Nuclear orphan receptor NR2F6 directly antagonizes NFAT and RORγt binding to the Il17a promoter

AbstractInterleukin-17A (IL-17A) is the signature cytokine produced by Th17 CD4+ T cells and has been tightly linked to autoimmune pathogenesis. In particular, the transcription factors NFAT and RORγt are known to activate Il17a transcription, although the detailed mechanism of action remains incompletely understood. Here, we show that the nuclear orphan receptor NR2F6 can attenuate the capacity of NFAT to bind to critical regions of the Il17a gene promoter. In addition, because NR2F6 binds to defined hormone response elements (HREs) within the Il17a locus, it interferes with the ability of RORγt to access the DNA. Consistently, NFAT and RORγt binding within the Il17a locus were enhanced in Nr2f6-deficient CD4+ Th17 cells but decreased in Nr2f6-overexpressing transgenic CD4+ Th17 cells. Taken together, our findings uncover an example of antagonistic regulation of Il17a transcription through the direct reciprocal actions of NR2F6 versus NFAT and RORγt

The German National Registry of Primary Immunodeficiencies (2012-2017)

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment

Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study

Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is characterized by a severe, cerebral perfusion pressure (CPP)-independent reduction in cerebral blood flow suggesting alterations on the level of cerebral microvessels. Therefore, we aimed to use in-vivo imaging to investigate the cerebral microcirculation after experimental SAH. Subarachnoid hemorrhage was induced in C57/BL6 mice by endovascular perforation. Pial arterioles and venules (10 to 80 μm diameter) were examined using in-vivo fluorescence microscopy, 3, 6, and 72 hours after SAH. Venular diameter or flow was not affected by SAH, while >70% of arterioles constricted by 22% to 33% up to 3 days after hemorrhage (P<0.05 versus sham). The smaller the investigated arterioles, the more pronounced the constriction (r(2)=0.92, P<0.04). Approximately 30% of constricted arterioles were occluded by microthrombi and the frequency of arteriolar microthrombosis correlated with the degree of constriction (r(2)=0.93, P<0.03). The current study demonstrates that SAH induces microarterial constrictions and microthrombosis in vivo. These findings may explain the early CPP-independent decrease in cerebral blood flow after SAH and may therefore serve as novel targets for the treatment of early perfusion deficits after SAH

Felix & Faustus Fortunatusque sit Annus! Programma, De Renovata Veteris Anni Memoria, Quo consentiente ... Comite ac Domino Dn. Alberto Anthonio, S. R. I. Qvatuor-Viro, Comite Schwartzburgi & Hohnsteini, ... ad Panegyrin Hyemalem, applaudentibus animis celebrandam, Omnium Ordinum Eruditos, unà cum Honoratissimo Dn. Rectore, invitat

FELIX & FAUSTUS FORTUNATUSQUE SIT ANNUS! PROGRAMMA, DE RENOVATA VETERIS ANNI MEMORIA, QUO CONSENTIENTE ... COMITE AC DOMINO DN. ALBERTO ANTHONIO, S. R. I. QVATUOR-VIRO, COMITE SCHWARTZBURGI & HOHNSTEINI, ... AD PANEGYRIN HYEMALEM, APPLAUDENTIBUS ANIMIS CELEBRANDAM, OMNIUM ORDINUM ERUDITOS, UNÀ CUM HONORATISSIMO DN. RECTORE, INVITAT Felix & Faustus Fortunatusque sit Annus! Programma, De Renovata Veteris Anni Memoria, Quo consentiente ... Comite ac Domino Dn. Alberto Anthonio, S. R. I. Qvatuor-Viro, Comite Schwartzburgi & Hohnsteini, ... ad Panegyrin Hyemalem, applaudentibus animis celebrandam, Omnium Ordinum Eruditos, unà cum Honoratissimo Dn. Rectore, invitat (1) Titelseite (1) Jesus (2

... Programma De Conversione Gentium Ab Obadia Prædicta, quo ... Comite ac Domino, Dn. Alberto Antonio, S. R. I. Quatuor-Viri, Comite Schwartzburgi & Hohnsteini ... ad Actum Oratorium Pentecostalem, solemniter celebrandum, Generosissimum Dn. Cancellarium ... Dn. Fautores ac Patronos suos decentissimè invitat

... PROGRAMMA DE CONVERSIONE GENTIUM AB OBADIA PRÆDICTA, QUO ... COMITE AC DOMINO, DN. ALBERTO ANTONIO, S. R. I. QUATUOR-VIRI, COMITE SCHWARTZBURGI & HOHNSTEINI ... AD ACTUM ORATORIUM PENTECOSTALEM, SOLEMNITER CELEBRANDUM, GENEROSISSIMUM DN. CANCELLARIUM ... DN. FAUTORES AC PATRONOS SUOS DECENTISSIMÈ INVITAT ... Programma De Conversione Gentium Ab Obadia Prædicta, quo ... Comite ac Domino, Dn. Alberto Antonio, S. R. I. Quatuor-Viri, Comite Schwartzburgi & Hohnsteini ... ad Actum Oratorium Pentecostalem, solemniter celebrandum, Generosissimum Dn. Cancellarium ... Dn. Fautores ac Patronos suos decentissimè invitat ([1]) Titelseite ([1]) Text (2

Nitric oxide inhalation reduces brain damage, prevents mortality, and improves neurological outcome after subarachnoid hemorrhage by resolving early pial microvasospasms.

Subarachnoid hemorrhage is a stroke subtype with particularly bad outcome. Recent findings suggest that constrictions of pial arterioles occurring early after hemorrhage may be responsible for cerebral ischemia and - subsequently - unfavorable outcome after subarachnoid hemorrhage. Since we recently hypothesized that the lack of nitric oxide may cause post-hemorrhagic microvasospasms, our aim was to investigate whether inhaled nitric oxide, a treatment paradigm selectively delivering nitric oxide to ischemic microvessels, is able to dilate post-hemorrhagic microvasospasms; thereby improving outcome after experimental subarachnoid hemorrhage. C57BL/6 mice were subjected to experimental SAH. Three hours after subarachnoid hemorrhage pial artery spasms were quantified by intravital microscopy, then mice received inhaled nitric oxide or vehicle. For induction of large artery spasms mice received an intracisternal injection of autologous blood. Inhaled nitric oxide significantly reduced number and severity of subarachnoid hemorrhage-induced post-hemorrhage microvasospasms while only having limited effect on large artery spasms. This resulted in less brain-edema-formation, less hippocampal neuronal loss, lack of mortality, and significantly improved neurological outcome after subarachnoid hemorrhage. This suggests that spasms of pial arterioles play a major role for the outcome after subarachnoid hemorrhage and that lack of nitric oxide is an important mechanism of post-hemorrhagic microvascular dysfunction. Reversing microvascular dysfunction by inhaled nitric oxide might be a promising treatment strategy for subarachnoid hemorrhage

Programma de hodiernis, iisque variis variarum Gentium precandi ritibus : Quo ad Illustrissimæ & Celsissimæ Comitis ac Dominæ, Dn. Æmiliæ Julianæ, Comitis Schwartzburgi & Hohnsteini, Natæ de Barby & Muhlinga Comitis ... Festum Natalitium, lætis Patriæ auspiciis recurrens, & ad devotissimas preces omnes ac singulos obstringens, Dn. Inspectores ac Ephoros, & quosvis non ingratos Sanctissimæ Pariæ Martis Cultores, unà cum plurimùm colendo Dn. Rectore, honorificè invitat

PROGRAMMA DE HODIERNIS, IISQUE VARIIS VARIARUM GENTIUM PRECANDI RITIBUS : QUO AD ILLUSTRISSIMÆ & CELSISSIMÆ COMITIS AC DOMINÆ, DN. ÆMILIÆ JULIANÆ, COMITIS SCHWARTZBURGI & HOHNSTEINI, NATÆ DE BARBY & MUHLINGA COMITIS ... FESTUM NATALITIUM, LÆTIS PATRIÆ AUSPICIIS RECURRENS, & AD DEVOTISSIMAS PRECES OMNES AC SINGULOS OBSTRINGENS, DN. INSPECTORES AC EPHOROS, & QUOSVIS NON INGRATOS SANCTISSIMÆ PARIÆ MARTIS CULTORES, UNÀ CUM PLURIMÙM COLENDO DN. RECTORE, HONORIFICÈ INVITAT Programma de hodiernis, iisque variis variarum Gentium precandi ritibus : Quo ad Illustrissimæ & Celsissimæ Comitis ac Dominæ, Dn. Æmiliæ Julianæ, Comitis Schwartzburgi & Hohnsteini, Natæ de Barby & Muhlinga Comitis ... Festum Natalitium, lætis Patriæ auspiciis recurrens, & ad devotissimas preces omnes ac singulos obstringens, Dn. Inspectores ac Ephoros, & quosvis non ingratos Sanctissimæ Pariæ Martis Cultores, unà cum plurimùm colendo Dn. Rectore, honorificè invitat ([1]) Title page ([1]) Text (2

Programma, De Controversia

PROGRAMMA, DE CONTROVERSIA Programma, De Controversia ([1]) Title page ([1]) Text ([2]