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The innate immune system responds immediately to PAMPs, comprising microbial constituents, and to DAMPs, comprising cellular constituents from stressed, neoplastic or dying cells (Table 2.2). Both PAMPs and DAMPs bind to pattern recognition receptors (PRRs) and other receptors expressed on neutrophils, dendritic cells (DCs), activated macrophages (including Kupffer cells), and natural killer (NK) and natural killer T (NKT) cells [3]. NK cells express killer receptors for stressed, dying or neoplastic cells and Fc receptors that mediate antibody‐dependent cell‐mediated cytotoxicity (ADCC) of target cells coated with antibodies [3]. Antigen‐presenting cells (APCs) activate NKT and γδT cells by invariant HLA class I‐like molecule (CD‐1) presentation of lipid or glycolipid antigens [3]. γδT cells protect from autoimmune 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).