diseases and microbial infections and participate in mucosal immunity and tumor surveillance.
Table 2.2 Comparison of selected features of innate and adaptive immunity.
| Innate immunity | Adaptive immunity | |
| Characteristics | ||
| Onset | Rapid responses mediated by preformed PRRs for microbial PAMPs and DAMPs | Delayed due to requirement for antigen activation, clonal proliferation and maturation of effector cell functions |
| Specificity | PAMPs, DAMPs, ROS, activated C′ proteins, apoptotic bodies | Epitopes of peptide antigens recognized by TCRs or B‐cell immunoglobulins |
| Genetics | Restricted, germline‐encoded | Complex with TCRs and antigen‐binding domains of immunoglobulins produced by somatic recombination of gene segments |
| Diversity | Limited Evolutionarily conserved | Virtually infinite due to TCR rearrangement |
| Memory | No | Yes. Memory T‐ and B‐cell responses capable of anamnestic reactivation |
| Self‐tolerance | Discriminates pathogens and endogenous DAMPs. Not responsive to autoantigens | Positive and negative selection of TCR and B‐cell immunoglobulin reduce autoreactive capacity |
| Components | ||
| Physical barriers | Skin, mucosal epithelia of oropharynx, gut and reproductive tract, antimicrobial proteins | Intraepithelial lymphocytes within gut, Peyer's patches |
| Cells | Dendritic cells, monocytes, macrophages (Kupffer cells), neutrophils, NK cells, NKT cells | Professional APCs, αβT cells, γδT cells, natural and inducible Treg cells, B cells, plasma cells |
| Proteins | C′ proteins, IFN‐α, ‐β, ‐γ, cytokines, chemokines | T‐cell cytokines IgM, IgG, IgA, IgE antibodies |
| Role of liver as an immunologic organ | Yes DCs, neutrophils, Kupffer cells, excessive concentrations of NK cells, NKT cells IFN‐α, ‐β, ‐γ, balance between proinflammatory and immunosuppressive chemokines | Yes Antigen presentation by Kupffer cells, LSECs, HSCs, cytokines stimulate hepatocytes and cholangiocytes, PD‐L1/2 induce senescent T‐cell apoptosis and inhibition of activated CD8 T cells |
C′, complement; DAMPs, damage‐associated molecular patterns; HSC, hepatic stellate cell; IFN, interferon; LSEC, liver sinusoidal endothelial cell; NK, natural killer; PAMPs, pathogen‐associated molecular patterns; PD‐L1/2, programmed death ligands 1 and 2; PRRs, pattern recognition receptors; ROS, reactive oxygen species; TCR, T cell receptor.
Examples of common PAMPs: (i) lipopolysaccharide (LPS), a cell wall constituent of all Gram‐negative bacteria; (ii) lipotechoic acid, a cell wall constituent of all Gram‐positive bacteria; (iii) peptidoglycans, essential cell wall components of all bacteria; (iv) viral proteins; and (v) unmethylated bacterial CpG dinucleotide motifs.
Examples of common DAMPs: (i) nuclear proteins; (ii) cytosolic proteins and lysosomal enzymes; and (iii) non‐proteins, such as ATP, DNA, RNA, mitochondrial DNA, U1 ribonucleoprotein (U1RNP) and uric acid.
Microbial PAMPs bind predominantly to PRRs called Toll‐like receptors (TLRs). DAMPs bind to PRRs and receptors for chemical ligands or nuclear constituents. Still other innate receptors bind apoptotic bodies and activated complement (C′) molecules. PAMPs and/or DAMPs activate DCs and macrophages (including Kupffer cells), increasing phagocytic activity and inducing secretion of chemokines and proinflammatory cytokines interleukin (IL)‐1β, IL‐6, IL‐12, and IL‐18 and tumor necrosis factor (TNF)‐α, as well as the immunosuppressant cytokine IL‐10 [3]. The relative amounts of specific PAMPs, DAMPs, cytokines and chemokines creates a dynamic balance between proinflammatory and immunosuppressive cytokines that determines whether the adaptive immune response promotes immunopathology (Figure 2.2).
Liver as an Innate Immune Organ
The liver is an essential innate immune organ that must either tolerate or respond to microbial PAMPs, toxins, xenobiotics, food antigens, microbial pathogens, and neoplastic cells [6]. The liver contains specialized liver sinusoidal endothelial cells (LSECs) and large quantities of Kupffer cells, DCs and NK, NKT and γδT cells. Most intrahepatic B cells are B1 cells, an innate B‐cell subset that secretes low‐affinity IgM antibodies against glycoproteins, called “natural antibodies.”
The liver also synthesizes C′ proteins, acute‐phase reactant proteins, and multiple cytokines. PAMP and DAMP activation of TLRs on Kupffer cells, LSECs, hepatocytes, DCs and HSCs primarily generates IL‐10, providing an immunosuppressive environment. However, high quantities of PAMPs or DAMPs induce the proinflammatory cytokines IL‐1β, IL‐6, IL‐12, IL‐18 and TNF‐α. HSCs normally produce matrix proteins, but once transformed into myofibroblasts they secrete collagen, resulting in fibrosis. PAMPs and DAMPs also induce NLRP3 inflammasome responses [5] in hepatocytes, cholangiocytes and HSCs, resulting in their secretion of proinflammatory cytokines and chemokines.
The reticuloendothelial function of the liver normally prevents PAMPs, DAMPs and microbial antigens in portal venous blood from entering the systemic circulation. This barrier function of the liver also plays a role in oral tolerance. Hepatic lymph formed in the space of Disse flows retrograde into portal tract lymphatics. Thus, hepatic lymph exposes portal bile ducts, arterioles and portal vein branches to variable amounts of PAMPs, DAMPs, cytokines, chemokines, proteins, lipoproteins, and lipids.
Adaptive Immunity and Adaptive Immune Functions of the Liver
As shown in Figure 2.2, the adaptive immune system in autoimmunity generates multiple, delayed, autoantigen‐specific effector immune responses [4]. Most adaptive immune responses occur in lymph nodes and spleen; thus, effector cells must circulate to tissues expressing autoantigens to mediate immunopathology. Class II HLA‐DR, ‐DQ or ‐DP molecules present peptide autoantigens to T‐cell receptors (TCRs) of autoreactive CD4 T cells. In contrast, class I HLA‐A, ‐B or ‐C molecules present peptide autoantigens to TCRs of autoreactive cytotoxic CD8 T cells, also known as cytotoxic T lymphocytes (CTLs). Polymorphisms in HLA class I and II alleles determine which autoantigens can be presented to T cells, which explains the strong association of autoimmunity with specific HLA alleles [2]. Polymorphic class III HLA alleles encode immune response proteins, including TNF‐α/β, complement (C′) factors and heat‐shock proteins. The balance between proinflammatory and anti‐inflammatory cytokines produced by local innate immune responses determines the polarization of cytotoxic mechanisms of the adaptive immune response (Figure 2.2).