Endotoxemia contributes to the immune paralysis in patients with cirrhosis

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Background/Aims

Immune paralysis, defined as decreased HLA-DR expression on monocytes and indicated immune dysfunctions, was found in sepsis, severe acute pancreatitis and acute liver failure. However, the relationship between HLA-DR expression and cirrhosis is unclear.

Methods

We enrolled 64 patients with liver cirrhosis and 23 healthy volunteers. HLA-DR expressions, functions of monocyte, serum cytokines and endotoxin levels were measured.

Results

Compared to healthy volunteers, HLA-DR expressions were significantly lower in Child-Pugh class C cirrhotic patients (89.28% vs 69.29%, p < 0.001). These low-HLA-DR-expressed monocytes were with decreased ability of tumor necrosis factor (TNF)-α secretion, decreased expression of inducible nitric oxide synthetase (iNOS) and decreased allo-stimulatory ability but normal phagocytosis ability. The co-stimulatory molecules like CD40 and CD86 were down-regulated as well but not CD80. Furthermore, HLA-DR expression was linearly correlated with the presence of hepatic encephalopathy (r2 = 0.2642; p = 0.008) and serum interleukin-10 (IL-10) (r2 = 0.2167; p = 0.019) in patients with Child-Pugh class C. Serum endotoxin level was in linear relationship to serum IL-10 level (r2 = 0.1868; p = 0.002) and HLA-DR expression (r2 = 0.0924; p = 0.036). In addition, endotoxin, mediated by IL-10, could down-regulate the HLA-DR expression.

Conclusions

Child-Pugh class C cirrhotic patients suffer from down-regulation of HLA-DR expression. Endotoxemia, possibly mediated by IL-10, contributes to this HLA-DR down-regulation.

Introduction

An increased susceptibility to sepsis and sepsis related mortality is found in patients with liver cirrhosis [1], [2]. This increased susceptibility has been attributed to various immune abnormalities like defective functions of neutrophil and macrophage/monocyte [3], [4], [5] and is correlated with the degree of liver dysfunction [6]. Furthermore, deranged immune responses, reflected as elevated serum levels of both pro-inflammatory and anti-inflammatory cytokines, could be found in cirrhotic patients with chronic endotoxemia [7], [8]. It had been proposed that an increase in anti-inflammatory cytokines is to counteract the damaging effect of pro-inflammatory responses as supported by evidence from sepsis and endotoxin tolerance model [9], [10]. This phenomenon of increase in both pro-inflammatory and anti-inflammatory cytokines is coined as immunological dissonance [11] and is found in several other clinical conditions like sepsis [12], acute pancreatitis [13] and acute liver failure [14]. Furthermore, this immunological dissonance is usually associated with high incidence of secondary bacterial complications and is thought to be mediated by IL-10 [9], [11].

On the other hand, a term named “immune paralysis”, defined as a down-regulation of HLA-DR expression on monocyte, is usually associated with the immune dissonance [15], [16] and with high bacterial complication [12], [13], [15]. Furthermore, it could be used as a predictor for later septic complication and mortality in severe acute pancreatitits [13] and mortality in septic patients [15], [17], [18]. Therefore, this immune paralysis is not only a useful parameter to represent the dysfunction of immune system but also a useful predictor for disease severity and prognosis.

Recently, this phenomenon of immune paralysis was found in patients with acute on chronic liver failure [8] and acute liver failure [14] and was suggested to be a good biomarker for disease severity and prognosis in acute liver failure [14]. However, the relationship between the immune paralysis and the severity of cirrhosis and the functions of these monocytes are largely unknown. Furthermore, the causes of down-regulation of HLA-DR expression in these patients are not elucidated yet. In this report, we studied the patients with liver cirrhosis to clarify these issues.

Section snippets

Patients and healthy controls

Patients with liver cirrhosis (n = 64) were recruited from outpatient clinic or liver wards of the Chang Gung Memorial Hospital. Another 23 healthy control subjects without any apparent diseases or infections were recruited from health check-up center in Chang Gung Memorial Hospital. Patients who were categorized as having liver cirrhosis were enrolled into study if they met the following criteria: (a) liver cirrhosis based on a histopathological diagnosis or compatible laboratory data and

Suppressed HLA-DR expression on monocyte was found in cirrhotic patients with Child-Puch class C

The expressions of HLA-DR on monocytes from liver cirrhotic patients and healthy volunteers were measured by flow cytometry as described in Section 2. As shown in Fig. 1a, the percentage of HLA-DR-expressed monocytes was significantly lower in patients with liver cirrhosis when compared with healthy volunteers. If we further categorized these liver cirrhotic patients by Child-Pugh classification, there was a significantly lower HLA-DR expression in patients with Child-Puch class C cirrhosis

Discussion

Our data demonstrate patients with liver cirrhosis of Child-Push class C suffer from immune paralysis which is not only associated with a down-regulation of HLA-DR expression but is also associated with altered functions of monocytes. Furthermore, our data suggested that endotoxemia contributes to this down-regulation of HLA-DR expression and is possibly mediated through IL-10.

Monocyte is known as an important phagocyte in defending invading micro-organisms by releasing nitric oxide and

Acknowledgements

This work was supported grants from the Chang Gung Memorial Hospital Research Project and National Science Council Research Project: CMRP G32018S and NMRPG340621.

References (39)

  • C. Fiuza et al.

    In vivo neutrophil dysfunction in cirrhotic patients with advanced liver disease

    J Infect Dis

    (2000)
  • A. Rimola et al.

    Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infections and prognosis

    Hepatology

    (1984)
  • F. Wong et al.

    Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club

    Gut

    (2005)
  • U. Thalheimer et al.

    Infection, coagulation, and variceal bleeding in cirrhosis

    Gut

    (2005)
  • V. von Baehr et al.

    Mechanisms of endotoxin tolerance in patients with alcoholic liver cirrhosis: role of interleukin 10, interleukin 1 receptor antagonist, and soluble tumour necrosis factor receptors as well as effector cell desensitisation

    Gut

    (2000)
  • M.A. West et al.

    Endotoxin tolerance: a review

    Crit Care Med

    (2002)
  • R.C. Bone

    Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS)

    Ann Intern Med

    (1996)
  • K. Tschaikowsky et al.

    Coincidence of pro- and anti-inflammatory responses in the early phase of severe sepsis: Longitudinal study of mononuclear histocompatibility leukocyte antigen-DR expression, procalcitonin, C-reactive protein, and changes in T-cell subsets in septic and postoperative patients

    Crit Care Med

    (2002)
  • Y.P. Ho et al.

    A strong association between down-regulation of HLA-DR expression and the late mortality in patients with severe acute pancreatitis

    Am J Gastroenterol

    (2006)
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    The authors who have taken part in this study declared that they have no relationship with the manufacturers of the drugs involved either in the past or present. They did not receive funding from the manufacturers to carry out their research. They received funding from the National Science Council of Taiwan and Chang Gung Memorial Hospital which enabled them to carry out their study.

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