Cirrhosis-associated immune dysfunction (CAID) – causes, phenotypes and consequences

Overview

The term cirrhosis-associated immune dysfunction represents a wide spectrum of alterations in the local and systematic immune response. CAID is characterised by parallel ongoing systematic inflammation and immune deficiency, the intensity of manifestation of which depends on the stage of the disease, predisposing and precipitating factors. The gut-liver axis plays a key role in the pathogenesis of CAID. Impaired interplay between the gut and liver and changes in microbio­me composition are responsible for damage to the intestinal barrier and continuous antigen stimulation, leading to the new proinflammatory setting of the immune system, which represents the low-grade inflammation phenotype CAID. Episodic aggravation of microbial translocation and episodic effect of precipitating factors cause a burst of systematic inflammation and breakthrough of the immune tolerance. The result is dysregulated hyperinflammatory immune response, which represents the high-grade inflammation phenotype of CAID. The change of the phenotype stays in the background of transition to decompensated cirrhosis. The systemic inflammation increases across the subtypes of decompensation with the highest degree reached in the ACLF, which represents the fulminant immunophenotype of CAID. Hyperinflammatory immune response, immunopathologic and immunometabolic changes act synergistically with organ-specific mechanisms in the development of organ dysfunctions. Lasting dysregulated pro-inflammatory reaction leads to immunity exhaustion and innate and adaptive immune cells reprogramming. This immune paralysis is the cause of problematic infections and represents the indolent immunophenotype of CAID.

Keywords:

Microbiome – cirrhosis-associated immune dysfunction (CAID) – low-grade inflammation phenotype – high-grade inflammation phenotype – systematic inflammation – fulminant immunophenotype – immune paralysis – indolent immunophenotype – gut-liver axis – inflam mation

Introduction

Inflammation is an essential component in the process of tissue regeneration and is the critical pathophysiological pathway involved in the natural history of advanced chronic liver disease (ACLD), leading to cirrhosis and complications thereof. An aetiological cause of ACLD and dysbio­sis drives the inflammatory reaction to restore homeostasis and activates the liver resident immune system to control the local response and prevent the inception of systematic inflammation. The consequence of a long-lasting cause of a particular aetiological factor is dysregulated immune response and subsequent chronic systematic inflammation with permanent release of proinflammatory mediators [1,2]. This process activates hepatic stellate cells and promotes fibrogenesis, leading to a distortion of the hepatic microarchitecture. This remodelling increases resistance to portal blood flow and results in the structural component of portal hypertension [3]. These changes correspond to the transition from chronic liver disease to cirrhosis.

Resident liver immunology

The unique arrangement of the liver parenchyma is responsible for metabolic and detoxicant function and is important for frontline immune response. Specialised innate and adaptive immune cells constitute about one-third of the total cell population in the liver. They comprise the carefully controlled network challenged by the continuous inflow of antigens from the gut or altered liver parenchyma. This microenvironment provides detection and subsequently clearance of pathogens and simultaneously maintains the balance between immunity and tolerance [4–6].

Kupffer cells are specialised liver resident macrophages mostly localised within the sinusoidal space. They are responsible for removing and degrading immunogenic molecules by phagocytosis, antigen presentation to T cells by MHC and costimulatory molecules, and the secretion of cytokines, chemokines and other inflammatory mediators. On the other hand, they induce immune tolerance [7].

Liver sinusoidal endothelial cells (LSEC) are highly specialised, fenestrated endothelial cells lining the hepatic sinusoids and they constitute the interface between blood cells, hepatocytes and hepatic stellate cells. This position is crucial to nutrient exchange, clearance and intrahepatic vascular tone regulation. LSECs represent gatekeepers for hepatic immunity because they function as antigen-presenting cells (APC), regulate leukocyte recruitment and in connection with PD-L1 expression, suppress the immune response and maintain immune tolerance by the generation of the anergic-like phenotype of an immune response [8,9].

Dendritic cells are derived from monocyte-macrophage progenitors residing around the central vein and periportal tracts. They sense the liver environment and after activation by antigen, they mature toward several functional antigens presenting cells (APCs) linking the innate and adaptive arms of the immune system. Dendritic cells are responsible for maintaining liver homeostasis and tolerance. They express MHC molecules and costimulatory molecules to present antigens to T-cells in a tolerogenic way. They promote the deletion of activated T-cells and activation of regulatory T-cells owing to the effect of their immuno-active products such as IL1, TGF-b, CTLA-4, PD-1; they reduce the expression of TLR and crosstalk with NK and NKT cells. If the liver microenvironment changes its character to proinflammatory, dendritic cells switch their phenotype and contribute to the production of pro-inflammatory cytokines like TNF-a and IL6, provoking oxidative stress and the activation of stellate cells [10].

Lymphocytes play an important role in maintaining liver homeostasis. Innate lymphoid cells (NK cells, ILC 1, 2, 3s) and innate-like T-lymphocytes (NK cells, gd T-cells, and MAITs) are scattered through the liver parenchyma and they share similar phenotypes and functional properties depending on the setting of the liver microenvironment. Many of them show tissue-resident features and act as sentinels and frontline defenders in response to antigen stimulation and function in immunosurveillance. They also contribute to immune regulation and maintain a tolerogenic environment [11,12].

Gut, microbio­me and the gut-liver axis

In addition to digestion and absorption, the gut plays an important role in human immunity. This function is provided by gut-associated lymphoid tissue (GALT), the largest immunological organ in the human body. GALT is composed of diffuse lymphoid tissue, intestinal lymphoid follicles, Payers patches and mesenteric lymph nodes (MLNs). Effector immune cells of diffuse lymphoid tissue are distributed along the mucosal epithelium and lamina propria and represent the first defense against gut-derived antigens and pathogens [13,14].

Activated B cells differentiate into plasma cells and produce high levels of specific IgA antibodies responsible for the neutralisation of bacterial toxins and pathogens and healthy microbio­ta composition.

Intraepithelial and diffuse T-lymphocytes comprise two subtypes according to their phenotype and maturation process – conventional, which provide the defence against pathogens crossing the epithelial barrier, and unconventional, which have regulation functions and represent immune memory. The other component of this milieu is innate immune cells [15].

Innate lymphoid cells, such as NK, ILC 1–3 and LTi cells, can activate independently of the MHC complex. This is possible owing to a wide spectrum of surface receptors, which intermediate the rapid secretion of cytokines, prompt immune or tolerogenic response and crosstalk with other immune cells [16].

Macrophages are diffusely scattered throughout the intestinal wall and with transepithelial dendrites, they are in direct contact with the epithelial layer, double-layered mucus and intraluminal microbio­me and metabolome content. This organisation enables them to capture and destroy in the process of phagocytosis any pathogens that breach the barrier, clearing impaired epithelial cells and they contribute to the regeneration of the epithelial barrier. Macrophages interplay with microbio­ta and in the physiological condition, they are adjusted to maintain gut homeostasis and immune tolerance through the production of immunoregulatory cytokines (IL-10, TGF-b, etc). They also drive the maturation of Treg cells, Th17 lymphocytes and ILC3. Moreover, they transfer acquired antigens to dendritic cells, which are professionals responsible for the antigen presentation [17].

Dendritic cells are localised in lamina propria and they are responsible for transporting antigen to MLNs for pre­sentation and modulation of the adaptive T-cell response. They also affect the maturation of B-cells and T-cells to effector intestine cells [18,19]. Lymphoid follicles and their aggregates, called Payers patches, act as immune sensors and play a role in immune response development. They integrate antigenic stimuli from the gut by reaching up into the follicles where they communicate with specialised cells (M cells), antigen-presenting cells, macrophages and dendritic cells, and create conditions for B-cell maturation and class switching with the help of T-lymphocytes. These cells then pass to the mesenteric lymph nodes, where the immune response is amplified [14].

Gut-liver axis. Between the gut, its microbio­ta, and the liver is a bidirectional relationship. Liver products through the biliary tract influence the composition of the gut microbio­me and the permeability of the gut barrier. On the other hand, signals from the gut generated by dietary, genetic and environmental factors impact the liver through the portal vein, immunological, synthetic and metabolic signals. This interplay, called the gut-liver axis, has a key role in maintaining immune homeostasis and its disruption contributes to the pathogenesis and progression of liver diseases [20].

Low-grade inflammation as a driver of progression of liver disease

The liver resident immune system is incessantly exposed to low levels of antigens derived from the gut (called MAMPs or PAMPs [Microbial-associated molecular patterns and Pathogen-associated molecular patterns]) and damaged liver parenchyma (called DAMPs [Damage- -associated microbial patterns]). Because of highly specialised self-regulatory mechanisms mediated via TLR-receptors, these antigens rapidly induce and later resolve inflammatory responses to maintain homeostasis [1].

Pathogen-associated molecular patterns represent microbes or microbial components such as lipopolysaccharides (LPS), flagellin, lipoteichoic acid, peptidoglycan, bacterial-associated unmethylated CpG motifs, single- or double-stranded RNA or DNA, fungal beta-glucan, cytolysin, candidalysin, etc [4,21,22].

Damage-associated molecular patterns represent intracellular molecules released from damaged cells, such as nuclear and mitochondrial DNA, HMBG1, ATP, etc [23]. These distinctive molecules bind to specific pattern recognition receptors (PRRs) located on the membrane (Toll-like receptors, TLRs) or inside the immune cells (Nucleotide-binding oli­gomerisation domain-like receptors, NLRs, Retinoic acid-inducible gene I-like receptors, RIGRs) and consequently activate signalling pathways leading to an inflammatory response. This process activates the formation of the cytosolic multiprotein complex called inflammasome, which promotes transcription, maturation and secretion of proinflammatory cytokines such as IL-1b and IL18 (canonical activation) or IL-1b and IL-1a (non-canonical activation) [24,25]. Activated hepatocytes, Kupffer cells, macrophages and other resident myeloid cells release cytokines, which promote local and systematic inflammatory response, activation and recruitment of immune effector cells and further cytokine production. Also activated are resident T-cells to functional effector T-cells responsible for pathogen clearance. The first immune cells that infiltrate the liver are neutrophils that remove pathogens by phagocytosis, releasing antimicrobial agents and generating extracellular traps. Simultaneously, neutrophils release a large number of proinflammatory cytokines (TNF-a, IL-1b, IL-6, plate-derived growth factor, TGF-b) and express activation markers (CD11b and CD62L). Other recruited cells are monocytes, which differentiate into macrophages and change their activation state and phenotype to M1 – proinflammatory or M2 – anti-inflammatory. Released cytokines also activate hepatic stellate cells responsible for extracellular matrix production and fibrogenesis initiation [6,26]. Physiologically, for the resolution of fibrosis, the responsible cells are macrophages, NK cells, and CD8+ tissue-resident memory T [27].

Persistent antigen stimulation from the gut together with an underlying liver disease generates a continuous pro-inflammatory response that overcomes anti-inflammatory mechanisms. This process comprises intracellular changes leading to abnormal sensitivity of signalling pathways to lipopolysaccharide, defective production of the anti-inflammatory cytokines such as IL-10 by Kupffer cells and LSECs [28], monocyte and macrophage polarisation toward M1 pro-inflammatory phenotype persistently releasing proinflammatory cytokines such as TNF-a, IL-1b, IL-6, etc [29]. These changes lead to progressive loss of tolerance and an excessive pro-inflammatory response upon antigen recognition. Chronic inflammation is responsible for progressive fibrogenesis and architectural distortion of the liver and contributes to haemodynamic disturbances and the development of portal hypertension [26,30].

An anatomical and functional relationship between the gut and the liver plays a key role in the pathogenesis of cirrhosis and the development of complications of cirrhosis [31–33]. The microbio­me composition and intestinal functions are affected by several aetiological factors of chronic liver diseases, such as alcohol use and a diet low in fiber, and on the other hand by changes during the progression of chronic liver disease [34,35]. Decreased gut motility caused by activated compensatory neurohumoral mechanism, reduced primary and secondary bile acid synthesis, decreased enterohepatic circulation, impaired FXR signalling which is important in the epithelial barrier, and portal hypertension contribute to gut and microbio­me changes [13].

The shift in the microbio­me composition comprises reduced bacterial diversity (number of different species and composition of species), imbalance in potentially pathogenic bacteria (Fusobacteria, Proteobacteria, Enterococcaceae and Streptococacceae), and potentially beneficial autochthonous bacteria (Bacteroidetes, Ruminococcus, Roseburia, Veillonellaceae and Lachnospiraceae), increased bacterial load and bacterial overgrowth. Alterations of the gut microbio­me (dysbio­sis) are comprised not only by bacteriome but also fungome and virome [36–39]. Bacterial overgrowth is associated with decreased motility and increased adherence of bacteria to the mucosal and epithelial layer, which results in fermentation of the luminal content and changes in the microbial metabolites, leading to thinning of the mucosal layer and loosening of epithelial tight junctions. Leaky gut ensues with a disruption of the intestinal barrier, leading to activation of mucosal immune cells and bacterial translocation to the portal and systematic circulation [40–43]

Dysbio­sis, bacterial overgrowth, increased adherence to the epithelial layer, breakdown of the intestinal-vascular barrier and bacterial translocation lead to persistent stimulation of gut-associated lymphatic tissue, resulting in subclinical inflammation. These changes are evidenced by the higher number of activated pro-inflammatory monocytes and dendritic cells, the higher number of T-lymphocytes polarised to Th1 regulatory phenotype and concomitant Th17 depletion [44,45]. The inflammatory process decreases secretion of antibacterial peptides, IgA, defensins, which along with pro-inflammatory cytokines such as IL6, TNF and INF gamma boost bacterial overgrowth and translocation [20,46–48].

The gut thus becomes the driver of low-grade systemic and liver inflammation and chronic liver disease progression. Microbial components and viable bacteria reach the portal circulation and as PAMPs activate inflammatory response in the liver. In addition, some of the bacterial products such as cytolysin (secreted by Enterococcus faecalis) and candidalysin (secreted by Candida albicans) translocated from the gut, directly damage hepatocytes and activate inflammatory response through DAMPs [13,49]. The inflammatory reaction in the liver is augmented by proinflammatory cytokines and activated immune cells released from the GALT. The progression of liver disease is also facilitated by proangiogenic molecules liberated from GALT, that promote angiogenesis and contribute to the development of portal hypertension [50–52]. This proinflammatory setting of the immune system represents the low-grade systematic inflammatory phenotype of CAIDS [4].

High-grade inflammation as the driver of decompensation and ACLF

Local inflammation in the liver driven by the proinflammatory setting of the gut-liver axis leads to the progression of chronic liver disease to cirrhosis. The breakthrough in immune tolerance is responsible for dysregulated immune response and the development of systematic inflammation. [53,54] This change is displayed by increased plasma levels of acute-phase proteins such as CRP, LPS-binding protein, pro-inflammatory cytokines (TNF, IL-1b, IL-6, IL-8, IL-17, IFNg) and their soluble receptors such as TNF soluble receptors I and II, and as cirrhosis, progresses to decompensated or ACLF continuous increase anti-inflammatory cytokines. (IL-10, IL-1RA) [55] The profile of circulating cytokines depends particularly on the aetiology of cirrhosis: while in alcohol-associated liver disease (ALD) IL-8 dominates, in chronic hepatitis B and C IL-6 and IL-18 dominate [56]. Lasting recruitments of immune cells into the liver represent an increased level of chemokines and endothelial activation markers (MIP, P-selectin, ICAM1, VCAM1, VEGF, etc). Inflammatory cytokines activate circulating immune cells [57]. Activated neutrophils increased their respiratory burst activity and express activation marker CD11b (receptor which mediates adhesion and cytotoxic activity) [58]. Circulating monocytes show an increased level and predominance of non-classical CD14+16+ pro-inflammatory and pro-fibrotic subset with increased expression of human leukocyte antigen DR (HLA-DR) and costimulatory molecules (CD80/CD86) and increased TNF production [59–61]. For activated T-cell, polarisation to TH1 – proinflammatory phenotype, which produces high levels of IFN-g, is typical [62]. Another sign of B-cell activation is increased expression of HLA-DR and costimulatory molecules [63].

Parallel with systematic inflammation, portal hypertension progresses and specific compensatory mechanisms are activated: splanchnic vasodilatation, activation of the compensatory neurohumoral mechanisms, the hyperkinetic circulation and portosystemic shunting. Portal hypertension and systematic inflammation, which also aggravate the dynamic component of portal hypertension, are pivotal factors in the transition from compensated to decompensated cirrhosis and the development of ascites, hepatic encephalopathy and variceal haemorrhage [26]. The systemic inflammation increases across the subtypes of acute decompensation (stable decompensated cirrhosis SDC > unstable decompensated cirrhosis UDC > pre-ACLF), with the highest degree reached in the ACLF phenotype where it intermediates multiple organ dysfunction [64]. The reason for the burst of systematic inflammation is an episodic aggravation of translocation of viable bacteria and bacterial products, or precipitant events such as bacterial infection, alcoholic hepatitis, the flare of hepatitis, etc [65].

Systematic inflammation plays an important role in the organ dysfunction associated with decompensated cirrhosis and ACLF by its synergic effect with already established effective arterial hypovolemia, portal hypertension, hyperammonemia, immune pathology and metabolic dysregulation [66].

Proinflammatory cytokines stimulate endothelial cells in splanchnic circulation to produce NO and other vasodilators, which intensify splanchnic vasodilatation and effective blood volume reduction. These changes simultaneously hyperactivate the compensatory mechanism and increase the level of circulating vasoconstrictors, such as noradrenaline, renin-angiotensin-aldosterone axis and vasopressin. [26,67,68].

Haemodynamic changes and exposure to vasoactive and pro-inflammatory substances induce and aggravate cirrhotic cardiomyopathy and cardiovascular dysfunction [69,70]. Proinflammatory cytokines also activate hepatic-stellate cells, which increase their fibroproduction and contractibility, and hand in hand with the local imbalance of vasoactive substances they significantly increase a dynamic component of portal hypertension [71]. Inflammatory molecules furthermore affect tissue and somatic cells and induce their damage in a process called immunopathology [66].

In the kidneys, they affect the highly metabolic active part – tubular cells – and cause mitochondrial injury, upregulation of renal TLR, inflammasome activation, hypersecretion of TNF alpha into the luminal fluid, leukocyte infiltration and oxidative burst damage, leading to tubular damage. In addition, they induce endothelial dysfunction, capillary micro-thrombosis and ischaemic injury. All these changes aggravate haemodynamically induced renal dysfunction and contribute to HRS-AKI (hepatorenal syndrome of the acute kidney injury type) [72–75].

Proinflammatory cytokines also affect the brain tissue and, along with hyperammonemia and translocated gut-driven microbial products and inflammatory substances, participate in the development of hepatic encephalopathy. They activate endothelial and resident immune cells such as microglia and astrocytes, induce local cytokine production and disrupt neurotransmission. Simultaneously, they affect the permeability of the haematoencephalic barrier, leading to the recruitment of circulating immune cells to the brain and a higher supply of ammonia and other toxic substances. These changes aggravate the clinical manifestation of hepatic encephalopathy [76].

Systematic inflammation is responsible for immunometabolic changes because of high metabolic demand requiring the reallocation of nutrients. Proinflammatory cytokines stimulate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system to proteo- and lipolysis, subsequently leading to the release of amino acids and lipids to fuel hypermetabolic active immune cells. In parallel, lipids and their derivates, acting directly as immune stimulants and amino acids (and ammonia) worsen mitochondrial function, leading to catabolism and neutrophil dysfunction. These cytokines also inhibit nutrient consumption in peripheral tissue. These processes lead to catabolism and loss of skeletal muscle mass and function (sarcopenia) and adipose tissue mass [77]. In addition, cytokines cause the metabolic switch to reduced oxidative glucose metabolism in the mitochondria, increased extramitochondrial glucose utilisation through aerobic glycolysis and pentose-phosphate pathway leading to decreased ATP production and increased ROS production responsible for further tissue injury and DAMPs release. Immunometabolic changes play an important role in the disease progression and progressive exhaustion of the immune system [26].

These changes represent a high-grade inflammation phenotype of CAIDS. [4] Systemic inflammation is the major driver of progression from compensated to decompensated cirrhosis, acting synergistically with organ-specific mechanisms in the development of major complications of cirrhosis and there is a specific connection to mortality. ACLF, a syndrome characterised by acute decompensation of chronic liver disease which is associated with organ failure and high short-term mortality, represents an example of the most severe systemic inflammation (e. g. much higher than in sepsis) [55,68]. This is called the fulminant immunophenotype of CAIDS and is exemplified by elevated CRP, white blood cells, and pro-inflammatory cytokines, together with increased anti-inflammatory cytokines and soluble markers of macrophage activation (sCD163 and mannose receptor) [78]. Discerning this immunological subtype of ACLF could lead to personalised prognostic stratification and therapy – e. g. the plasma exchange (Fig. 1) [79].

Immune paralysis

Chronic systemic inflammation with dysregulated pro-inflammatory reactions and damage of barriers in diverse compartments all cause immune cell exhaustion and reprogramming. Continuously stimulated immune cells switch into non-responsive phenotype leading to dysfunctional effector response and immune paresis. Whilst each cirrhosis aetiology has its distinctive features of immune paresis, most of the pathophysiological mechanisms are common to all aetiologies [66,79].

Innate immune cells

Neutrophils, thought of as pawns of the immune system, are paralysed in many of their functions [60,80,81]. Long-lasting exposition to proinflammatory cytokines affects many intracellular pathways leading to defect chemotaxis, migration (reduced expression CXCR1 and CXCR2 receptors [82], defect activation IL33/ST2 [83]), opsonisation, impaired phagocytic activity, respiratory burst (defect activation AKT, MAPK, NADPH oxidase pathway) [84,85] and reduced formation of neutrophil extracellular traps [86–88]. Besides functional derangement to immune paresis contributes also splenic sequestration [89].

Monocytes. The switch to the immunosuppressed state also impacts monocytes. [60] Immunogenetic and immunometabolic reprogramming of mainly classical (CD14+CD16−) monocytes is responsible for defective chemotaxis, phagocytosis (e. g. Fcg receptor impairment) [90], enzymatic and superoxide production (dampened expression of IRIF and PRKCE is associated with defective NADPH oxidase) [91]. Abundantly present in the circulation are immunoregulatory monocytes − AXL-expressing monocyte population (CD14+CD16highHLA-DRhigh) characterised by attenuated TNF-a/IL-6 responses and T-cell activation [92] and monocytes that express MER receptor tyrosine kinase (MERTK) responsible for downregulation of innate inflammatory immune responses and inhibition of TLR activation and pro-inflammatory cytokine production [93]. Functional analyses of immunoparalysed monocytes show decreased HLA-DR expression, which refers reduced antigen-presenting ability, decreased production of pro-inflammatory cytokines (e. g. IFN- g, TNF-a, IL-6) after microbial challenge through NF-kB pathway inhibition, and enhanced anti-inflammatory (e. g. SLPI) mediator secretion [94–96].

Adaptive immune cells.

Ineffective production of naïve T-cells because of defective thymopoiesis [97] and increased splenic sequestration is responsible for T-cell depletion in circulation. T-cell lymphopenia is also worsened by an imbalance between apoptosis and peripheral proliferation. Continuously stimulated memory lymphocytes express a higher level of apoptosis marker CD95+, and they are unable to proliferate in response to new antigenic stimulation [98]. In circulation, dysregulated specific types of lymphocytes are also present. MAIT cells (mucosal-associated invariant T-cells) with high antimicrobial potency are reduced, hyperactivated and incompetent in response to antimicrobial and cytokine stimulation [99,100]. Also present is the immunosuppressive subset of HLA-DR+CD8+T-cells with co-expression PD1 (program cell death protein 1), TIM3 (T-cell immunoglobulin and mucin domain-containing protein 3) resulting in reduced TNF and IFN production [101,102]. The B-cell compartment is also affected due to reduced count and pathological function, especially in the memory cell subset. The loss of CD27+ memory cells associated with impaired TNF-b and IgG production and impaired allostimulatory capacity contributes to immune paresis. The remaining B-cells are less effective at stimulating CD4+ T-cell responses, hyporesponsive to activation via CD40 and TLR9, with impaired upregulation of costimulatory markers, production of TNF-b and production of IgG [103]. Dysfunction of NK cells with reduced cytotoxic activity also contributes to immune paralysis [104].

Lasting systematic inflammation triggers the expansion of mononuclear CD14+CD15−CD11b+HLA-DR− myeloid-derived suppressor cells (M-MDSCs), which continuously dampen the immune response. M-MDSCs are responsible for suppressing T-cell activation, pathogen uptake and Toll-like receptor (TLR) -elicited proinflammatory responses to microbial challenge. They are associated with ACLF, and their persistence during disease progression predicts a poor outcome and an increased incidence of infections [105].

A key role in immune reprogramming is also played by soluble molecules such as anti-inflammatory cytokines IL-10 and IL-1RA. IL-10 through inhibition of NF-kB reduces monocyte secretion of TNF, IL-1, IL-6, IL-8 and IL-12, reduces the secretion of IFN- g and correlates with the expression of inhibitory receptors in monocytes (MERKT), lymphocytes (PD1) and TIM3 [106–108].

In addition to changes in immune cells and circulating immune molecules, structural derangements of liver parenchyma contribute to the immunological burn-out. Capillarisation of sinusoids, fibrosis and a damaged reticuloendothelial system cause reduced decreased clearance, portosystemic shunting leads to the continual spread of microbes and distinctive molecules to systematic circulation, impairment of Kupfer cells contribute to immune dysregulation [109]. Moreover, decreasing the synthesis of immune proteins and receptors such as complement, soluble PRRs, albumin, proteins of the acute phase (CRP, MBL, hepcidin, fibrinogen, proteinase inhibitors) plays a role in an incompetent immune response [110]. Albumin is physiologically able to bind immunoactive molecules (pro-inflammatory and immunosuppressive) such as prostaglandin E (PGE2). Because of structural dysfunction and decreased concentration of albumin, the plasmatic concentration of PGE2 is significantly higher and it contributes to macrophage dysfunction [111,112]. Other molecules that have a negative impact on immune tolerance are circulating catecholamines, tryptophan catabolites and ammonia, causing neutrophil swelling and impaired phagocytosis [113].

Conclusion

Dynamic alterations of the immune system which parallel the pathophysiological cascade from chronic liver disease to liver cirrhosis to ACLF are comprised of the spectrum of phenotypes of CAIDS from long-lasting low-grade inflammation of CLD to a high-grade inflammation of acute decompensation of cirrhosis and ACLF, to immune exhaustion and so-called indolent death. The disruption of tolerogenic mechanisms in the liver leads to low-grade systematic inflammation, which is responsible for progressive fibrogenesis. A key role in the disease progression is played by the gut-liver axis, because of continuous antigen stimulation driving inflammatory response and cirrhosis progression. The ongoing dysregulation of systematic immune response leads to high-grade inflammation, which acts complementarily to organ-specific mechanisms in the development of cirrhosis decompensation or ACLF and a fulminant phase of CAIDS. Long-lasting high-grade inflammation causes immune cell exhaustion and reprogramming to non-responsive phenotype – an indolent immunophenotype of CAIDS. This phase is characterised by problematic infections by opportunist pathogens [114–116]. It is very important to recognise these phenotypes, as they represent the evolutionary phases of progression, convey prognosis and govern the management.

ORCID authors

D. J. Havaj ORCID 0000-0001-5979-8326,

Ľ. Skladaný ORCID 0000-0001-5171-3623.

Doručené/Submitted: 16. 3. 2022

Prijaté/Accepted: 28. 3. 2022

Daniel Ján Havaj, MD

Internal Med Department II

Slovak Medical University

Division of Hepatology, Gastroenterology and Liver Transplantation

FD Roosevelt Hospital

L. Svobodu 1 Square

975 17 Banska Bystrica

havaj.daniel@gmail.com