Klassische Konditionierung immunologischer Funktionen bei nierentransplantierten Patienten und die Mechanismen der β2-Adrenozeptor-vermittelten Inhibition der IL-2-Produktion in humanen CD4+ T-Zellen

Die klassische Konditionierung immunsuppressiver Effekte ist ein eindrucksvolles Beispiel für die bidirektionale Kommunikation zwischen Nerven- und Immunsystem. In tierexperimentellen Studien konnten bereits die Mechanismen und die potentielle klinische Relevanz der Konditionierung von T-Zellfunktionen dokumentiert werden. Auch beim Menschen lassen sich immunsuppressive Effekte konditionieren. Dafür wurde ein Paradigma etabliert, in dem das Immunsuppressivum Cyclosporin A (CsA) als unkonditionierter Stimulus (US) mehrmals mit einem gustatorischen Reiz (konditionierter Stimulus/CS) gepaart wird. Das Ziel dieser Studien war es die potentielle klinische Relevanz dieses assoziativen Lernprozesses bei immunsupprimierten Patienten zu analysieren. Vor diesem Hintergrund wurde im Rahmen dieser Arbeit erstmalig ein Konditionierungsparadigma erfolgreich in eine bereits bestehende pharmakologische Behandlung mit Calcineurin (CaN)-Inhibitoren bei nierentransplantierten Patienten eingebettet. Dafür wurden die Teilnehmer (24 Männer und 6 Frauen) gebeten ihre Medikamenteneinnahmen mit einem neuartigen grünen Getränk (CS) zu kombinieren. Nach sechs Paarungen in der Akquisition, wurden in der Evokation zwischen die Einnahmen der Immunsuppressiva zwei Placeboeinnahmen integriert, die ebenfalls mit dem CS kombiniert wurden. Vor und nach der Konditionierung wurde den Patienten zu drei Zeitpunkten Blut abgenommen und die anti-CD3-induzierte IL-2- und IFN-γ-Produktion, sowie die Proliferation der CD4+ T-Zellen gemessen. Die gelernte Immunsuppression führte zu einer signifikanten Inhibition des zirkadianen Anstiegs der Proliferation von CD4+ TZellen. Des Weiteren wurden in dieser Arbeit die intrazellulären Mechanismen der Konditionierung immunsuppressiver Effekte in humanen CD4+ T-Zellen untersucht. In tierexperimentellen Studien konnte nachgewiesen werden, dass die Konditionierung des Immunsystems durch die Aktivierung des sympathischen Nervensystems und die Ausschüttung von Katecholaminen vermittelt wird. Über β-Adrenozeptoren (AR) wird der Effekt der Katecholamine an immunkompetente Zellen weitergeleitet. Aus Experimenten mit CD4+ TZellen der Ratte ist bekannt, dass die Aktivierung des β2AR auf T-Zellen über die Inhibition von CaN zur Reduktion der IL-2-Produktion führt. In dieser Arbeit konnte gezeigt werden, dass die Stimulation des β2AR bei humanen CD4+ T-Zellen zwar ebenfalls eine dosisabhängige Inhibition der IL-2-Produktion bedingt, der zugrunde liegende Mechanismus allerdings sowohl CaN- als auch Proteinkinase A-unabhängig ist. Zusammen bilden diese Befunde einen weiteren wichtigen Schritt für den Einsatz von Konditionierungsprozessen als ergänzende Therapie im Rahmen einer immunopharmakologischen Behandlung

Sex differences in lipidomic and bile acid plasma profiles in patients with and without coronary artery disease

Background: Lipids, including phospholipids and bile acids, exert various signaling effects and are thought to contribute to the development of coronary artery disease (CAD). Here, we aimed to compare lipidomic and bile acid profiles in the blood of patients with and without CAD stratified by sex. Methods: From 2015 to 2022, 3,012 patients who underwent coronary angiography were recruited in the INTERCATH cohort. From the overall cohort, subgroups were defined using patient characteristics such as CAD vs. no CAD, 1st vs. 3rd tertile of LDL-c, and female vs. male sex. Hereafter, a matching algorithm based on age, BMI, hypertension status, diabetes mellitus status, smoking status, the Mediterranean diet score, and the intake of statins, triglycerides, HDL-c and hs-CRP in a 1:1 ratio was implemented. Lipidomic analyses of stored blood samples using the Lipidyzer platform (SCIEX) and bile acid analysis using liquid chromatography with tandem mass spectrometry (LC‒MS/MS) were carried out. Results: A total of 177 matched individuals were analyzed; the median ages were 73.5 years (25th and 75th percentile: 64.1, 78.2) and 71.9 years (65.7, 77.2) for females and males with CAD, respectively, and 67.6 years (58.3, 75.3) and 69.2 years (59.8, 76.8) for females and males without CAD, respectively. Further baseline characteristics, including cardiovascular risk factors, were balanced between the groups. Women with CAD had decreased levels of phosphatidylcholine and diacylglycerol, while no differences in bile acid profiles were detected in comparison to those of female patients without CAD. In contrast, in male patients with CAD, decreased concentrations of the secondary bile acid species glycolithocholic and lithocholic acid, as well as altered levels of specific lipids, were detected compared to those in males without CAD. Notably, male patients with low LDL-c and CAD had significantly greater concentrations of various phospholipid species, particularly plasmalogens, compared to those in high LDL-c subgroup. Conclusions: We present hypothesis-generating data on sex-specific lipidomic patterns and bile acid profiles in CAD patients. The data suggest that altered lipid and bile acid composition might contribute to CAD development and/or progression, helping to understand the different disease trajectories of CAD in women and men. Registration: https://clinicaltrials.gov/ct2/show/NCT04936438, Unique identifier: NCT04936438

Sex differences in lipidomic and bile acid plasma profiles in patients with and without coronary artery disease

Background: Lipids, including phospholipids and bile acids, exert various signaling effects and are thought to contribute to the development of coronary artery disease (CAD). Here, we aimed to compare lipidomic and bile acid profiles in the blood of patients with and without CAD stratified by sex. Methods: From 2015 to 2022, 3,012 patients who underwent coronary angiography were recruited in the INTERCATH cohort. From the overall cohort, subgroups were defined using patient characteristics such as CAD vs. no CAD, 1st vs. 3rd tertile of LDL-c, and female vs. male sex. Hereafter, a matching algorithm based on age, BMI, hypertension status, diabetes mellitus status, smoking status, the Mediterranean diet score, and the intake of statins, triglycerides, HDL-c and hs-CRP in a 1:1 ratio was implemented. Lipidomic analyses of stored blood samples using the Lipidyzer platform (SCIEX) and bile acid analysis using liquid chromatography with tandem mass spectrometry (LC‒MS/MS) were carried out. Results: A total of 177 matched individuals were analyzed; the median ages were 73.5 years (25th and 75th percentile: 64.1, 78.2) and 71.9 years (65.7, 77.2) for females and males with CAD, respectively, and 67.6 years (58.3, 75.3) and 69.2 years (59.8, 76.8) for females and males without CAD, respectively. Further baseline characteristics, including cardiovascular risk factors, were balanced between the groups. Women with CAD had decreased levels of phosphatidylcholine and diacylglycerol, while no differences in bile acid profiles were detected in comparison to those of female patients without CAD. In contrast, in male patients with CAD, decreased concentrations of the secondary bile acid species glycolithocholic and lithocholic acid, as well as altered levels of specific lipids, were detected compared to those in males without CAD. Notably, male patients with low LDL-c and CAD had significantly greater concentrations of various phospholipid species, particularly plasmalogens, compared to those in high LDL-c subgroup. Conclusions: We present hypothesis-generating data on sex-specific lipidomic patterns and bile acid profiles in CAD patients. The data suggest that altered lipid and bile acid composition might contribute to CAD development and/or progression, helping to understand the different disease trajectories of CAD in women and men. Registration: https://clinicaltrials.gov/ct2/show/NCT04936438, Unique identifier: NCT04936438

An arrhythmogenic metabolite in atrial fibrillation

Abstract Background Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. Methods and results Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF