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Gastroenterology & Hepatology
End-stage liver disease (ESLD) from acute liver failure to compensated advanced chronic liver disease and decompensated cirrhosis at different stages (chronic decompensation, acute decompensation with or without acute-on-chronic liver failure) has high disease severity and poor patient outcome. Infection is a common complication in patients with ESLD and it is associated with a high mortality rate. Multiple mechanisms are involved in this marked susceptibility to infections, noticeably the inadequate immune response known as immune paresis, as part of cirrhosis-associated immune dysfunction (CAID). Specifically in the adaptive immune arm, lymphocyte impairments—including inadequate activation, reduced ability to secrete effector molecules and enhanced immune suppressive phenotypes—result in compromised systemic immune responses and increased risk of infections.
- adaptive immune
- T cell
- B cell
- immune paresis
1. Introduction
End-stage liver disease (ESLD) covers a large spectrum of disease severities; it includes acute liver failure (ALF) without underlying chronic liver disease, compensated advanced chronic liver disease (cACLD) (defined according to the Baveno VII criteria [1]) complicated cirrhosis at different stages (chronic decompensation (CD) and acute decompensation (AD) without or with organ failure, referred to as acute-on-chronic liver failure (ACLF). ESLD patients’ outcome is significantly impaired compared to the general population, with a poor prognosis associated with disease severity (>90% 1-year survival in compensated cirrhotic patients versus 60% in decompensated cirrhotic patients [2]). Following AD, a 27% 1-year mortality rate has been reported in a European multicentric cohort in the absence of organ failure [3], whereas the highest mortality risk has been described for patients with multiple organ failure (79% 3-month mortality for grade-3 ACLF patients [4]). Several complications, including bacterial infections, contribute to the impairment of cirrhotic patients’ survival at any stage.
2. Clinical Definitions and Main Pathophysiological Concepts
2.1. Acute Liver Failure
ALF is a rapid-onset clinical syndrome occurring in the absence of pre-existing chronic liver disease [30]. ALF cases can present with jaundice, coagulopathy (raised INR) and hepatic encephalopathy [31]. It is a rare but severe condition in which coagulopathy and neurological disorders due to hepatic encephalopathy and systemic inflammation associated with elevated risk of secondary infection result in high mortality [31]. Rapid overwhelming hepatocyte damage can be seen histologically as widespread necrosis and apoptosis of hepatocytes [31]. This contributes to high sterile inflammation, leading to the promotion of pro-resolution monocytes/macrophages and CD4+ T cells [22,23,26]. However, this compensatory anti-inflammatory immune response leads to high infection susceptibility, infections and multi-organ failure, representing the most frequent causes of death in ALF patients [32].
2.2. Natural Evolution of Cirrhosis: From cACLD to AD and ACLF
Chronic liver diseases may lead to progressive intrahepatic fibrosis development, finally resulting in cirrhosis, which is defined by annular fibrosis and the destruction of normal liver histological architecture [33]. While alcohol is the most common underlying cause of liver disease in Europe, viral hepatitis is responsible for most cirrhosis diagnosed in Asia-Pacific regions. The early stage of cirrhosis is usually poorly symptomatic, also referred to as non-complicated cirrhosis or compensated cirrhosis. Recently, the concept of compensated advanced chronic liver disease (cACLD) has been proposed by the Baveno VII conference to reflect the continuum between severe fibrosis and compensated cirrhosis. cACLD is defined by the absence of previous cirrhosis complications and liver stiffness above 10 kPa (a liver stiffness between 10 and 15 kPa being suggestive of cACLD and a value > 15 kPa highly suggestive of cACLD). These values are also relevant to rule out the risk of clinically significant portal hypertension and a 3-year risk of liver decompensation or related death (<1% for liver stiffness < 10 kPa) [1].
The sudden onset of one or more events related to cirrhosis complications (ascites, gastrointestinal haemorrhage, hepatic encephalopathy) defines acute decompensation of cirrhosis. Whether bacterial infection should be considered a cirrhosis complication or just a precipitating event is still under debate [1,34]. While an acute event occurring within a 2-week period determines AD, the slow development of cirrhosis complications defines non-acute decompensation of cirrhosis [35]. Chronic decompensation of cirrhosis encompasses the persistence of decompensation following AD and non-acute decompensation of cirrhosis.
The occurrence of organ failure in association with AD characterises a specific condition named acute-on-chronic liver failure (ACLF). The CANONIC study by the European Foundation for the study of Chronic Liver Failure (EF-CLIF) consortium aimed to define ACLF in AD patients with the worst clinical course and prognosis, which led to the CLIF ACLF definition: cirrhosis AD associated with no organ failure (or single organ failure without renal and brain dysfunction) or multiple organ failures [4].
The definition of ACLF remains controversial due to the various distinct descriptions published by different organisations. Another definition is given by the Asian Pacific Association for the Study of the Liver (APASL): underlying chronic liver disease (cirrhotic or non-cirrhotic, excluding isolated steatosis) with an acute hepatic insult (viral hepatitis, alcohol consumption or drug-induced liver toxicity) causing liver failure (defined by jaundice and coagulopathy) [36]. The negative criteria in the APASL definition exclude prior decompensation, and bacterial infection is not considered as an acute hepatic insult.
2.3. Inflammation Hypothesis
Inflammation has been proposed to play a central role in the pathophysiology of ESLD. Besides its implication in CAID, inflammation may be crucial in the natural history of cirrhosis, being the main driver for the evolution of compensated cirrhosis toward decompensated diseases [37]. Bacterial translocation or other pro-inflammatory triggers (alcohol, infections, etc.) can induce a hyperinflammatory state, leading to AD and immune dysfunction. Interleukin (IL)-6 and IL-8 levels have been mostly associated with disease severity in decompensated cirrhotic patients, with or without ACLF [25,38,39,40]. The prognostic value of C-reactive protein (CRP) levels to determine outcomes following admissions for cirrhotic patients has also contributed to developing this hypothesis [41]. Recently, an association between CRP, plasma IL-6 levels and the severity of cirrhosis has been confirmed in different studies [34,37,42]. IL-6 levels and CRP have been reported as independent predictive factors of 1-year death or liver transplantation in cACLD patients (IL-6) and chronic decompensated cirrhotic patients (IL-6 and CRP) [42]. Regarding AD course, IL-6 and CRP levels are increased in cirrhotic patients who develop toward unstable decompensated cirrhosis following a first AD episode, being even higher for patients who will develop ACLF in the future, and IL-6 levels rise with ACLF grade [34,37]. Enhanced baseline inflammasome activation (defined as high levels of circulating IL-1α and IL-1β) may be determinant for future ACLF development in AD and CD cirrhotic patients [43]. The highly inflammatory status of AD and ACLF patients has also been supported by a study of plasma lipid mediators’ profile, showing a pro-inflammatory balance in AD and ACLF compared to healthy volunteers and an association with disease severity [39]. ACLF accounts for a specific cirrhosis decompensation, associated with multiple organ failure, more pronounced immune paresis and the highest risk of death. In this setting, inflammation parameters vary from those described in cACLD, CD and AD, with notably high circulating levels of pro-inflammatory cytokines involved in innate immunity (such as TNF-α, MIP-1β, IL-10) [25,40].
3. Circulating T Cell Alterations in End-Stage Liver Disease
3.1. Changes in CD4 Subsets in Cirrhosis
In a cohort of cACLD and decompensated cirrhotic patients, Lario et al. showed that bacterial translocation could induce hyperactivated HLA-DR+ CD4+ T helper (Th) cells, shifting naïve Th cells towards effector and effector memory lineages. This sustained activation also drove increased apoptosis in all Th subsets, therefore participating in Th depletion, despite increased proliferation rates (Ki67+ cells) observed in all memory Th subsets [44]. In agreement with this, Marquez et al. found both higher frequencies of memory CD4+ T cells expressing the CD95 apoptosis marker and of activated CD4+ T cells in viral- and alcohol-related cirrhosis. These changes were equally observed regardless of the severity of cirrhosis and were not influenced by the presence of ascites or high levels of lipoprotein binding protein (LBP) [45]. Conversely, other authors found that an imbalance between naïve and activated CD4+ T cells was specifically marked in ascitic patients with high levels of LBP, suggesting bacterial translocation as a key driver of CD4+ T cell impairment [46].
Besides phenotypic shifts, several reports suggest functionally altered T cells in cirrhosis (encompassing both CD4+ and CD8+ compartments). In a recent study, the authors suggested that impairment of CD4+ T cell function occurs even at the early stage of cirrhosis. In a cohort of cACLD patients recently vaccinated against hepatitis B virus (HBV) or SARS-CoV-2, they reported lower IL-21 and IFN-γ production by CD4+ T cells following antigen-specific stimulation [49]. In other studies, cytokine production appears to be impaired only in the most severe patients, with defective production of IFN-γ and TNF-α by T cells in AD patients [50].
3.2. Impairment of Circulating CD4+ T Helper Cells in Acute Liver Failure
In ALF, the naïve peripheral CD4+ pool expands while the effector memory CD4+ T cell subset is markedly decreased compared to healthy controls and to cirrhotic patients [26]. Khamri et al. showed that CD4+ T cells displayed an immunosuppressive phenotype characterised by the increased expression of checkpoint CTLA-4, known to negatively regulate T cell activation. The frequency of CTLA-4+CD4+ T cells positively correlated with MELD score and was even more elevated in ALF patients who developed secondary infections. However, no change in CTLA-4 expression was found in ACLF patients.
3.3. Expansion of Regulatory T Cells in Cirrhosis
Tregs inhibit both the proliferation and cytokine production of other CD4+ and CD8+ T cells. Tregs could thus prevent host immune-mediated damage but could also participate in cirrhosis-associated immune dysfunction. However, previous studies on circulating Tregs in the setting of cirrhosis are inconsistent. Some authors reported a significant down-regulation of Tregs in cirrhosis or AH [56,57], while others found them to increase in all cirrhotic patients [29,58] regardless of the severity [50] or found them to be higher in ACLF patients [59,60].
Bacterial translocation has been proposed to promote Treg preferential differentiation since patients with elevated levels of LBP display a significantly higher frequency of Tregs than those with normal levels [45]. The pathogenicity of Tregs in cirrhosis is currently not established, but a previous report has suggested a detrimental role, with an increase in peripheral Tregs being predictive of subsequent bacterial infections in cirrhotic patients [58].
Apart from thymic-derived CD25+CD127− Tregs, Khamri et al. recently reported the expansion of non-classical CD4+ regulatory T cells in AD expressing the tolerogenic marker HLA-G [27]. These cells suppressed peripheral blood mononuclear cells’ (PBMCs) proliferation and pro-inflammatory cytokine production in in vitro experiments, an effect that was both HLA-G- and CTLA-4-mediated. Interestingly, the expansion of regulatory HLA-G+CD4+ T cells was induced by Kupffer cells through IL-35 secretion and these unconventional Tregs specifically down-regulated Th17-related cytokine production [27].
3.4. Alterations in Circulating CD8+ T Cells in Cirrhosis: Activation to Exhaustion Profile
Regarding circulating CD8+ T cells, previous studies reported either a reduction in the absolute numbers of both naïve and memory subsets or only of naïve cells [46,50]. Additionally, the phenotypic profile of peripheral CD8+ T cells may change with disease severity with the co-expression of activation and exhaustion/senescence markers.
In a recent study, Rueschenbaum et al. demonstrated that CD8+ T cells of cirrhotic patients exhibited simultaneously increased surface expression of activation markers (HLA-DR, CD38, CD69), inhibitory receptors (KLRG1, PDPN, TIM3) and the apoptotic marker CD95 [50]. In this cohort, changes in the CD8+ phenotype were observed in patients with cACLD and chronic decompensated cirrhosis and in AD and ACLF patients. The expansion of activated CD8+ T cells has been previously suggested in another cohort of cirrhotic patients, where CD8+ lymphocytes displayed an altered phenotype with elevated surface expression of the activation marker HLA-DR and checkpoint inhibitor TIM-3 compared to healthy subjects. While HLA-DR expression on CD8+ T cells was increased in AD patients with concomitant infections, TIM-3 expression was associated with disease severity and the co-expression of HLA-DR and PD-1 was predictive of poor disease outcome in all cirrhotic patients.
3.5. Alterations in Circulating Follicular T Helper Cells Linked to Impaired Humoral Immunity
Follicular T helper cells (Tfh) are specialised CD4+ T cells that enable the emergence of effective antibody responses against microbial pathogens through B cell activation and differentiation. A reduction in the frequency of this T cell population has been reported in cirrhosis [57,61]. In alcoholic liver disease, the level of circulating Tfh cells, as reflected by the level of the soluble CD40 ligand (sCD40L), was significantly lower compared to controls. sCD40L, released into circulation upon Tfh activation, was an independent predictor of mortality [64].
Recently, Basho et al. investigated the exact role of Tfh in decompensated liver cirrhosis in a cohort of patients with hepatitis C virus (HCV), alcohol-related or non-alcoholic steatohepatitis (NASH)-related underlying liver diseases [29]. Patients with decompensated cirrhosis had significantly fewer liver resident Tfh and circulating Tfh cells compared to compensated cirrhosis patients and healthy controls. The Tfh cells of cirrhotic patients exhibited phenotypic (CD25highOX40highCD127high) and transcriptional changes (low expression of TCF1 ad FOXP3) compared to healthy controls. These alterations were systemic effects, likely driven by elevated circulating pro-inflammatory IL-2 levels in these patients.
4. Alterations in Circulating B Cell Subset
4.1. Global B Cell Depletion
Like T cells, the B lymphocyte absolute count has been reported to decrease in patients with chronic liver disease. However, B cell frequency varies according to disease stage and cirrhosis aetiology. Decreased B cell frequency is found in alcoholic liver disease [67]. Increased B cell frequency is reported in decompensated cirrhotic patients, consisting of a mixed-aetiology population [68], while no change in B cell frequency is reported in HCV-related decompensated cirrhotic patients [69].
4.2. Loss of Memory Subset
Depletion in CD27+ memory B cells is widely reported in decompensated cirrhosis [68,69,70] as well as in ACLF [71]. The loss of the memory subset is associated with high susceptibility towards infections [68,69], and it might also contribute to the poor B cell response to vaccination observed in cirrhotic patients [72,73].
4.3. Hyperglobulinaemia
In cirrhotic patients, B cells show an up-regulation of the activation markers HLA-DR and CD86. Doi et al. also reported the up-regulation of TLR9 and BAFF in memory B cells. This hyperactivation of B cells leads to enhanced production of immunoglobulins A and G [69,70,74], which is commonly observed in advanced cirrhosis. Data regarding the significance of immunoglobulin levels are contradictory.
4.4. Regulatory B Cells
Regulatory B cells are a small subset of the B cell population involved in immunomodulation. One of the best-known mechanisms of immune suppression used by regulatory B cells is the secretion of the anti-inflammatory cytokine IL-10. The loss of regulatory B cells is a well-described contributing factor to autoimmune hepatitis. In cirrhosis, alterations in regulatory B cell populations may contribute to the effector B cell hyporesponsiveness. The expansion of circulating CD19+CD24highCD38high regulatory B cells has been reported in HBV-related chronic decompensated cirrhotic patients [76].
5. Decrease in Circulating Mucosal-Associated Invariant T Cells
Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in blood, mucosal tissues and the liver [78]. MAIT cells express a semi-invariant T cell receptor consisting of Va7.2-Ja12/20/33 combined with limited β chain variable region (Vb) diversity. They recognise riboflavin metabolites of bacteria or fungi with the help of MHC class-I and thus contribute to immune defence against pathogens. Circulating MAIT cells have been reported to be severely diminished in cirrhosis from the early stages [79,80]. Conflicting results have been published regarding whether they accumulate in liver fibrotic septa [79] or not [80]. In ascites, MAIT cells increase together with monocytes, innate lymphoid cells and NK cells [80]. Circulating MAIT cells displayed an activated phenotype, typified by high surface expression of HLA-DR, CD56, CD25 and CD38, and high proliferation levels indicated by Ki-67 detection.
This entry is adapted from the peer-reviewed paper 10.3390/livers3030028
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