Benedikt H. Siegler

Sepsis Induces Specific Changes in Histone Modification Patterns in Human Monocytes

Background Sepsis is a global burden and the primary cause of death in intensive care units worldwide. The pathophysiological changes induced by the host’s systemic inflammatory response to infection are not yet fully understood. During sepsis, the immune system is confronted with a variety of factors, which are integrated within the individual cells and result in changes of their basal state of responsiveness. Epigenetic mechanisms like histone modifications are known to participate in the control of immune reactions, but so far the situation during sepsis is unknown. Methods and Findings In a pilot approach, we performed combined chromatin immunoprecipitation followed by high-throughput sequencing to assess the genome-wide distribution of the chromatin modifications histone 3 lysine 4 and 27 trimethylation and lysine 9 acetylation in monocytes isolated from healthy donors (n = 4) and patients with sepsis (n = 2). Despite different underlying causes for sepsis, a comparison over promoter regions shows a high correlation between the patients for all chromatin marks. These findings hold true also when comparing patients to healthy controls. Despite the global similarity, differential analysis reveals a set of distinct promoters with significant enrichment or depletion of histone marks. Further analysis of overrepresented GO terms show an enrichment of genes involved in immune function. To the most prominent ones belong different members of the HLA family located within the MHC cluster together with the gene coding for the major regulator of this locus—CIITA. Conclusions We are able to show for the first time that sepsis in humans induces selective and precise changes of chromatin modifications in distinct promoter regions of immunologically relevant genes, shedding light on basal regulatory mechanisms that might be contributing to the functional changes occurring in monocytes.

Are there new approaches for diagnosis, therapy guidance and outcome prediction of sepsis?

Beside many efforts to improve outcome, sepsis is still one of the most frequent causes of death in critically ill patients. It is the most common condition with high mortality in intensive care units. The complexity of the septic syndrome comprises immunological aspects - i.e., sepsis induced immunosuppression - but is not restricted to this fact in modern concepts. So far, exact mechanisms and variables determining outcome and mortality stay unclear. Since there is no typical risk profile, early diagnosis and risk stratification remain difficult, which hinders rapid and effective treatment initiation. Due to the heterogeneous nature of sepsis, potential therapy options should be adapted to the individual. Biomarkers like C-reactive protein and procalcitonin are routinely used as complementary tools in clinical decision-making. Beyond the acute phase proteins, a wide bunch of promising substances and non-laboratory tools with potential diagnostic and prognostic value is under intensive investigation. So far, clinical decision just based on biomarker assessment is not yet feasible. However, biomarkers should be considered as a complementary approach.

Use of biomarkers in sepsis. Update and perspectives

Sepsis and related complications are a challenge for intensive care medicine. Despite many advances in antibiotic therapy sepsis remains one of the most common diseases of patients in intensive care units and is designated as the main cause of death in critically ill patients. Persisting sepsis leads to impaired immunity, resulting in immunosuppression. Unspecific predictive signs complicate an early diagnosis; however, an early initiation of adequate therapy is of crucial importance for the prognosis. Scoring systems can be applied for the initial evaluation but are controversially discussed concerning the monitoring of disease progression and therapy as well as outcome prediction. Biomarkers are considered as a complementary approach.ZusammenfassungDie Sepsis und damit verbundene Komplikationen sind eine große Herausforderung für die Intensivmedizin. Trotz vieler Fortschritte in der antibiotischen Therapie gehört die Sepsis zu den häufigsten Krankheitsentitäten auf Intensivstationen und ist als Haupttodesursache kritisch kranker Patienten beschrieben. Persistiert die Sepsis, kommt es zu einer Störung der Immunität bis zur Immunsuppression. Unspezifische Frühzeichen erschweren oftmals eine schnelle Diagnose. Der rasche Beginn einer adäquaten Therapie ist allerdings für die Prognose von besonderer Bedeutung. Scoring-Systeme dienen der initialen Evaluation, werden aber in Bezug auf Verlaufs- und Therapie-Monitoring sowie Vorhersagekraft für die Sterblichkeit kontrovers diskutiert. Biomarker gelten hierfür als ergänzender Ansatz.AbstractSepsis and related complications are a challenge for intensive care medicine. Despite many advances in antibiotic therapy sepsis remains one of the most common diseases of patients in intensive care units and is designated as the main cause of death in critically ill patients. Persisting sepsis leads to impaired immunity, resulting in immunosuppression. Unspecific predictive signs complicate an early diagnosis; however, an early initiation of adequate therapy is of crucial importance for the prognosis. Scoring systems can be applied for the initial evaluation but are controversially discussed concerning the monitoring of disease progression and therapy as well as outcome prediction. Biomarkers are considered as a complementary approach.

The Glyoxalase System and Methylglyoxal-Derived Carbonyl Stress in Sepsis: Glycotoxic Aspects of Sepsis Pathophysiology

Sepsis remains one of the leading causes of death in intensive care units. Although sepsis is caused by a viral, fungal or bacterial infection, it is the dysregulated generalized host response that ultimately leads to severe dysfunction of multiple organs and death. The concomitant profound metabolic changes are characterized by hyperglycemia, insulin resistance, and profound transformations of the intracellular energy supply in both peripheral and immune cells. A further hallmark of the early phases of sepsis is a massive formation of reactive oxygen (ROS; e.g., superoxide) as well as nitrogen (RNS; e.g., nitric oxide) species. Reactive carbonyl species (RCS) form a third crucial group of highly reactive metabolites, which until today have been not the focus of interest in sepsis. However, we previously showed in a prospective observational clinical trial that patients suffering from septic shock are characterized by significant methylglyoxal (MG)-derived carbonyl stress, with the glyoxalase system being downregulated in peripheral blood mononuclear cells. In this review, we give a detailed insight into the current state of research regarding the metabolic changes that entail an increased MG-production in septicemia. Thus, we point out the special role of the glyoxalase system in the context of sepsis.

Einsatz von Biomarkern in der Sepsis

Sepsis and related complications are a challenge for intensive care medicine. Despite many advances in antibiotic therapy sepsis remains one of the most common diseases of patients in intensive care units and is designated as the main cause of death in critically ill patients. Persisting sepsis leads to impaired immunity, resulting in immunosuppression. Unspecific predictive signs complicate an early diagnosis; however, an early initiation of adequate therapy is of crucial importance for the prognosis. Scoring systems can be applied for the initial evaluation but are controversially discussed concerning the monitoring of disease progression and therapy as well as outcome prediction. Biomarkers are considered as a complementary approach.ZusammenfassungDie Sepsis und damit verbundene Komplikationen sind eine große Herausforderung für die Intensivmedizin. Trotz vieler Fortschritte in der antibiotischen Therapie gehört die Sepsis zu den häufigsten Krankheitsentitäten auf Intensivstationen und ist als Haupttodesursache kritisch kranker Patienten beschrieben. Persistiert die Sepsis, kommt es zu einer Störung der Immunität bis zur Immunsuppression. Unspezifische Frühzeichen erschweren oftmals eine schnelle Diagnose. Der rasche Beginn einer adäquaten Therapie ist allerdings für die Prognose von besonderer Bedeutung. Scoring-Systeme dienen der initialen Evaluation, werden aber in Bezug auf Verlaufs- und Therapie-Monitoring sowie Vorhersagekraft für die Sterblichkeit kontrovers diskutiert. Biomarker gelten hierfür als ergänzender Ansatz.AbstractSepsis and related complications are a challenge for intensive care medicine. Despite many advances in antibiotic therapy sepsis remains one of the most common diseases of patients in intensive care units and is designated as the main cause of death in critically ill patients. Persisting sepsis leads to impaired immunity, resulting in immunosuppression. Unspecific predictive signs complicate an early diagnosis; however, an early initiation of adequate therapy is of crucial importance for the prognosis. Scoring systems can be applied for the initial evaluation but are controversially discussed concerning the monitoring of disease progression and therapy as well as outcome prediction. Biomarkers are considered as a complementary approach.

The immunosuppressive face of sepsis early on intensive care unit—A large-scale microarray meta-analysis

Background Sepsis is defined as a life-threatening condition, resulting from a dysregulated and harmful response of the hosts’ immune system to infection. Apart from this, the (over-)compensating mechanisms counterbalancing the inflammatory response have been proven to render the host susceptible to further infections and increase delayed mortality. Our study aimed to unravel the heterogeneity of immune response in early sepsis and to explain the biology behind it. Methods A systematic search of public repositories yielded 949 microarray samples from patients with sepsis of different infectious origin and early after clinical manifestation. These were merged into a meta-expression set, and after applying sequential conservative bioinformatics filtering, an in-deep analysis of transcriptional heterogeneity, as well as a comparison to samples of healthy controls was performed. Results We can identify two distinct clusters of patients (cluster 1: 655 subjects, cluster 2: 294 subjects) according to their global blood transcriptome. While both clusters exhibit only moderate differences in direct comparison, a comparison of both clusters individually to healthy controls yielded strong expression changes of genes involved in immune responses. Both comparisons found similar regulated genes, with a stronger dysregulation occurring in the larger patient cluster and implicating a loss of monocyte and T cell function, co-occurring with an activation of neutrophil granulocytes. Conclusion We propose a consistent—but in its extent varying—presence of immunosuppression, occurring as early in sepsis as its clinical manifestation and irrespective of the infectious origin. While certain cell types possess contradictory activation states, our finding underlines the urgent need for an early host-directed therapy of sepsis side-by-side with antibiotics.

[Epigenetic regulation in sepsis : current state of knowledge].

ZusammenfassungDie Sepsis ist das Krankheitsbild, das aus einer schweren systemischen Immunreaktion des Körpers auf eine Infektion unterschiedlicher Ursache resultiert. Initial reagiert das Immunsystem mit einer überschießenden Aktivierung von Entzündungszellen und der Ausschüttung proinflammatorischer Zytokine. Gleichzeitig wirken körpereigene Mechanismen durch antiinflammatorische Mediatoren und Immunzellen dieser generalisierten Entzündungsreaktion als Gegenregulation entgegen. Auch diese kompensatorische antiinflammatorische Immunantwort kann entsprechend der proinflammatorischen Reaktion übersteigert sein und resultiert dann in einer prolongierten sepsisinduzierten Immunsuppression. Die Gründe für eine solche persistierende antiinflammatorische Reaktion und die daraus folgende Vulnerabilität sind unklar. Allerdings gibt es Hinweise, dass ein septisches Ereignis die Grundeigenschaften der Immunzellen durch epigenetische Modifikation verändert. Veränderungen von Histonmodifikationen und Änderungen der Aktivierungsmechanismen von Transkriptionsfaktoren scheinen dabei in vielen Zellen des Immunsystems, wie Makrophagen, wichtige Rollen zu spielen sowie dadurch die Genregulation und Transkriptionsmechanismen der Zelle zu beeinflussen. Dieser Beitrag gibt einen Überblick über den aktuellen Stand der epigenetischen Sepsisforschung und über bisherige Erkenntnisse zu den langfristigen Auswirkungen der Sepsis auf das Immunsystem.AbstractSepsis is known to be a severe systemic immune reaction based on an infection of various origins. The initial immune response is accompanied by excess activation of immune cells and release of proinflammatory cytokines. Simultaneously initiated compensatory mechanisms lead to high levels of anti-inflammatory mediators to counterbalance the generalized inflammatory reaction; however, the compensatory immunoreaction itself equally overreacts and results in a prolonged sepsis-induced immunosuppression. The underlying mechanisms for these exaggerated immune responses and the resulting global immunosuppression that increase the risk for secondary infection are still unknown. Recent findings indicate that epigenetic mechanisms change basic properties of important immune cells by mechanisms leading to changes in gene expression. Dynamic exchanges of histone modifications result in a variation of transcription and seem to play a key role in cell function of macrophages and other immune cells. This article provides a current overview of epigenetic sepsis research and the sepsis-induced effects on the immune system.

Epigenetische Regulation in der Sepsis@@@Epigenetic regulation in sepsis: Aktueller Wissensstand@@@Current state of knowledge

ZusammenfassungDie Sepsis ist das Krankheitsbild, das aus einer schweren systemischen Immunreaktion des Körpers auf eine Infektion unterschiedlicher Ursache resultiert. Initial reagiert das Immunsystem mit einer überschießenden Aktivierung von Entzündungszellen und der Ausschüttung proinflammatorischer Zytokine. Gleichzeitig wirken körpereigene Mechanismen durch antiinflammatorische Mediatoren und Immunzellen dieser generalisierten Entzündungsreaktion als Gegenregulation entgegen. Auch diese kompensatorische antiinflammatorische Immunantwort kann entsprechend der proinflammatorischen Reaktion übersteigert sein und resultiert dann in einer prolongierten sepsisinduzierten Immunsuppression. Die Gründe für eine solche persistierende antiinflammatorische Reaktion und die daraus folgende Vulnerabilität sind unklar. Allerdings gibt es Hinweise, dass ein septisches Ereignis die Grundeigenschaften der Immunzellen durch epigenetische Modifikation verändert. Veränderungen von Histonmodifikationen und Änderungen der Aktivierungsmechanismen von Transkriptionsfaktoren scheinen dabei in vielen Zellen des Immunsystems, wie Makrophagen, wichtige Rollen zu spielen sowie dadurch die Genregulation und Transkriptionsmechanismen der Zelle zu beeinflussen. Dieser Beitrag gibt einen Überblick über den aktuellen Stand der epigenetischen Sepsisforschung und über bisherige Erkenntnisse zu den langfristigen Auswirkungen der Sepsis auf das Immunsystem.AbstractSepsis is known to be a severe systemic immune reaction based on an infection of various origins. The initial immune response is accompanied by excess activation of immune cells and release of proinflammatory cytokines. Simultaneously initiated compensatory mechanisms lead to high levels of anti-inflammatory mediators to counterbalance the generalized inflammatory reaction; however, the compensatory immunoreaction itself equally overreacts and results in a prolonged sepsis-induced immunosuppression. The underlying mechanisms for these exaggerated immune responses and the resulting global immunosuppression that increase the risk for secondary infection are still unknown. Recent findings indicate that epigenetic mechanisms change basic properties of important immune cells by mechanisms leading to changes in gene expression. Dynamic exchanges of histone modifications result in a variation of transcription and seem to play a key role in cell function of macrophages and other immune cells. This article provides a current overview of epigenetic sepsis research and the sepsis-induced effects on the immune system.

Epigenetische Regulation in der Sepsis

ZusammenfassungDie Sepsis ist das Krankheitsbild, das aus einer schweren systemischen Immunreaktion des Körpers auf eine Infektion unterschiedlicher Ursache resultiert. Initial reagiert das Immunsystem mit einer überschießenden Aktivierung von Entzündungszellen und der Ausschüttung proinflammatorischer Zytokine. Gleichzeitig wirken körpereigene Mechanismen durch antiinflammatorische Mediatoren und Immunzellen dieser generalisierten Entzündungsreaktion als Gegenregulation entgegen. Auch diese kompensatorische antiinflammatorische Immunantwort kann entsprechend der proinflammatorischen Reaktion übersteigert sein und resultiert dann in einer prolongierten sepsisinduzierten Immunsuppression. Die Gründe für eine solche persistierende antiinflammatorische Reaktion und die daraus folgende Vulnerabilität sind unklar. Allerdings gibt es Hinweise, dass ein septisches Ereignis die Grundeigenschaften der Immunzellen durch epigenetische Modifikation verändert. Veränderungen von Histonmodifikationen und Änderungen der Aktivierungsmechanismen von Transkriptionsfaktoren scheinen dabei in vielen Zellen des Immunsystems, wie Makrophagen, wichtige Rollen zu spielen sowie dadurch die Genregulation und Transkriptionsmechanismen der Zelle zu beeinflussen. Dieser Beitrag gibt einen Überblick über den aktuellen Stand der epigenetischen Sepsisforschung und über bisherige Erkenntnisse zu den langfristigen Auswirkungen der Sepsis auf das Immunsystem.AbstractSepsis is known to be a severe systemic immune reaction based on an infection of various origins. The initial immune response is accompanied by excess activation of immune cells and release of proinflammatory cytokines. Simultaneously initiated compensatory mechanisms lead to high levels of anti-inflammatory mediators to counterbalance the generalized inflammatory reaction; however, the compensatory immunoreaction itself equally overreacts and results in a prolonged sepsis-induced immunosuppression. The underlying mechanisms for these exaggerated immune responses and the resulting global immunosuppression that increase the risk for secondary infection are still unknown. Recent findings indicate that epigenetic mechanisms change basic properties of important immune cells by mechanisms leading to changes in gene expression. Dynamic exchanges of histone modifications result in a variation of transcription and seem to play a key role in cell function of macrophages and other immune cells. This article provides a current overview of epigenetic sepsis research and the sepsis-induced effects on the immune system.

Einsatz von Biomarkern in der Sepsis@@@Use of biomarkers in sepsis: Update und Ausblick@@@Update and perspectives

Sepsis and related complications are a challenge for intensive care medicine. Despite many advances in antibiotic therapy sepsis remains one of the most common diseases of patients in intensive care units and is designated as the main cause of death in critically ill patients. Persisting sepsis leads to impaired immunity, resulting in immunosuppression. Unspecific predictive signs complicate an early diagnosis; however, an early initiation of adequate therapy is of crucial importance for the prognosis. Scoring systems can be applied for the initial evaluation but are controversially discussed concerning the monitoring of disease progression and therapy as well as outcome prediction. Biomarkers are considered as a complementary approach.ZusammenfassungDie Sepsis und damit verbundene Komplikationen sind eine große Herausforderung für die Intensivmedizin. Trotz vieler Fortschritte in der antibiotischen Therapie gehört die Sepsis zu den häufigsten Krankheitsentitäten auf Intensivstationen und ist als Haupttodesursache kritisch kranker Patienten beschrieben. Persistiert die Sepsis, kommt es zu einer Störung der Immunität bis zur Immunsuppression. Unspezifische Frühzeichen erschweren oftmals eine schnelle Diagnose. Der rasche Beginn einer adäquaten Therapie ist allerdings für die Prognose von besonderer Bedeutung. Scoring-Systeme dienen der initialen Evaluation, werden aber in Bezug auf Verlaufs- und Therapie-Monitoring sowie Vorhersagekraft für die Sterblichkeit kontrovers diskutiert. Biomarker gelten hierfür als ergänzender Ansatz.AbstractSepsis and related complications are a challenge for intensive care medicine. Despite many advances in antibiotic therapy sepsis remains one of the most common diseases of patients in intensive care units and is designated as the main cause of death in critically ill patients. Persisting sepsis leads to impaired immunity, resulting in immunosuppression. Unspecific predictive signs complicate an early diagnosis; however, an early initiation of adequate therapy is of crucial importance for the prognosis. Scoring systems can be applied for the initial evaluation but are controversially discussed concerning the monitoring of disease progression and therapy as well as outcome prediction. Biomarkers are considered as a complementary approach.