If microbes should penetrate the body’s first line of defense—the mechanical, chemical, and biological barriers—the innate immune system provides the second line of defense (the first immunologic line of defense) against infection. Because its components are always in an activated or near-activated state, responses by the innate immune system occur much faster than those of the adaptive immune system that provides the third line of defense (the second immunologic line of defense).
Once the adaptive system becomes involved, the innate and adaptive immune systems often interact with one another to coordinate their activities. To respond quickly, components of the innate immune system are genetically programmed to recognize molecules associated with broad classes of pathogens. Innate immune responses include the rapid destruction of an infectious organism, activation of phagocytic cells, and the localized protective response known as inflammation. In inflammation, innate (and sometimes adaptive) cells and molecules are stimulated to isolate and destroy infectious agents and trigger tissue repair.
The innate immune system uses a limited number of pattern recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs)—conserved, structural features expressed by microbes but not by the host (see Fig. 2.5). Unlike the epitope-specific somatically generated receptors of the adaptive immune system expressed by B and T lymphocytes, genes encoding PRRs are encoded within the genome and require no additional modification. Because the host does not produce PAMPs, the innate immune system is able to discriminate between self and nonself.
A. Pathogen-associated molecular patterns
The innate immune system distinguishes infectious microbes from noninfectious self cells by recognizing a limited number of widely expressed viral and bacterial molecular structures. PAMPs may be sugars, proteins, lipids, nucleic acids, or combinations of these types of molecules. PRRs on phagocytic cells recognize PAMPs either directly or indirectly by cell-surface PRRs or by soluble molecules that engage a microbe prior to cell-surface receptor contact (e.g., complement and complement receptors, discussed later in this chapter).
PAMP binding immobilizes the infectious organism and may culminate in its ingestion by phagocytes. In addition, PRR engagement often leads to the activation of the host cell, causing it to alter its activity and increase its secretion of antimicrobial substances (Fig. 5.1).
Figure 5.1. PAMP-PRR engagement activates phagocytes.
Binding of PAMPs on microbial surfaces by PRRs on the surfaces of phagocytes activates the phagocytes to ingest and degrade the microbes.
Two common bacterial products that contain PAMPs are lipopolysaccharide and peptidoglycan. Bacterial lipopolysaccharide (LPS) is a major constituent of the outer cell membrane of gram-negative bacteria. Cell-surface molecules on monocytes, macrophages, dendritic cells, mast cells, and intestinal epithelial cells bear toll-like receptor 4 (TLR4) (see Table 2.2) and other cell-surface molecules that bind LPS.
Peptidoglycans are major components of the cell walls of gram-positive bacteria and are recognized by TLR2 receptors on host phagocytic cells (Fig. 5.2). Peptidoglycans are also expressed to a lesser degree and in a slightly different form on gram-negative bacteria. As a result of receptor engagement, the microbes are ingested and degraded, the macrophage is activated, and cytokine production and inflammation result (see Section IV.A).
Figure 5.2. Lipopolysaccharide and peptidoglycan structures.
Major bacterial PAMPs are found in lipopolysaccharides (carbohydrates + lipids) of gram-negative bacteria and in peptidoglycans (carbohydrates + proteins) associated with both gram-negative and gram-positive bacteria.
B. Pattern recognition receptors
PRRs are divided into the categories described later and are present as extracellular proteins or as membrane-bound proteins on phagocytic cells in the bloodstream. During recognition of PAMPs, multiple receptors may be simultaneously engaged to mediate internalization, activate the killing of microbes, and induce the production of inflammatory cytokines and chemokines.
1. Toll-like receptors
Toll-like receptors (TLRs) mediate recognition of diverse pathogens. After binding to PAMPs, signal transduction from a TLR to the nucleus leads to enhanced activation of genes encoding cytokines and other molecules involved in antimicrobial activity. The result is synthesis and secretion of the cytokines that promote inflammation and the recruitment of leukocytes to the site of infection.
2. Scavenger receptors
Scavenger receptors are involved in binding of modified low-density lipoproteins, some polysaccharides, and some nucleic acids. They are involved in the internalization of bacteria and in the phagocytosis of host cells undergoing apoptosis.
Opsonins are molecules that, when attached to the surface of microbes, make them more attractive to phagocytic cells, thus facilitating microbe destruction. Opsonins bind to microbial surfaces. Receptors for opsonins are present on phagocytic cells, and the subsequent increased phagocytic destruction of microbes is termed opsonization.
C. Markers of abnormal self
An evasive maneuver that microorganisms sometimes employ to avoid recognition by the immune system is to subvert the host cells. Some viruses cause an infected host cell to reduce its expression of MHC class I molecules that are critical to the proper functioning of the adaptive immune system (discussed in Chapters 7 and 10). Similar changes sometimes occur in cells undergoing cancerous transformation.
Host cells that become abnormal as a result of such events can alert the immune system to their situation by expressing molecules on their surfaces that act as stress signals. In humans, these include some heat shock proteins and two molecules known as MICA and MICB (Fig. 5.3). These stress signals are detected by various receptors, including some of the TLRs (e.g., TLR2 and TLR4) (see Table 2.2) and the killer activation receptors (KARs) of natural killer (NK) cells (see Section IV.B).
Figure 5.3. Infection of cells may lead to the surface expression of stress molecules.
In response to viral infection, host cells may express stress molecules such as MICA and MICB on their surface and may also reduce their surface expression of MHC class I molecules. These surface changes can be detected by NK cells that seek to eliminate virally infected cells.
Soluble Defense Mechanisms
In addition to the actions of whole cells, the innate immune system employs soluble molecules as weaponry for protection from viral infection, for lytic destruction of microbes, or for increasing the susceptibility of microbes to ingestion by phagocytic cells.
A. Type I interferons
Type I interferons (IFNs) are produced by a subset of dendritic cells (IFN-?), by nonleukocytes such as fibroblasts (IFN-?), and by other cells in response to viral infection (Fig. 5.4). IFN-? and IFN-? are rapidly produced, within 5 minutes, by cells when viral PAMPs interact with certain PRRs. Very little is currently known about the signal transduction pathways responsible for expression and secretion of IFN-? and IFN-?.
Secreted type I IFNs induce both virally infected and noninfected cells to activate numerous antiviral defenses including RNA-dependent protein kinase (PKR) and apoptotic (programmed cell death) pathways. In addition, IFN-? and IFN-? influence the activities of macrophages and dendritic cells.
Figure 5.4. Type 1 interferon response to intracellular microbial invasion.
Some cells respond to infection by producing and secreting type I interferons that signal adjacent cells to activate their antimicrobial defenses.
B. Microcidal molecules
Various cells, including epithelial cells, neutrophils, and macrophages, in the skin and mucous membranes secrete cysteine-rich peptides called defensins. These peptides form channels in the cell membranes of bacteria, which cause the influx of certain ions and eventually bacterial death. Other molecules with microcidal functions include cathelicidin, lysozyme, DNases and RNases, and others, as discussed in Chapter 3.
Complement is a collective term for a system of enzymes and proteins that function in both the innate and adaptive branches of the immune system as soluble means of protection against pathogens that evade cellular contact. A series of circulating and self-cell-surface regulatory proteins keep the complement system in check. In the innate immune system, complement can be activated in two ways: via the alternative pathway, in which antigen is recognized by particular characteristics of its surface, or via the mannan-binding lectin (MBL) pathway.
Complement can also be activated in the adaptive immune system via the classical pathway that begins with antigen–antibody complexes (which is described in subsequent chapters) (Fig. 5.5). Regardless of the pathway of activation, functions of complement include lysis of bacteria, cells, and viruses; promotion of phagocytosis (opsonization); triggering of inflammation and secretion of immunoregulatory molecules; and clearance of immune complexes from circulation.
Figure 5.5. Three complement pathways lead to formation of the membrane attack complex.
- Components C1 through C9, B and P are native complement (protein) components.
- Fragments of native complement components are indicted by lowercase letter (e.g., C4a, C5b, Bb). Smaller cleavage fragments are assigned the letter “a,” and major (larger) fragments are assigned the letter “b.”
- A horizontal bar above a component or complex indicates enzymatic activity (e.g., ).
1. The alternative pathway
The alternative pathway is initiated by cell-surface constituents that are recognized as foreign to the host, such as LPS (Fig. 5.6). Various enzymes (e.g., kallikrein, plasmin, elastase) cleave C3, the most abundant (~1300 mg/mL) serum complement component, into several smaller fragments. One of these, the continuously present, short-lived, and unstable C3b fragment, is the major opsonin of the complement system and readily attaches to receptors on cell surfaces (Fig. 5.7).
Figure 5.6. Alternative pathway of complement activation.
Beginning with the binding of C3b to a microbial surface, this pathway results in an amplified production of C3b and formation of a C5 convertase.
Figure 5.7. Multiple functional roles for complement fragment C3b.
- C3b binds Factor B.
- Factor B in the complex is cleaved by Factor to produce , an unstable C3 convertase.
- Two proteins, C3b inactivator (I) and ?1H-globulin (H), function as important negative regulators, making an inactive form of C3b (C3b) to prevent the unchecked overamplification of the alternative pathway.
- Alternatively, binds properdin (Factor P) to produce stabilized C3 convertase, .
- Additional C3b fragments join the complex to make , also known as C5 convertase. C5 convertase cleaves C5 into C5a and C5b.
- C5b inserts into the cell membrane and is the necessary step leading to formation of the membrane attack complex (MAC) and cell lysis.
2. The terminal or lytic pathway
The terminal or lytic pathway can be entered from the alternative, mannan-binding lectin, or classical pathway of complement activation. Attachment of C5b to the bacterial membranes initiates formation of the membrane attack complex (MAC) and lysis of the cell (Fig. 5.8). The attachment of C5b leads to the addition of components C6, C7, and C8. C8 provides a strong anchor into the membrane and facilitates the subsequent addition of multiple C9 molecules to form a pore in the membrane. Loss of membrane integrity results in the unregulated flow of electrolytes and causes the lytic death of the cell (Fig. 5.9).
Figure 5.8. Terminal or membrane attack complex (MAC) of complement.
The MAC forms a pore in the surfaces of microbes to which it is attached, causing lytic death of those microbes.
Figure 5.9. Insertion of the membrane attack complex (MAC) components into a cell membrane.
Formation of the MAC requires a sequential addition of several complement components, beginning with C5a and terminating with multiple C9 components, to form the pore in the microbial membrane.
3. Mannan-binding lectin pathway
Lectins are proteins that bind to specific carbohydrates. This pathway is activated by binding of mannan-binding lectin (MBL) to mannose-containing residues of glycoproteins on certain microbes (e.g., Listeria spp., Salmonella spp., Candida albicans). MBL is an acute phase protein, one of a series of serum proteins whose levels can rise rapidly in response to infection, inflammation, or other forms of stress. MBL, once bound to appropriate mannose-containing residues, can interact with MBL-activated serine protease (MASP). Activation of MASP leads to subsequent activation of components C2, C4, and C3 (Fig. 5.10).
Figure 5.10. Mannan-binding lectin (MBL) pathway of complement activation.
The lectin binding pathway is initiated by the binding of certain glycoproteins commonly found on microbial surfaces, and results in the formation of a C3 convertase (that acts to produce C3b) and a C5 convertase (that can lead to MAC formation).
The small fragments (C3a, C4a, C5a) generated by the cleavage of C3 and C5 in the alternative pathway and of C3, C4, and C5 in the MBL pathway act as anaphylotoxins. Anaphylotoxins attract and activate different types of leukocytes (Table 5.1). They draw additional cells to the site of infection to help eliminate the microbes. C5a has the most potent effect, followed by C3a and C4a.
Table 5.1. Anaphylotoxins in Decreasing Order of Potency
Activation of vascular endothelium
Attraction/activation of neutrophils
Mast cell degranulation
Activation of vascular endothelium
Mast cell degranulation (release of cytoplasmic granules)
Mast cell degranulation
D. Cytokines and chemokines
Cytokines are secreted by leukocytes and other cells and are involved in innate immunity, adaptive immunity, and inflammation (Table 5.2). Cytokines act in an antigen-nonspecific manner and are involved in a wide array of biologic activities ranging from chemotaxis to activation of specific cells to induction of broad physiologic changes.
Chemokines are a subgroup of cytokines of low molecular weight and particular structural patterns that are involved in the chemotaxis (chemical-induced migration) of leukocytes. The roles of specific cytokines and chemokines are described in the contexts of the immune responses in which they participate (see Section IV.A of this chapter).
Table 5.2. Cytokines and Chemokines Produced by Activated Phagocytes
|Interleukin-1 (IL-1)||Vascular endothelium||Increased permeability of vascular endothelium
Stimulates production of IL-6
|Interleukin-6 (IL-6)||Liver||Production of acute phase proteins (e.g., C-reactive protein); elevated temperature (fever)|
|Interleukin-8 (IL-8), a chemokine||Vascular endothelium||Activation of vascular endothelium
Attraction/activation of neutrophils
|Interleukin-12 (IL-12)||NK cells||Activates NK cells
Influences lymphocyte differentiation
|Tumor necrosis factor-? (TNF-?)||Vascular endothelium||Increased permeability of vascular endothelium
Activation of vascular endothelium