The innate immune system provides defense against, and an immediate response to, all types of pathogen. It works at two levels in the body. An external defense system is designed to prevent active pathogens gaining access to internal tissues and body fluids (by internal tissues, we mean those beyond the surface epithelium of the skin, digestive tract, respiratory tract, urinary tract, and so on). The external defense system comprises some barriers that simply act as passive defensive shields plus active defense systems that seek to inactivate pathogens before they get to internal tissues.
The second level of defense is internal. It occurs when the external barriers have been breached, and pathogens have gained access to internal tissues and body fluids. Then a rapid immune response (which is much the same from one normal individual to another) is mounted to combat infection. (If the defense is unsuccessful after about four or so days, the adaptive immune system is pressed into action as a last resort.)
Innate immune responses depend on two components. First, there must be highly accurate pattern-recognition mechanisms that identify microbial pathogens as being foreign, for example by identifying protein or carbohydrate components of the cell walls or cell membranes of the pathogen. Second, effector mechanisms are then activated to kill the recognized invaders, requiring diverse immune system cells and many different soluble proteins and cell surface proteins.
Defensive barriers
To protect us against dangerous pathogens, defense is a priority: surface layers in con tact with the environment must be securely protected from pathogens, notably those of the skin and the gastrointestinal and respiratory tracts. In the case of skin, the epidermis (the top, outermost layers) is made of stratified squamous epithelium sheets that are renewed by stem cells in the lower (basal) layers. The layers lying above the basal layers progressively contain differentiated cells, culminating in an outer layer of very tough keratinocytes that lack nuclei and other organelles, providing a resistant outer coat. If the skin is damaged by cuts, the resulting bleeding and blood clotting process can provide a temporary repair while the skin effects proper repairs.
Epithelial cells, such as those of the intestinal epithelium, can also benefit by a type of cell junction known as a tight junction that provides the closest contact between adjacent cells in nature. The tight junctions act like bands that encircle each epithelial cell close to the surface and also attach the cell tightly to its neighbors, preventing molecules from diffusing across the epithelial sheet between adjacent cells.
Mucus, a viscous, slippery substance secreted by mucous membranes, acts as a protective lubricant coating the cells and glands of some mucous membranes, such as the nasal mucosa and mucosal tissues lining the airways. The thick mucus can trap bacteria; thereafter, coordinated beating of cilia lining the surrounding epithelia drives the trapped bacteria upward to the throat, to be expelled by coughing or sneezing, or to be swallowed and destroyed in the stomach.
Chemical and biological barriers include hydrochloric acid in the stomach, antimicrobial enzymes (lysozyme) in tears and saliva, antimicrobial peptides (notably defensins), and the nonpathogenic bacteria of our microbiome. Defensins, peptides with about 35–40 amino acids, are constitutively secreted at mucosal surfaces and can enter the cell membranes of microbes and disrupt them by forming pores. The nonpathogenic microbes on our skins, and notably in the gut, discourage colonization by pathogenic microbes simply by providing competition for growth resources.
Complement activation
In addition to phagocytosis (by macrophages, monocytes, and neutrophils), one of the very first innate immune responses is provided by the complement system, often just called complement. This group of more than 20 interacting soluble complement proteins is found in blood and lymph and works with complement receptors, found notably on the plasma membranes of macrophages. Complement proteins are mostly made by the liver, but blood monocytes, tissue macrophages, and epithelial cells of the gastrointestinal and genitourinary tracts can also make significant amounts.
Constitutively produced complement proteins circulate in blood and lymph but remain inactive until the complement system is activated by some trigger. Then the complement proteins work in pathways that begin with a protease cascade (an activated complement protease specifically cleaves another complement protein, converting it in turn to an active protease that cleaves the next complement protein in order to activate it, and so on).
The major purpose of complement is to kill or inactivate microbial pathogens and induce inflammatory responses. In the former case, pathogenic bacteria can be killed directly when complement proteins form a membrane attack complex that punches holes in the pathogen’s cell membrane (Figure 1A). An additional option is indirect killing of pathogenic microbial cells (and inactivation of viruses) by assisting macro phages: a complement protein, C3b, is deposited on the surface of microbial pathogens to make them more readily recognized and destroyed by phagocytes such as macro phages (a process called opsonization; see Figure 1B).
Fig1. Two principal effector mechanisms of the complement system. (A) Killing of microbial pathogens by assembling a membrane attack complex to perforate the cell membrane. A complex of complement proteins C5b, C6, C7, and C8 assembles at the cell membrane of the pathogen and is able to recruit multiple copies of the complement C9 that integrates into the cell membrane and forms a large pore. Dark gray arrows indicate the resulting efflux of essential material from the cell, causing it to be destroyed. (B) Assisting macrophages by opsonization. Complement C3b selectively coats the surfaces of microbial pathogens (by covalently binding to amino or hydroxyl groups of cell surface molecules) and targets them for destruction by phagocytes, notably macrophages. The latter have cell surface complement receptors (CR) plus pattern-recognition receptors to identify microbial cells (and viruses). After binding the C3b coated pathogen they internalize it and destroy it by phagocytosis (as shown in Figure 3.19B). (Adapted from Parham P [2014] The Immune System, 4th edn. Garland Science. With permission from WW Norton.)
According to the trigger, three variant complement pathways are sequentially employed in innate immune responses (Table 1). Although the initiating steps are different in the three pathways, in each case production of the key complement C3 protein is amplified to very large quantities. Small amounts of C3 spontaneously hydrolyze to give two fragments, C3a and C3b, but when a complement pathway is initiated, C3 convertase enzymes are produced that cleave C3 to produce large amounts of C3a and C3b and they become important effector molecules (Figure 2).
Table1. CHARACTERISTICS OF THE THREE PATHWAYS OF COMPLEMENT ACTIVATION
Fig2. Complement proteins and effector functions. Different upstream initiation events are used in the three different complement pathways that respond to different triggers (see Table 3.4). In each case, complement activation results in cleavage of the complement C3 protein (which is produced in large amounts) to give two fragments. The larger fragment, C3b, is used in two ways. First, it works in opsonization, coating the surface of microbial pathogens so that they can be recognized and killed by phagocytes (such as macrophages, which have complement receptors). Second, it binds to various other complement proteins to produce a complex that cleaves the complement C5 protein to give a small fragment C5a plus a large C5b protein. C5b binds to other complement proteins to form a membrane attack complex that directly kills pathogens (see Figure 3.20). The small peptides C3a and C5a act on nearby blood vessels to augment local inflammatory responses.
When C3 is cleaved, a thioester bond that had been hidden in the hydrophobic interior of C3 is suddenly exposed, as part of C3b, to the hydrophilic environment. Although the thioester bonds of most C3b fragments are spontaneously hydrolyzed by water, some react with hydroxyl and amino groups on molecules on the surface of a pathogenic microbial cell or virus and C3b becomes covalently bound to the pathogen (complement fixation). The C3b tags on the surface of the pathogen allow it to be recognized and bound by macrophages (which have complement receptors—see Figure 3.20B—plus other receptors that can recognize cell surface components of pathogens, as described in the next section). C3b also gives rise to C5b, which is important in forming membrane attack complexes, and C3a and another complement peptide that are important in inflammatory responses (see Figures A and 2).
Pattern-recognition mechanisms
In the adaptive immune system, special mechanisms exist to diversify antibodies and T-cell receptors so that we can each recognize huge numbers of foreign antigens. Given the extensive variety of pathogenic organisms and viruses, how does the innate immune response distinguish pathogens? The answer is pattern-recognition mechanisms used by a wide variety of receptors in various cell types, including epithelial cells as well as immune system cells such as macrophages. The receptors scan for particular types of molecular patterns that are unusual for body cells but are instead associated with pathogens (for example, components of cell walls of bacteria) or with danger.
As an illustration of the diversity of pattern-recognition receptors, we provide some characteristics of three of the more important receptor families in Table 2. Classification of receptor families is primarily based on shared structural motifs, but there can be wide variation in the types of ligand recognized by members of a receptor family. Thus, whereas members of the C-lectin receptor family recognize various carbohydrate patterns on the surface of fungal and bacterial cells, members of the Toll-like receptor family detect a very wide range of ligands (Table 2).
Table2. SOME CHARACTERISTICS OF THREE IMPORTANT FAMILIES OF INNATE RESPONSE PATTERN RECEPTORS
Scanning for pathogen-associated molecular patterns occurs at different levels. Plasma membrane receptors carry out extracellular scans, and receptors located on internal endosomal membranes detect their ligands in intracellular vesicles. Some pattern-recognition receptors act as true intracellular sentinels, including cytoplasmic and occasionally nuclear receptors, and are able to detect unusual molecular patterns within these intracellular compartments. For example, the cytoplasmic receptors NOD1 and NOD2 detect bacteria or bacterial components entering the cytoplasm, and in response initiate an NF-κB signaling pathway that produces various cytokines that trig ger inflammatory responses.
Note that the pattern-specific receptors are also important in recruiting the adaptive immune system. For example, once stimulated, Toll-like receptors induce the surface expression of co-stimulatory molecules that are essential for initiating adaptive immune responses (see below) and stimulate the secretion of pharmacologically active molecules (mostly prostaglandins and cytokines) that both initiate an inflammatory response and also help induce an adaptive immune response.
Natural killer (NK) cells
NK cells, a class of giant, granular, cytotoxic lymphocyte (but lacking antigen- specific receptors), have an effector function that is broadly similar to that of cytotoxic T lymphocytes (CTLs) in the adaptive immune system: to induce apoptosis in virus infected cells and other damaged or abnormal body cells, such as tumor cells. In the former case, recall that extracellular viruses can be coated by complement C3b and then targeted for destruction by macrophages, but viruses remaining inside cells are not visible to the complement system. However, once viruses have been detected inside body cells, NK cells are recruited to induce the virus-infected cells to undergo apoptosis.
Both intrinsic and extrinsic apoptosis pathways are used by NK cells. In the former case, NK cells bind to diseased cells, and via exocytosis release the contents of their secretory granules (perforins and granzymes) into the intercellular space (Figure 3). The perforins insert into the membrane of the target cell in a way that creates pores in the membrane to allow the pro-apototic granzymes to enter the target. For the extrinsic pathway, Fas ligands on NK cell membranes activate Fas receptors on the surface of target cells to initiate apoptosis.
Fig3. NK cells can induce apoptosis by secreting perforins and granzymes close to the surface of target cells. (A) Cytoplasmic secretory granules, containing perforin and granzyme molecules, are transported via the microtubule network toward the NK cell membrane at a point close to the target cell. (B) The secretory granules fuse with the NK cell plasma membrane (exocytosis) and released perforins form large transmembrane pores in the target cell membrane, enabling the diffusion of granzymes into the cytosol of the target cell. The granzymes then initiate intrinsic apoptosis pathways by cleaving procaspases or by cleaving the proapoptotic BID protein to activate the mitochondrial apoptosis pathway (see Figure 3.10). (Adapted from Voskoboinik I et al. [2015] Nat Rev Immunol 15:388–400; PMID 25998963. With permission from Springer Nature. Copyright © 2015.)
