Cirrhosis-associated innate and humoral immune deficits
| Cell type | Physiological role | Functional impairment in cirrhosis |
| Intestinal epithelial cells (IECs) | IECs contribute to the maintenance of symbiotic host–microbiome interactions not only through maintenance of the epithelial barrier and segregation of gut luminal contents but also active secretion of immune mediators and selective antigen presentation. | IECs demonstrate significant alterations in expression of tight junction proteins with reduced expression of occludin and claudin-1 which correlates with severity of chronic liver disease. |
| Liver Sinusoidal Endothelial Cells (LSECs) | LSECs are specialised fenestrated endothelial cells that line the hepatic sinusoids and form an interface between mixed portal venous and hepatic arterial blood and the hepatocyte parenchyma. | Sinusoidal cells become capillarised with loss of fenestration which is an early hallmark of liver fibrosis and not only predisposes to the development of portal hypertension but interrupts the selective transfer of molecules between hepatic sinusoidal blood and the liver parenchyma. |
| Hepatocytes | Hepatocytes play key roles in the biosynthesis of acute phase proteins involved in innate immunity that are upregulated in response to proinflammatory cytokines. Hepatocytes constitutively produce complement proteins that are further expressed in response to inflammation. | Reduced synthesis of immune-active proteins: cirrhotic patients demonstrate reduced levels of complement, soluble PRRs (LPS-BP, soluble CD14) and APPs (mannose binding lectin, ferritin, C reactive protein, hepcidin, fibrinogen). This reduces opsonisation and the effective bactericidal and phagocytic capacity of myeloid cells. |
| Liver Resident Macrophages (Kupffer cells, KCs) | KCs are liver resident macrophages that reside in the liver sinusoids and are able to directly clear bacteria through phagocytosis; they express PRRs and play key roles in regulation of the innate immune response and hepatic fibrogenesis. | KCs have impaired phagocytosis in vivo which is correlated with subsequent development of infection and mortality. KCs demonstrate increased soluble CD163, a marker of activation, in a manner proportional to the hepatic-venous pressure gradient. |
| Neutrophils | Neutrophils are circulating polymorphonuclear cells that comprise an important part of the early innate immune response; they are able to migrate rapidly to sites of inflammation where they facilitate pathogen clearance through phagocytosis and the release of microbicidal proteins. | Neutrophils are primed and exhausted in cirrhosis with increased markers of activation and release of reactive oxygen species. In addition to this they are functionally deficient and have been shown to have impaired chemotaxis, phagocytosis and intracellular killing. Neutrophil dysfunction correlates with 90 day survival. |
| Circulating monocytes | Monocytes are a population of circulating myeloid-derived cells that preserve the potential to differentiate to macrophages and dendritic cells. Monocytes are capable of selective trafficking to sites of inflammation where they phagocytose opsonised microbes, secrete cytotoxins and propagate inflammatory signalling. | Cirrhotic patients demonstrate an increased peripheral frequency of monocytes that show increased baseline markers of activation at the same time as impaired phagocytosis and reduced cytokine responses to bacterial stimulation. Increased monocyte oxidative burst is an independent predictor of transplant-free survival. |
| Natural killer (NK) cells | NK cells are a heterogeneous population of cells that perform critical roles in host defence; they link innate and adaptive responses to tumorigenic and pathogen-infected cells. NK cells directly release cytotoxins in response to microbial challenge and secrete signalling molecules that regulate adaptive cellular responses. | NK cells are conditionally dysregulated in settings of liver diseases. They appear exhausted in settings of chronic infections and tumorigenicity while pro-inflammatory and fibrogenic in responding to acute insults. |
| B lymphocytes | B lymphocytes are important cells of the humoral immune system that function by producing antibodies. Presentation of antigen to the B-cell receptor with T cell costimulation leads to B cell activation, proliferation and differentiation to plasma and memory B cells and the production of specific antibodies. | Vaccine hyporesponsiveness is well documented in patients with cirrhosis and correlates inversely with severity of liver disease. CD27+ memory B cells are depleted in peripheral blood of cirrhotic patients and demonstrate reduced responsiveness to TLR9 activation. |
| CD4+T Cells | CD4 +T cells are essential adaptive immune cells that recognise antigens presented on MHC Class II molecules and augment CD8+T cell, IgG B cell and innate immune cell differentiation and effector function through the release of T cell cytokines. | There is a T cell lymphopenia in cirrhosis affecting both helper (Th) and cytotoxic (Tc) T cell populations. Absolute CD4+T cell counts are reduced in patients with cirrhosis. Reduced peripheral T cell function as assessed by CD4 ATP concentration is independently associated with the risk of developing SBP in cirrhotic patients. |
| CD8+T cells | Cytotoxic CD8+T cells play an important role in surveying cancer cells and virally infected cells through the recognition of antigens presented via MHC Class I molecules. T-cell receptors stimulate CD8+cells to produce cytotoxins in addition to the release of cytokines and local immune cell recruitment. | Decreased levels of interferon-γ and increased levels of the anti-inflammatory cytokine IL-10 were seen in bacterially challenged CD8+T cells in alcoholic hepatitis, reversible through blockade of PD1/TIM3. |
| Th17 and T regulatory cells | Th17 cells and T regulatory cells (Treg) are derived from common naïve T cell precursors with oppositional differentiation and function with respect to the propagation and inhibition of inflammatory responses to antigenic challenge at mucosal surfaces. | T regulatory cells in cirrhotic patients are expanded with a memory phenotype which correlates with bilirubin level and predicts subsequent bacterial complications. There is a Treg/Th17 imbalance in cirrhosis with elevated levels of Th17 correlating with advancing fibrosis. |
| Unconventional T cell populations | This heterogeneous group of highly specialised T cells play a major role in mucosal innate and humoral immune regulation. Mucosa-associated invariant T (MAIT) cells and invariant NKT (iNKT) cells possess semi-invariant T-cell receptors which recognise bacterial metabolites and lipid moieties on antigen-presenting cells and are important regulators of mucosal immune surveillance. | MAIT cells are peripherally depleted in cirrhosis and demonstrate a hyperactivated cellular phenotype with defective cytokine and cytotoxin release in response to bacterial stimulation. Differential subset expression of iNKT populations are demonstrated in varied aetiologies and stages of chronic liver injury. Their role in the development of cirrhosis-associated liver dysfunction requires further evaluation. |
| Innate lymphoid cells (ILCs) | ILCs are important regulators of mucosal immunity and are able to rapidly produce cytokines and chemokines in response to stimulation. They are broadly categorised into three subtypes based on their transcriptional regulation and cytokine expression with differential inflammatory and tolerogenic profiles. | ILC subsets demonstrate differential roles in inflammation, fibrogenesis and tumorigenicity that evolve with the progression of chronic liver disease. Further understanding of the role of conditionally dysregulated ILC populations in contributing to cirrhosis-associated immune dysfunction is required. |
APP, acute-phase protein; ATP, adenosine triphosphate; LPS-BP, lipopolysaccharide-binding protein; MHC, major histocompatibility complex; PRR, pattern recognition receptor; SBP, spontaneous bacterial peritonitis.;