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Chapter 2 : Innate Immunity

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Innate Immunity, Page 1 of 2

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Abstract:

The innate defenses are either constitutively active or rapidly mobilized and are effective against many types of microbial agents, whereas the acquired immune response is activated slowly, depends on the entry of an antigenic stimulus into an individual’s tissues, and is specific to a particular foreign material. The acquired and the innate immune responses supplement each other and stimulate and regulate each other’s activity. In terms of innate immunity, there are other differences between the cornea and the skin. Individuals also possess a large battery of enzymes that can damage bacteria, viruses, and other even nonviable foreign antigens. These enzymatic effectors of innate immunity generally function by damaging the structural integrity of the microbial surface, although the different effectors accomplish this in different ways. Many of the enzymatic effectors of innate immunity are present in mucosal secretions such as tears and saliva. Proteases are enzymatic effector molecules that contribute to innate immunity at mucosal surfaces. Most important in innate immunity to viruses are the type I interferons, IFN-α and IFN-β. During viral infection, the cytokines are secreted by lymphocytes, monocytes, and macrophages and bind to a receptor (IFN-α and IFN-β bind to the same receptor) expressed by almost all cell types. When a type I interferon binds to its receptor, the cell enters an "antiviral state" during which viral replication is inhibited by interference with protein synthesis within the infected cell.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2

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Complement System
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Human immunodeficiency virus 1
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Tumor Necrosis Factor alpha
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Figures

Image of Figure 2.1
Figure 2.1

Mechanisms of innate immunity against bacterial infection at a physical barrier such as the skin or mucosal surfaces. Symbiotic or commensal bacteria residing on the skin occupy limiting attachment sites on the skin and consume limiting nutrients, making colonization by potentially pathogenic microorganisms unlikely. If pathogens do attach, the skin is an effective physical barrier and bacterial growth is retarded by the low pH of lactic acid-containing sebum secreted by sebaceous glands. Secretions on the mucosal surfaces contain destructive enzymes such as lysozyme that degrade the cell walls of bacteria. The respiratory tract is protected by the mucociliary escalator by which a mucus layer is continuously propelled upward toward the nasopharynx by the motion of epithelial cell cilia. The mucus layer is biphasic, with a less viscous layer where epithelial cilia beat and a more viscous layer that entraps bacteria (red). Bacteria caught in the more viscous layer are carried with the mucus and thus removed from the airways. The mucosal secretions of the respiratory and digestive tracts contain antimicrobial peptides that can kill infectious agents directly. () A potential pathogen that manages to penetrate these barriers to the tissue below can be killed by complement proteins forming MACs and ingestion by phagocytes such as macrophages.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Figure 2.2

Comparison of innate immunity and acquired immunity. Overlap of the two arms of immunity where cross-regulation occurs is shown where the ovals intersect.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Image of Figure 2.3
Figure 2.3

Diagram of the peptidoglycan of bacterial cell walls. Horizontal lines represent alternating molecules of NAG (circles) and NAM (squares). Blue and green lines represent peptide cross-bridges that join the NAG-NAM copolymers into a three-dimensional matrix. Red arrows represent potential target sites for cleavage of peptidoglycan by lysozyme. The heavy red arrow shows a site where lysozyme has cleaved the backbone of the NAG-NAM copolymer.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Figure 2.4

Activators of the complement system. Many different entities can activate the complement system. Simplified sequence of events leading to killing of a bacterium by the complement system. Note that the complement system can kill a bacterium even if the original activator was completely unrelated to the bacterium, as long as the microbe is close to the site of complement activation.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Figure 2.5

NK cells and other cytotoxic cells can kill target cells by causing the target cells to undergo programmed cell death or apoptosis. Apoptosis can be triggered by either proteases called or the membrane protein . Granzymes enter the target cell through transmembrane pores generated by the protein . Fas ligand delivers its cell death signal by binding to its receptor protein, called . In either case, a protease cascade is initiated, resulting in the activation of a family of cytoplasmic proteases called . The caspase cascade ultimately results in the cleavage of critical molecules such as cytoskeletal elements, DNA, and chromatin proteins, bringing about the death of the target cell. A target cell that is triggered to undergo apoptosis undergoes characteristic morphological changes, including compaction of the cell, condensation of the chromatin, and the formation of membrane-bound cellular fragments called or apoptotic bodies. These apoptotic bodies are recognized and phagocytosed by nearby macrophages.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Figure 2.6

General principles and components of signal transduction. Representation of the composition of lipid rafts, also known as microdomains, detergent-insoluble glycolipid-rich membranes or glycolipid- enriched membrane fractions. Sphingolipids and cholesterol aggregate together within the plasma membrane. On the outer side of the cell there is enrichment for glycophosphatidylinositol-anchored proteins and glycosphingolipids. On the cytoplasmic side, membrane-anchored signal transduction molecules are found. When a cell binds to stimulatory ligand, lipid rafts are recruited to the receptor complex via a raft-associated coreceptor protein. Localization of the lipid raft to the receptor complex results in recruitment of signaling molecules such as G proteins and Src family kinases. Activation of signal transduction molecules. In the resting state there is a balance between the protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) such that the Src-like kinases are held mostly in an inactive form When acted upon by a PTP, the dephosphorylated Src-like kinase can open up into an active form Other PTK enzymes then phosphorylate a tyrosine residue to produce an enzymatically active molecule Since the Src-like kinase is itself a PTK, it will act on other phosphate groups to promote cell activation. Ligation of membrane receptors by stimulatory ligands allows adaptor molecules to bind to the aggregated receptors, promoting their interaction with PTK or PTP enzymes.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Figure 2.7

Activation of a macrophage by bacterial lipoarabinomannan (LAM), lipoteichoic acid (LTA), or LPS. In each case, the bacterial product interacts with a macrophage TLR, sometimes requiring the participation of the proteins CD14 and MD-2. The bacterial product triggers homodimerization of the TLR. This dimerization event recruits the adaptor molecules MyD88 and MAL to the receptor complex, which in turn recruits the serine kinases IRAK or IRAK-2. In the cytoplasm, IRAK is associated with the protein Tollip, which appears to assist the recruitment of IRAK to the TLR complex. The IRAKs activate the kinases NIK (NF-κB-inducing kinase) or TAK-1 (transforming growth factor-β-activated kinase 1). Activation of NIK and TAK-1 requires the assistance of the cofactor protein TRAF6 (tumor necrosis factor receptor-associated factor 6). NIK or TAK-1 phosphorylates the protein IKK (inhibitor of κB kinase), which in turn phosphorylates the protein inhibitor of κB (IκB), resulting in the degradation of IκB. This releases the transcription factor NF-κB, which can then translocate to the nucleus to participate in gene transcription.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Image of Figure 2.8
Figure 2.8

Evolutionary conservation of the Toll/TLR signaling pathway. The left side shows signaling via TLR4 in response to bacterial LPS, generating an innate immune response. The right side shows an orthologous signaling pathway in that leads to dorsal-ventral patterning during embryogenesis. TRAF, tumor necrosis factor receptor-associated factor; ECSIT, evolutionarily conserved signaling intermediate in Toll pathways; NIK, NF-κB-inducing kinase; IKK, inhibitor of κB kinase; IκB, inhibitor of κB; DLAK, LPS-activated kinase. “d” preceding an acronym (e.g., dECSIT) indicates the ortholog of the component. “???” indicates a component hypothesized to exist but not yet positively identified. Adapted from T. K.Means et al., 219—232, 2000, with permission.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Figure 2.9

C-type lectins on DCs and LCs.Within the type I C-type lectins such as macrophage mannose receptor (MMR) and DEC-205 is a cysteine-rich repeat (S—S) in the amino terminus, a repeat domain for binding type II fibronectin (FN), and between 8 and 10 CRDs. The type II C-type lectins have an intracellular amino terminus and express only one CRD in the extracellular carboxy terminus. Within the cytoplasm are portions of the C-type lectins that express some important properties: a domain with tyrosines involved in the intracellular targeting of the lectin and targeting it to endocytic vesicles known as coated pits, and other motifs known by the presence of a triad of acidic amino acids and a dileucine motif. Transmembrane molecules involved in immune responses also contain portions involved in signaling such as the immunoreceptor tyrosine-based activation motif (ITAM) and immunoreceptor tyrosine-based inhibitory motif (ITIM) and proline-rich regions (PPP). CLEC-1, C-type lectin receptor 1; DCIR, dendritic cell immunoreceptor; DC-SIGN, dendritic- cell specific ICAM-3 grabbing nonintegrin; DLEC, dendritic cell lectin. Used with permission from C. G. Figdor et al., 77—84, 2002.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Image of Figure 2.10
Figure 2.10

The innate immune response to viral infection is mediated by the cytokines called type I interferons. Without interferons a virus can infect a host cell, replicate within the infected cell by producing new viral nucleic acid and protein, and spread progeny viruses from the infected cell to other host cells. When type I interferons are produced in response to infection the interferons bind to receptors on the surface of most host cells, terminating protein synthesis. This prevents synthesis of new viral proteins and thus the replication of viruses. Interferons act by inducing the synthesis of the protein DAI. DAI is activated upon binding to dsRNA, which is common in the genomes of many viruses. Active DAI phosphorylates and inactivates eukaryotic initiation factor 2, shutting down protein synthesis. Some viruses, e.g., adenovirus and Epstein-Barr virus, are able to inhibit the activity of DAI with small RNAs, e.g., adenovirus VA RNA L.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Image of Figure 2.11
Figure 2.11

The localized inflammatory response. Injury or infection can result in the activation of the plasmin and kinin cascades. The kinin cascade produces vasoactive peptides that act on vascular endothelium to increase vascular permeability; the enzymes of the kinin cascade also can activate the complement cascade. The plasmin cascade is important in the remodeling of extracellular matrix that accompanies wound healing; the enzymes of the plasmin cascade also can activate the complement cascade. Once activated, complement proteins cause leukocytes such as PMNs, lymphocytes, and monocytes to leave the blood circulation () and home to the site of infection or injury. Extravasation and homing of leukocytes also are regulated by cytokines produced by local mast cells (activated by complement proteins) and macrophages (activated by bacterial products).

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Image of Figure 2.12
Figure 2.12

The kinin system (also called the kallikrein system) produces the vasoactive peptides bradykinin and kallidin, which regulate inflammation. Diagrams of the vasoactive peptides bradykinin and kallidin. Amino acids are indicated in the one-letter code (see inside front cover). Essential arginine amino acids, which are required for biological activity, are highlighted. After its generation, kallidin can be converted to bradykinin by the action of aminopeptidase enzyme. Further cleavage of bradykinin leads to a loss of biological activity. The enzymes of the kinin system (kallikrein and factor XII) become activated during blood clotting and wound repair. Activated factor XII cleaves the proenzyme prekallikrein to its active form, kallikrein. Active kallikrein then acts on its substrate, kininogen, to form the vasoactive peptides bradykinin and kallidin. This process is negatively regulated at several steps, indicated by double red lines. In addition to the generation of bradykinin and kallidin, kallikrein can also activate the complement cascade, resulting in a stimulation of innate immunity. In this way, the innate immune system is set to become activated at wound sites, which are likely entry points for microbes.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Image of Figure 2.13
Figure 2.13

The plasmin cascade can be initiated by a number of proteases (e.g., elastase, kallikrein, cathepsin G, and thrombin) normally found at a site of injury or infection. The cascade results in the production of the active protease plasmin from the precursor plasminogen. Plasmin functions in the remodeling of extracellular matrix during wound repair and also can activate the complement cascade.

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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Image of Figure 2.14
Figure 2.14

The systemic inflammatory response: the acute-phase response. The acute-phase response increases production of effectors consumed during inflammation (PMNs, complement components) and induces increases in body temperature to inhibit microbial growth. The acute-phase response is initiated by cytokines produced at the site of infection that travel to distant tissues via the circulation. The most crucial cytokines appear to be IL-1, tumor necrosis factor alpha (TNF-α), IL-6, leukemia inhibitory factor, and oncostatin M. Targets of these cytokines include the hypothalamus of the brain (which produces prostaglandins, resulting in the fever response), the liver (which begins to synthesize immunologically important proteins at the expense of the synthesis of some housekeeping proteins), and bone marrow (which increases production of leukocytes such as neutrophils—a reaction called ). The proteins whose synthesis is stimulated within the liver during the acute-phase response include many components of the complement cascade and are commonly referred to as

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
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References

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1. Caamaño, J.,, and C. A. Hunter. 2002. NF-κB family of transcription factors: central regulators of innate and adaptive immune functions. Clin. Microbiol Rev. 15:414429.
2. Devine, D. A.,, and R. E. Hancock. 2002. Cationic peptides: distribution and mechanisms of resistance. Curr. Pharm. Des. 8:703714.
3. Figdor, C. G.,, Y. van Kooyk,, and G. J. Adema. 2002. C-type lectin receptors on dendritic cells and Langerhans cells. Nat. Rev. Immunol. 2:7784.
4. Ganz, T. 2001. Fatal attraction evaded: how pathogenic bacteria resist cationic polypeptides. J. Exp. Med. 193:F31F34.
5. Modlin, R. L. 2002.Mammalian toll-like receptors. Ann. Allergy Asthma Immunol. 88:543547.
6. Uthaisangsook, S.,, N. K. Day,, S. L. Bahna,, R. A. Good,, and S. Haraguchi. 2002. Innate immunity and its role against infections. Ann. Allergy Asthma Immunol. 88:253264.
7. Yang, D.,, A. Biragyn,, L. W. Kwak,, and J. J. Oppenheim. 2002. Mammalian defensins in immunity: more than just microbicidal. Trends Immunol. 23:291296.

Tables

Generic image for table
Table 2.1

Products of the oxidative burst

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
Generic image for table
Table 2.2

TLRs and their ligands

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2
Generic image for table
Table 2.3

Characteristics of C-type lectins produced by DCs and LCs

Citation: Lyczak J. 2004. Innate Immunity, p 29-46. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch2

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