Cirrhosis-associated immune dysfunction

Albillos, Agustı́n; Martín-Mateos, Rosa; Merwe, Schalk van der; Wiest, Reiner; Jalan, Rajiv; Álvarez‐Mon, Melchor

doi:10.1038/s41575-021-00520-7

Cited by 216 publications

(175 citation statements)

References 253 publications

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“…Such comparisons between compensated and decompensated patients substantiate that CAID evolves in parallel with liver disease progression ( 1 , 7 , 52 ), with an augmented immune response observed in the decompensated versus compensated patients. This may, in part, be due to the increased expression of pathogen recognition receptors, including TLRs, seen in cirrhotic patients with ascites ( 32 , 53 , 54 ).…”

Section: Discussionmentioning

confidence: 56%

“…Cirrhosis-associated immune dysfunction (CAID) describes the wide array of abnormalities observed in the immune system of cirrhotic patients. It encompasses both overt systemic inflammation and acquired immunodeficiency with impaired response to pathogens ( 1 ). CAID plays a pivotal role in the development of disease progression, acute-on-chronic liver failure (ACLF), and organ failure and increases the propensity to infection ( 1 – 5 ).…”

Section: Introductionmentioning

confidence: 99%

“…It encompasses both overt systemic inflammation and acquired immunodeficiency with impaired response to pathogens ( 1 ). CAID plays a pivotal role in the development of disease progression, acute-on-chronic liver failure (ACLF), and organ failure and increases the propensity to infection ( 1 – 5 ). The natural history of cirrhosis progresses from an asymptomatic phase termed compensated cirrhosis, to the development of complications from portal hypertension and hepatic insufficiency, named decompensated cirrhosis ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

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Exaggerated inflammatory response to bacterial products in decompensated cirrhotic patients is orchestrated by interferons IL-6 and IL-8

Kronsten

Woodhouse

Zamalloa

et al. 2022

American Journal of Physiology-Gastrointestinal and Liver Physi

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Cirrhosis-associated immune dysfunction (CAID) contributes to disease progression and organ failure development. We interrogated immune system function in non-septic compensated and decompensated cirrhotic patients using the TruCultureÔ whole-blood stimulation system, a novel technique that allows a more accurate representation than traditional methods, such as peripheral blood mononuclear cell culture, of the immune response in vivo. 30 cirrhotics (21 decompensated, 9 compensated) and 7 healthy controls (HC) were recruited. Whole blood was drawn directly into 3 TruCultureÔ tubes [unstimulated, pre-loaded with heat-killed E.Coli 0111:B4 (HKEB) or lipopolysaccharide (LPS)] and incubated in dry heat blocks at 37°C for 24 hours. Cytokine analysis of the supernatant was performed by multiplex assay. Cirrhotic patients exhibited a robust pro-inflammatory response to HKEB compared to HCs, with increased production of IP-10 and IFNλ1, and to LPS, with increased production of IFNλ1. Decompensated patients demonstrated an augmented immune response compared to compensated patients, orchestrated by an increase in type I, II and III interferons, and higher levels of IL-1b, IL-6 and IL-8 post-LPS stimulation. IL-1b, TNF-a and IP-10 post-HKEB stimulation and IP-10 post-LPS stimulation negatively correlated with biochemical markers of liver disease severity and liver disease severity scores. Cirrhotic patients exposed to bacterial products exhibit an exaggerated inflammatory response orchestrated by IFNs, IL-6 and IL-8. Post-stimulation levels of a number of pro-inflammatory cytokines negatively correlate with markers of liver disease severity raising the possibility that the switch to an immunodeficient phenotype in CAID may commence earlier in the course of advanced liver disease.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exaggerated inflammatory response to bacterial products in decompensated cirrhotic patients is orchestrated by interferons IL-6 and IL-8

Kronsten

Woodhouse

Zamalloa

et al. 2022

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Liver-derived complement proteins form a necessary component of host defense, as evidenced by recurrent infections in patients with cirrhosis ( 9, 40 ). To that effect, we found that splenic dissemination of bacteria was significantly higher in the mice deficient in liver-derived C3 compared to controls, suggesting its role in enhancing immune resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, genetic and acquired deficiencies of complement characteristically lead to recurrent bacterial infections in both children and adults ( 8, 9 ). However, there has been an increasing appreciation recently of how the system functions to promote tissue resilience in the setting of acute infections ( 10, 11 ).…”

Section: Introductionmentioning

confidence: 99%

Lung epithelial cell-derived C3 protects against pneumonia-induced lung injury

Ozantürk¹,

Sahu²,

Kulkarni³

et al. 2022

Preprint

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The complement component C3 is a fundamental plasma protein for host defense. However, recent work has demonstrated the critical importance of local C3 expression in cell survival. Here we analyzed the effects of local versus peripheral sources of C3 expression in a model of bacterial pneumonia. While mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient in liver-deficient C3 remain protected, comparable to wildtype mice. Human lung transcriptome analysis showed secretory epithelial cells are a major source of C3. Mice with a C3 gene ablation from lung epithelial cells had worse pulmonary injury compared to wild type, despite maintaining normal circulating C3 levels. Finally, in human cellular and mouse pneumonia models, we show that C3 reduces epithelial cell death mediated through the alternative pathway component Factor B. Thus, our findings suggest that a locally-derived C3-Factor B pathway protects the lung mucosal barrier.

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The Role of Prophylactic Antibiotics for Patients With Severe Alcohol-Related Hepatitis

Forrest

Bernal

2023

JAMA

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Cirrhosis-associated immune dysfunction

Cited by 216 publications

References 253 publications

Exaggerated inflammatory response to bacterial products in decompensated cirrhotic patients is orchestrated by interferons IL-6 and IL-8

Exaggerated inflammatory response to bacterial products in decompensated cirrhotic patients is orchestrated by interferons IL-6 and IL-8

Lung epithelial cell-derived C3 protects against pneumonia-induced lung injury

The Role of Prophylactic Antibiotics for Patients With Severe Alcohol-Related Hepatitis

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