Alcohol takes the toll on immune function

In 30–50% patients with cirrhosis, infection is the precipitating event that brings them into the hospital. A further 15–35% develop nosocomial infections during their hospital stay as compared with 5–7% in the general hospital population (1). Patients with alcoholic cirrhosis have a 6.3-fold increased risk to die from an episode of bacteraemia (2). These data support the hypothesis that patients with alcoholic cirrhosis are likely to have underlying immune dysfunction that makes them susceptible to increased risk of infections. The mechanism of this immune dysfunction is unclear. The paper by PimentelNunes et al. (3) in the present issue of the journal suggest that even patients with stable alcoholic cirrhosis who are abstinent have a defect of the innate immune system mediated through a dysfunction of the toll-like receptor2 (TLR-2) pathway. Toll-like receptors are a family of receptors that recognize pathogen-associated, molecular patterns and promote the activation of leukocytes. Recognition of circulating endotoxin is dependent on complex formation of endotoxin with lipopolysaccharide binding protein (LBP). Lipopolysaccharide–LBP complexes are recognized by CD14 and TLR-4, which are found on many immune and non-immune cells (4). Neutrophils and peripheral blood mononuclear cells express all known TLRs except TLR-3. The most widely studied TLRs in liver cirrhosis are TLR-2, -4 and -9, because they respond to bacterial products thought to be important in the pathogenesis of immune dysfunction. TLR-4 is the designated endotoxin receptor, as well as TLR-2, which also senses peptidoglycans (products of Gram-positive bacteria). TLR-9 is an intracellular molecule which is activated by bacterial DNA (5). Activated TLRs enable cellular recruitment and lead to the generation of reactive oxygen species, regulation of phagocytosis and secretion of chemokines, cytokines and antimicrobial products. In alcoholic hepatitis, neutrophil dysfunction is associated with endotoxaemia and increased incidence of infection (6). In the same patient group an overexpression of TLR2, TLR-4 and TLR-9, most likely because of the presence of endotoxin and other bacterial products has been observed (7). Constant stimulation of peripheral blood mononuclear cells (PBMC) with endotoxin leads to the development of endotoxin tolerance, which is characterized by reduced capacity to produce pro-inflammatory cytokines. In contrast to the findings on neutrophils alone, investigations of TLR-2 and -4 in PBMCs showed that TLR-2 is significantly upregulated in patients with high endotoxin levels in contrast to TLR-4, which was downregulated (8). This indicates that TLRs are important players in orchestrating an immune response and may react differently on different cell types. In a human study, over expression of TLR-2 but not TLR-4 was found on PBMCs of cirrhotic patients, with TLR-2 expression correlating with circulating levels of the pro-inflammatory cytokines TNF-a and the soluble TNF receptor (9). The study by Pimentel-Nunes et al. (3), addressed the TLR-2and TLR-4-mediated immune response in stable well-compensated alcoholic cirrhosis and their observations extends previous results by showing high endotoxin levels as well as high levels of CD14 and LBP (3). They studied the response of PBMC to TLR-2 and TLR-4 ligands and found an attenuated TLR-2 response whereas the TLR-4-mediated response to endotoxin was not different to controls. They also studied a subset of patients with decompensated liver disease, where in addition to the blunted TLR-2 response; the TLR-4 response to endotoxin was also defective. Interestingly, they could not find any changes in protein or mRNA expression of TLRs between patients and controls, which is in contra-distinction to neutrophils from patients with alcoholic cirrhosis suggesting that different cell types behave differently (10). Alcohol intake alters the functional abnormalities in the PBMCs depending on the duration of alcohol intake and the presence or absence of alcoholic liver disease and effects of alcohol persist on the immune function in chronic alcoholic patients despite abstinence (11). Acute alcohol intake/exposure renders monocytes hyporesponsive to LPS through increased IRAK-M which negatively modulates signalling downstream of TLR ligation (12). Pimentel-Nunes et al. (3) also found evidence of a blunted immune response, which surprisingly is TLR-2 mediated. It is possible that the monocytes in patients with stable alcoholic cirrhosis are in transition between the anti-inflammatory status of the acute alcohol exposure to chronic hyper-inflammatory phenotype and as shown by Mandrekar et al. (12). IRAK-M might play a role in transformation of this status on chronic exposure to alcohol. This will need to be studied in careful longitudinal studies. Data on neutrophil function in alcoholic hepatitis or cirrhosis is paradoxical with some studies suggesting neutrophil priming (13). On the other hand some studies