Paralysed monocytes in acute on chronic liver disease

Antoniades, Charalambos; Wendon, Julia; Vergani, Diego

doi:10.1016/j.jhep.2004.12.005

Cited by 40 publications

(30 citation statements)

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“…In view of the importance of the inflammatory microenvironment in modulating immune cell function in ALF,4, 6, 7, 32 we investigated the effects of sera, derived from ALF patients, on CTLA4 expression in CD4 + T cells from HC. Exposure to sera from ALF patients resulted in up-regulation of CTLA4 expression on CD4 + T cells after 24 and 48 hours in culture ( P = .01) (Figure 4 A ).…”

Section: Resultsmentioning

confidence: 99%

“…Although the initiating event in ALF is acute hepatocellular death, mortality is attributable to a profound activation of systemic inflammatory response syndrome and multiple organ dysfunction 1, 2, 3. Recent studies identify defects in innate immune responses to microbial cues, termed immune paresis , which cause an increased susceptibility to secondary infections, a leading cause of mortality in ALF 4, 5, 6, 7…”

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confidence: 99%

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Increased Expression of Cytotoxic T-Lymphocyte−Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure

et al. 2017

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Background & AimsPatients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte−associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulator of T-cell activation. We collected T cells from patients with ALF and investigated whether inhibitory signals down-regulate adaptive immune responses in patients with ALF.MethodsWe collected peripheral blood mononuclear cells from patients with ALF and controls from September 2013 through September 2015 (45 patients with ALF, 20 patients with acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute decompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 healthy individuals). Circulating CD4+ T cells were isolated and analyzed by flow cytometry. CD4+ T cells were incubated with antigen, or agonist to CD3 and dendritic cells, with or without antibody against CTLA4; T-cell proliferation and protein expression were quantified. We measured levels of soluble B7 molecules in supernatants of isolated primary hepatocytes, hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays.ResultsPeripheral blood samples from patients with ALF had a higher proportion of CD4+ CTLA4+ T cells than controls; patients with infections had the highest proportions. CD4+ T cells from patients with ALF had a reduced proliferative response to antigen or CD3 stimulation compared to cells from controls; incubation of CD4+ T cells from patients with ALF with an antibody against CTLA4 increased their proliferative response to antigen and to CD3 stimulation, to the same levels as cells from controls. CD4+ T cells from controls up-regulated expression of CTLA4 after 24−48 hours culture with sera from patients with ALF; these sera were found to have increased concentrations of soluble B7 compared to sera from controls. Necrotic human primary hepatocytes exposed to acetaminophen, but not hepatic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, secreted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells.ConclusionsPeripheral CD4+ T cells from patients with ALF have increased expression of CTLA4 compared to individuals without ALF; these cells have a reduced response to antigen and CD3 stimulation. We found sera of patients with ALF and from mice with liver injury to have high concentrations of soluble B7, which up-regulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces level...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Increased Expression of Cytotoxic T-Lymphocyte−Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure

et al. 2017

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“…High levels of ammonia have been demonstrated to induce neutrophil swelling and impaired neutrophil phagocytosis, resulting in neutrophil dysfunction in rats fed an ammoniagenic diet and in patients with cirrhosis (28). Patients with acute-on-chronic liver failure had a similar degree of depression of cellular immunity and monocyte levels, which contributed to the increased infection morbidity of these patients (29,30). In a previous study, Child-Pugh class C cirrhotic patients that presented with downregulation of HLA-DR expression on monocytes exhibited immune dysfunctions (31).…”

Section: Discussionmentioning

confidence: 99%

A study on the position and etiology of infection in cirrhotic patients: A potential precipitating factor contributing to hepatic encephalopathy

Wang

Duan

et al. 2013

Experimental and Therapeutic Medicine

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Hepatic encephalopathy (HE) is a severe and high-mortality complication in cirrhotic patients. In this study, we analyzed infection, one of the common precipitating factors of HE in patients with cirrhosis, in order to identify common infection sites and the etiology. In addition, we aimed to identify information useful in the early prevention and effective treatment of HE. Ninety-two patients presenting with hepatitis B virus-related cirrhosis with HE (HBC-HE) and 45 patients presenting with alcoholic cirrhosis with HE (ALD-HE) were enrolled in this study. We collected and analyzed data concerning the precipitating factors of HE using blood tests, biochemical detection and bacterial culture to identify which precipitating factor was the most common. Fifty-three patients with HE (37 with HBC-HE and 16 with HBC-HE) had infection as the precipitating factor. These infections included respiratory tract infection (56.6%), intestinal tract infection (20.7%), peritoneal infection (17.0%) and urinary tract infection (5.7%). The white blood cell (WBC) counts increased in 17 cases (32.1%) and neutrophil (NEUT) numbers increased in 39 cases (73.6%), while WBC counts were lower in the patients with respiratory tract infection compared with those in the patients with infections at other sites (P<0.05). The levels of plasma ammonia were significantly higher in patients with intestinal tract infection than in those with other sites of infection (P<0.05). The proportions of patients with hyperammonemia, increased NEUT numbers, hyponatremia and low albumin were higher in the infection group compared with those in the non-infection group (P<0.05). Pneumococci and E. coli were common bacteria that induced infection in the respiratory tract and at other infection sites, respectively. Respiratory tract infection was identified to be the most common precipitating factor for HE.

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“…Immune paralysis, which is defined as decreased human leukocyte antigen-D related (HLA-DR) expression of monocytes, is a well-known feature in ACLF and septic shock but it was recently found also in patients with liver cirrhosis 16. Immune paralysis is characterized by increase in anti-inflammatory cytokines, like IL-6 and IL-10, and suppression of proinflammatory cytokines, like IL-1 and TNF-α 17,44,45,54.…”

Section: Immunological Dysfunction In Cirrhosismentioning

confidence: 99%

Immune Dysfunction in Cirrhosis

Noor¹,

Manoria²

2017

Journal of Clinical and Translational Hepatology

119

105

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Cirrhosis due to any etiology disrupts the homeostatic role of liver in the body. Cirrhosis-associated immune dysfunction leads to alterations in both innate and acquired immunity, due to defects in the local immunity of liver as well as in systemic immunity. Cirrhosis-associated immune dysfunction is a dynamic phenomenon, comprised of both increased systemic inflammation and immunodeficiency, and is responsible for 30% mortality. It also plays an important role in acute as well as chronic decompensation. Immune paralysis can accompany it, which is characterized by increase in antiinflammatory cytokines and suppression of proinflammatory cytokines. There is also presence of increased gut permeability, reduced gut motility and altered gut flora, all of which leads to increased bacterial translocation. This increased bacterial translocation and consequent endotoxemia leads to increased blood stream bacterial infections that cause systemic inflammatory response syndrome, sepsis, multiorgan failure and death. The gut microbiota of cirrhotic patients has more pathogenic microbes than that of noncirrhotic individuals, and this disturbs the homeostasis and favors gut translocation. Prompt diagnosis and treatment of such infections are necessary for better survival. We have reviewed the various mechanisms of immune dysfunction and its consequences in cirrhosis. Recognizing the exact pathophysiology of immune dysfunction will help treating clinicians in avoiding its complications in their patients and can lead to newer therapeutic interventions and reducing the morbidity and mortality rates. Citation of this article: Noor MT, Manoria P. Immune dysfunction in cirrhosis.

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Paralysed monocytes in acute on chronic liver disease

Cited by 40 publications

References 21 publications

Increased Expression of Cytotoxic T-Lymphocyte−Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure

Increased Expression of Cytotoxic T-Lymphocyte−Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure

A study on the position and etiology of infection in cirrhotic patients: A potential precipitating factor contributing to hepatic encephalopathy

Immune Dysfunction in Cirrhosis

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