Introduction Increased prevalence of bacterial infectious diseases has been observed in cirrhotic patients, classically attributed to immunosuppression-associated liver cirrhosis. Conversely, advanced states of liver cirrhosis predispose to increased antigenic load. A possible role has been ascribed to the translocation of bacteria and endotoxins (lypopolysaccharide, LPS) from the gut. LPS increases the plasma levels of LPS-binding protein (LBP), the principal plasma protein responsible for transporting LPS to immune effector cells. High serum LBP has been proposed to identify a subset of cirrhotic patients with ascitis characterised by an activation of the immune cells to producer proinflammatory cytokines. Moreover, raised levels of circulating LBP or proinflammatory cytokines have been implicated in the endothelial activation and haemodynamic derangement observed in cirrhosis. A chronic antigenic stimulus will induce a monocyte and lymphocyte activation.
Aim Intestinal permeability and bacterial translocation and their influence on T lymphocytes activation and differentiation in T reg were analysed in patients with compensated and decompensated liver cirrhosis. In particular, the regulation of T cell activation, mediated by co-stimulatory molecules, the expression of activation markers and the proportion of T CD4+ regulatory cells, as a function of bacterial translocation, were studied.
Method 40 patients with liver cirrhosis, 20 of them without previous decompensation (CC) and 20 with ascetic decompensation (DC), and 20 healthy controls (HC) were studied. Bacterial translocation was analysed by serum concentrations of lypopolysacharide-binding protein (LBP). Membrane expression of co-stimulatory molecules (CD28), activation markers (CD25 and CD122) and proportion of T regulatory cells (defined as those CD4+CD25highintracellular FoxP3+) were studied by flow cytometry with specific antibodies. Values of the variables were expressed as median (interquartile range). Comparisons between variables were made by the Mann–Whitney U test. Associations between variables were analysed by the Pearson's correlation coefficient.
Results Serum concentrations of LBP were significantly elevated in patients with compensated (7.7 (5.7–9.1 microg/ml) and decompensated (28.2 (10.7–40.6)) cirrhosis when compared with healthy controls (3.4 (2.7–4.2)) (p<0.001). Significantly higher concentrations of LBP were detected in those patients with higher portal hypertension. Those patients with decompensated cirrhosis shows an activation state characterised by increased percentages of CD25+ and CD122+ expression on CD4+ T cells. A decrease of CD28 expression was detected in T CD4+ lymphocytes from patients with decompensated cirrhosis (DC, 94% (89–98%); CC, 97% (92–98%); HC, 98 (96–99), DC vs HC: p=0.010). Moreover, T reg lymphocytes, expressed as a proportion of global T CD4+ cells, were significantly increased in patients with compensated and decompensated cirrhosis (DC, 14.7% (13.3–16.1%); CC, 10.3 (10.1–11.2); HC, 8.4 (7.2–8.7), p<0.001 in each case). A significant and positive correlation was detected between serum LBP concentration and percentage of CD4+ T reg (r=0.787, p<0.001).
Conclusion Patients with liver cirrhosis, fundamentally those with previous decompensation, shows increased intestinal permeability and chronic systemic antigenic stimuli. As a response to those, T lymphocyte activation is detected. Probably as a mean to decrease the continuous antigenic stimuli, a diminution of co-stimulation and an expansion of suppressor populations are observed in them.
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