Liver damage and immune responses

Abstract

Chronic liver disease (CLD) has massive systemic repercussions including major impacts on the body’s immune system. Abnormalities in phenotype, function and numbers of various immune cell subsets have been established by a large number of clinical and pre-clinical studies. The loss of essential immune functions renders CLD-patients exceptionally susceptible to bacterial and viral infections and also impairs the efficacy of vaccination. Consequently, infections represent a major clinical issue causing significant morbidity and mortality in these patients. Mechanistically, the immune dysfunction associated with CLD results from the increased translocation of bacteria and bacterial cues from the intestine. These trigger a signaling axis around the cytokines IFN I and IL-10 in hepatic myeloid cells, which aside from impairing the function of the myeloid cells themselves, also has notable negative impacts on the functionality of other immune cells. T cells in CLD-patients and -models are especially affected by this signaling axis and display a variety of quantitative and qualitative defects. Due to the high clinical relevance, understanding the mechanisms underlaying CED-associated immune dysfunction is of critical importance to discover and develop new therapeutic targets.

Zusammenfassung

Chronische Erkrankungen der Leber (CED) haben massive systemische Auswirkungen auf den Körper und beeinflussen auch die Funktionen des Immunsystems. In einer großen Anzahl klinischer und präklinischer Studien wurde etabliert, dass CED mit einer großen Bandbreite an Abnormalitäten in Phänotyp, Funktion und Anzahl verschiedener Immunzellpopulationen einhergehen. Der Verlust wichtiger Immunfunktionen macht CED-Patienten besonders anfällig für bakterielle und virale Infektionen und reduziert die Effektivität von Impfungen. Folglich stellen Infektionen in CED-Patienten ein bedeutendes klinisches Problem dar und gehen mit stark erhöhter Morbidität und Mortalität einher. Mechanistisch resultieren CED-assoziierte Immundysfunktionen aus der erhöhten Translokation von Bakterien und bakteriellen Produkten aus dem Darm. Diese induzieren in hepatischen myeloiden Zellen eine Signalachse mit den Zytokinen IFN I und IL-10, die, neben der Funktion der myeloiden Zellen selbst, auch die Funktionalität anderer Immunzellen vermindert. Dies manifestiert sich vor allem im T-Zellkompartment, das in CED-Patienten und -modellen bedeutende qualitative und quantitative Defekte aufweist. Aufgrund der hohen klinischen Relevanz von CED-assoziierter Immundysfunktion, ist das Verständnis der zugrunde liegenden Mechanismen von großer Bedeutung für die Entwicklung neuer therapeutischer Ansätze.

Keywords

Liver - gut - chronic liver disease - microbial translocation - CAID - type I interferon - interleukin 10

Schlüsselwörter

Leber - Darm - Chronische Lebererkrankung - Mikrobielle Translokation - CAID - type I interferon - Interleukin 10

Publikationsverlauf

Eingereicht: 30. August 2024

Angenommen nach Revision: 13. November 2024

Artikel online veröffentlicht:
10. Januar 2025

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