatic Organ Donors (nPOD), with HLA-II, CD68 and insulin. Each tissue section was acquired with a widefield slide scanner and then analysed with QuPath software. In total, we analysed 7415 islets that contained 338,480 cells. Widefield microscopy was further complemented by high resolution imaging of 301 randomly selected islets, acquired using a Zeiss laser scanning confocal (LSM880) to confirm our findings. Selected beta cells were acquired in enhanced resolution using LSM880 with an Airyscan detector. Further, we cultured healthy isolated human islets and reaggregated human islet microtissues with varying concentrations of proinflammatory cytokines (IFN-γ, TNF-α and IL-1β). After proinflammatory cytokine culture, islet function was measured by glucose-stimulated insulin secretion, and HLA-I and HLA-II expression was subsequently evaluated with immunostaining or RNA sequencing.
Results
Insulin-containing islets (ICIs) of donors with type 1 diabetes had a higher percentage of HLA-II positive area (24.31%) compared with type 1 diabetic insulin-deficient islets (IDIs, 0.67%), non-diabetic (3.80%), and Aab+ (2.31%) donors. In ICIs of type 1 diabetic donors, 45.89% of the total insulin signal co-localised with HLA-II, and 27.65% of the islet beta cells expressed both HLA-II and insulin, while in non-diabetic and Aab+ donors 0.96% and 0.59% of the islet beta cells, respectively, expressed both markers. In the beta cells of donors with type 1 diabetes, HLA-II was mostly present in the cell cytoplasm, co-localising with insulin. In the experiments with human isolated islets and reaggregated human islets, we observed changes in insulin secretion upon stimulation with proinflammatory cytokines, as well as higher expression of HLA-II and HLA-I when compared with controls cultured with media, and an upregulation of HLA-I and HLA-II RNA transcripts.
Conclusions/interpretation
After a long-standing controversy, we provide definitive evidence that HLA-II can be expressed by pancreatic beta cells from patients with type 1 diabetes. Furthermore, this upregulation can be induced in vitro in healthy isolated human islets or reaggregated human islets by treatment with proinflammatory cytokines. Our findings support a role for HLA-II in type 1 diabetes pathogenesis since HLA-II expressing beta cells can potentially become a direct target of autoreactive CD4
+
lymphocytes.
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
IL-17 is an important effector cytokine driving immune-mediated destruction in autoimmune diseases such as psoriasis. Blockade of the IL-17 pathway after the initiation of insulitis was effective in ...delaying or preventing the onset of type 1 diabetes (T1D) in rodent models. Expression of IL-17 transcripts in islets from a donor with recent-onset T1D has been reported, however, studies regarding IL-17 protein expression are lacking. We aimed to study whether IL-17 is being expressed in the islets of diabetic donors.
We stained human pancreatic tissues from non-diabetic (n = 5), auto-antibody positive (aab+) (n = 5), T1D (n = 6) and T2D (n = 5) donors for IL-17, Insulin, and Glucagon, and for CD45 in selected cases. High resolution images were acquired with Zeiss laser scanning confocal microscope LSM780 and analyzed with Zen blue 2.3 software. Cases stained for CD45 were also acquired with widefield slide scanner and analyzed with QuPath software.
We observed a clear cytoplasmic staining for IL-17 in insulin-containing islets of donors with T1D and T2D, accounting for an average of 7.8 ± 8.4% and 14.9 ± 16.8% of total islet area, respectively. Both beta and alpha cells were sources of IL-17, but CD45+ cells were not a major source of IL-17 in those donors. Expression of IL-17 was reduced in islets of non-diabetic donors, aab+ donors and in insulin-deficient islets of donors with T1D.
Our finding that IL-17 is expressed in islets of donors with T1D or T2D is quite intriguing and warrants further mechanistic studies in human islets to understand the role of IL-17 in the context of metabolic and immune stress in beta cells.
•IL-17 is expressed in insulin containing islets of donors with type 1 (T1D) and type 2 diabetes (T2D).•Both beta and alpha cells can express IL-17 in donors with T1D and T2D.•Donors with T2D have the highest expression of IL-17 in the islets, mainly present in beta and alpha cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Zusammenfassung
Hintergrund
Auswirkungen der COVID-19-Pandemie auf die psychische Gesundheit zeigten sich bereits früh. Das Ausmaß der Auswirkungen, insbesondere kumulativ über die lang anhaltende ...Zeit der Pandemie, ist für Deutschland noch nicht umfassend untersucht worden.
Ziel der Arbeit
Ziel der Studie war es, psychische Belastungen sowie COVID-19-bezogene Erlebens- und Verhaltensweisen zu erheben und deren Veränderung über die verschiedenen Phasen der Pandemie in Deutschland darzustellen.
Material und Methoden
In die deutschlandweite onlinebasierte Querschnittsstudie (10.03.–27.07.2020) konnten 22.961 Menschen eingeschlossen werden (Convenience Sample). Erhoben wurden: generalisierte Angst (GAD-7), Depression (PHQ-2), psychischer Distress (DT) sowie COVID-19-bezogene Erlebens- und Verhaltensweisen wie
COVID-19-bezogene Angst, Vertrauen in staatliche Maßnahmen, subjektives Informiertheitslevel, adhärentes Sicherheitsverhalten
und
persönliche Risikoeinschätzung für Ansteckung/Erkrankungsschwere
. Die Pandemie wurde retrospektiv in 5 Phasen (Anfangs‑, Krisen‑, Lockdown‑, Neuorientierungsphase und „neue Normalität“) eingeteilt.
Ergebnisse
Es zeigten sich im Vergleich zu Prä-COVID-19-Referenzwerten anhaltend erhöhte Werte in GAD‑7, PHQ‑2 und DT.
COVID-19-bezogene Angst, Informiertheitslevel, Vertrauen, Sicherheitsverhalten
und
die Einschätzung, an COVID-19 zu erkranken,
zeigten, nach initial starkem Anstieg, einen Abfall bis z. T. unter den Ausgangswert. Ausnahme waren konstante
Einschätzungen, einen schweren Verlauf von COVID-19 zu haben
bzw.
daran zu versterben
.
Diskussion
Die durch alle Pandemiephasen anhaltend erhöhten Werte psychischer Belastung verdeutlichen die Notwendigkeit nachhaltiger Unterstützungsangebote. Sinkende Werte in Bezug auf Vertrauen in staatliche Maßnahmen und das subjektive Informiertheitslevel unterstreichen das Gebot gezielter Aufklärung.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This collection of essays in Governing Global Land Deals provides new empirical and theoretical analyses of the relationships between global land grabs and processes of government and governance. ...Reframes debates on global land grabs by focusing on the relationship between large-scale land deals and processes of governance. Offers new theoretical insights into the different forms and effects of global land acquisitions Illuminates both the micro-processes of transaction and expropriation, as well as the broader structural forces at play in global land deals. Provides new empirical data on the different actors involved in contemporary land deals occurring across the globe and focuses on the specific institutional, political, and economic contexts in which they are acting.
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