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Bacterial infection is one of the most frequent and severe complications of advanced alcoholic liver disease (ALD), including alcoholic cirrhosis and severe alcoholic hepatitis (SAH). Patients who suffered from SAH are susceptible to bacterial infection with one study reporting 50% of them developed bacterial infection.1 Additionally, standard corticosteroid treatment further increased the risk of bacterial infection in patients with SAH.1 Thus, infection is highly relevant for the outcome of SAH and represents an important therapeutic target. However, except antibiotic treatment, there are currently no other specific therapies that effectively control bacterial infection in SAH due to incomplete understanding of the pathogenesis of bacterial infection in these patients.
The mechanisms underlying the increased risk of bacterial infection in ALD are complex and multifactorial. The high incidence of bacterial infection may be partly explained by gut bacterial overgrowth, dysbiosis and translocation of gut bacteria and their products in patients with ALD.2 3 Impaired host defence against bacterial infection is probably another important mechanism contributing to the increased risk of bacterial infection in patients with ALD. It has been well documented that excessive alcohol consumption has broad and significant inhibitory effects on many key components of the immune system. For example, neutrophils, the first cellular line of defence against microorganisms, have impaired functions in patients with SAH, such as weakened reactive oxygen species production, reduced exocytosis/phagocytosis, declined chemotaxis and severe bactericidal defect.4 T cells from patients with SAH, but not alcoholic cirrhosis, expressed elevated levels of inhibitory mediators (eg, programmed cell death 1, PD ligand 1) that markedly inhibited T cell functions against bacterial infection.4 Although many types of immune cells have been found dysregulated and such dysregulation likely contributes to the increased bacterial infection in patients with SAH, the exact underlying mechanisms are not fully understood. In this issue of Gut, the study from Riva et al5 added another type of immune cells called mucosa-associated invariant T cells (MAIT) that are also altered in patients with SAH, and such alteration probably plays a role in promoting bacterial infection in these patients.
MAIT cells are a recently identified subset of innate-like T cells with a conserved invariant T cell antigen receptor (TCR) α-chain, composed of Vα7.2-Jα33 in humans and Vα19-Jα33 in mice, and express high levels of the C-type lectin receptor CD161 or the interleukin (IL)-18 receptor α subunit.6 MAIT cells are initially called ‘mucosal-associated’ because of relative abundance of the Vα7.2-Jα33 transcript detected in human gut biopsies and the enrichment of homologous Vα19-Jα33 transcript among murine lamina propria lymphocytes compared with intraepithelial lymphocytes or mesenteric lymph nodes.7 Now it is known that MAIT cells are most abundant in human liver, representing 20%–50% of intrahepatic T cells, and are also abundant in human gut, peripheral blood and lungs.8–10 In contrast to humans, MAIT cells are detected at low levels in commonly used laboratory mouse strains, accounting for less than 1% of intrahepatic T cells in C57BL/6 and BABL/c mice.8–10 Thus, most of murine studies on MAIT cells have been performed in invariant Vα19-Jα33 TCR transgenic mice.11
One major function of MAIT cells is to inhibit bacterial infection through the invariant TCR that recognises microbial riboflavin/vitamin B2 metabolites presented by the major histocompatibility complex class I-related protein 1.6 MAIT cells can be also activated by inflammatory cytokines such as IL-12 and IL-18 in a TCR-independent manner, and subsequently produce a variety of cytokines such as tumour necrosis factor-alpha, interferon gamma, IL-17 and IL-22, suggesting that in addition to their antibacterial functions, MAIT cells may play a role in modulating immune responses in various types of liver diseases.6 For example, Bolte et al12 recently reported that intrahepatic MAIT cells were depleted in patients with viral hepatitis, which was likely due to activation-induced cell death caused by inflammatory cytokines. Intrahepatic frequency of MAIT cells inversely correlated with liver inflammation and fibrosis in patients with viral hepatitis, suggesting a role of MAIT cells in regulating liver inflammation during viral hepatitis infection.
Despite of an important antibacterial function of MAIT cells,13 their roles in the pathogenesis of severe ALD, which is often associated with bacterial infection, have not been investigated until this study by Riva et al.5 In this paper, the authors found that circulating MAIT cells were depleted and displayed defective antibacterial cytokine/cytotoxic response in alcoholic cirrhosis and SAH, which is probably an important mechanism contributing to the increased risk of bacterial infection in these patients (figure 1). Furthermore, Riva et al5 demonstrated that intestinal bacterial antigens and metabolites but not ethanol itself selectively depleted MAIT cells without affecting CD8/CD3 T cells in vitro, suggesting that selective MAIT cell depletion and dysfunction are likely caused by chronic exposure to bacteria in patients with SAH. Because patients with ALD are associated with significant bacterial translocation from the gut to the liver,14 it is plausible to speculate that intrahepatic MAIT cells are exposed to these bacteria/bacterial products and are subsequently depleted in these patients. Surprisingly, by performing immunohistochemistry analysis, the authors found that the number of intrahepatic MAIT cells was comparable in patients with alcoholic cirrhosis compared with healthy controls.5 However, these studies were carried out in only a small number of patients with alcoholic cirrhosis without flow cytometric analysis and were not investigated in patients with SAH. In contrast, the authors found that the expression of transcription factors (such as RORC/RORγt, ZBTB16/PLZF, Eomes), which control the differentiation of innate-like T cells including MAIT cells, was lower in the liver samples from patients with SAH than that from healthy controls, indicating that intrahepatic MAIT cell number/functions may be reduced in patients with SAH. Therefore, extensive studies are urgently needed to characterise intrahepatic MAIT cells in patients with SAH.
In summary, given a strong antibacterial function of MAIT cells and high incidence of bacterial infection in patients with SAH, MAIT cells likely play an important role in controlling the bacterial infection in these patients. The study from Riva et al5 opened a new direction but just began to divulge this field; the exact roles of MAIT cells in the pathogenesis of SAH still remain largely unknown. Many questions remain unanswered (figure 1). First, intrahepatic MAIT cells in patients with SAH need to be characterised. Second, ALD is associated with bacterial overgrowth2 3 in the gut where MAIT cells are enriched. It will be interesting to study how gut MAIT cells affect gut-liver axis and intestinal dysbacteriosis in ALD, and whether chronic alcohol consumption affects the riboflavin metabolism in bacteria. Third, current antibiotic treatment has led to the increasing emergence of multidrug-resistant bacteria and steroid treatment further increases the risk of bacterial infection in patients with SAH. Given an important role of MAIT cells in controlling bacterial infection and their defects in SAH, restoration of functional MAIT cells could be an attractive strategy to ameliorate/prevent bacterial infection in these patients.
Contributors BG, JM and XX wrote the paper. BG and JM made the figure. BG supervised to write the paper.
Funding This study was funded by the National Institute on Alcohol Abuse and Alcoholism (Intramural programme).
Competing interests Bin Gao is a US Federal Government employee acting in the course of his employment.
Provenance and peer review Commissioned; internally peer reviewed.
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