Chapter 16 Innate Immunity Nonspecific Defenses of the

Chapter 16 Innate Immunity: Nonspecific Defenses of the Host © 2013 Pearson Education, Inc. Copyright © 2013 Pearson Education, Inc. Lectures prepared by Christine L. Case Lectures prepared by Christine L.

Insert Fig CO 16 © 2013 Pearson Education, Inc.

Fever § Advantages § Increases transferrins § Increases IL-1 activity § Produces interferon © 2013 Pearson Education, Inc. § Disadvantages § § Tachycardia Acidosis Dehydration 44– 46°C fatal

The Concept of Immunity § § Susceptibility: lack of resistance to a disease Immunity: ability to ward off disease Innate immunity: defenses against any pathogen Adaptive immunity: immunity or resistance to a specific pathogen © 2013 Pearson Education, Inc.

Figure 16. 1 An overview of the body’s defenses. First line of defense • Intact skin • Mucous membranes and their secretions • Normal microbiota © 2013 Pearson Education, Inc. Second line of defense • Phagocytes, such as neutrophils, eosinophils, dendritic cells, and macrophages • Inflammation • Fever • Antimicrobial substances Third line of defense • Specialized lymphocytes: T cells and B cells • Antibodies

The Concept of Immunity § Host Toll-like receptors (TLRs) attach to pathogen-associated molecular patterns (PAMPs) § TLRs induce cytokines that regulate the intensity and duration of immune responses © 2013 Pearson Education, Inc.

Physical Factors § Skin § Epidermis consists of tightly packed cells with § Keratin, a protective protein © 2013 Pearson Education, Inc.

Figure 16. 2 A section through human skin. Top layers of epidermis with keratin Epidermis Dermis © 2013 Pearson Education, Inc.

Physical Factors § Mucous membranes § Mucus: traps microbes § Ciliary escalator: transports microbes trapped in mucus away from the lungs © 2013 Pearson Education, Inc.

Figure 24. 7 Ciliated cells of the respiratory system infected with Bordetella pertussis. B. pertussis Cilia © 2013 Pearson Education, Inc.

Figure 16. 4 The ciliary escalator. Trapped particles in mucus Cilia Goblet cells Insert Fig 16. 4 Ciliated cells Computer-enhanced © 2013 Pearson Education, Inc.

Physical Factors § § Lacrimal apparatus: washes eye Saliva: washes microbes off Urine: flows out Vaginal secretions: flow out © 2013 Pearson Education, Inc.

Figure 16. 3 The lacrimal apparatus. Lacrimal glands Upper eyelid Lacrimal canal Nasolacrimal duct Nose © 2013 Pearson Education, Inc.

Chemical Factors § § § Fungistatic fatty acid in sebum Low p. H (3– 5) of skin Lysozyme in perspiration, tears, saliva, and urine Low p. H (1. 2– 3. 0) of gastric juice Low p. H (3– 5) of vaginal secretions © 2013 Pearson Education, Inc.

Normal Microbiota and Innate Immunity § Microbial antagonism/competitive exclusion: normal microbiota compete with pathogens or alter the environment § Commensal microbiota: one organism (microbe) benefits, and the other (host) is unharmed § May be opportunistic pathogens © 2013 Pearson Education, Inc.

Table 16. 1 Formed Elements in Blood (Part 1 of 2) Insert Table 16. 1 If possible, break into multiple slides © 2013 Pearson Education, Inc.

Table 16. 1 Formed Elements in Blood (Part 2 of 2) Insert Table 16. 1 If possible, break into multiple slides © 2013 Pearson Education, Inc.

Differential White Cell Count § Percentage of each type of white cell in a sample of 100 white blood cells Neutrophils 60– 70% Basophils 0. 5– 1% Eosinophils 2– 4% Monocytes 3– 8% Lymphocytes 20– 25% © 2013 Pearson Education, Inc.

Figure 16. 5 a The lymphatic system. Right lymphatic duct Right subclavian vein Thoracic (left lymphatic) duct Left subclavian vein Tonsil Thymus Heart Thoracic duct Spleen Lymphatic vessel Large intestine Red bone marrow (a) Components of lymphatic system © 2013 Pearson Education, Inc. Small intestine Peyer’s patch Lymph node

Figure 16. 5 b-c The lymphatic system. Venule Interstitial fluid Blood capillary Tissue cell Blood One-way opening Arteriole Blood Lymphatic capillary Interstitial fluid (between cells) Lymph Tissue cell Lymphatic capillary Relationship of lymphatic capillaries to tissue cells and blood capillaries © 2013 Pearson Education, Inc. Lymph Details of a lymphatic capillary

Phagocytosis § Phago: from Greek, meaning eat § Cyte: from Greek, meaning cell § Ingestion of microbes or particles by a cell, performed by phagocytes © 2013 Pearson Education, Inc.

Figure 16. 6 A macrophage engulfing rod-shaped bacteria. Macrophage Bacterium Pseudopods © 2013 Pearson Education, Inc.

Phagocytosis § Neutrophils § Fixed macrophages § Wandering macrophages © 2013 Pearson Education, Inc.

Figure 16. 7 The Phases of Phagocytosis. A phagocytic macrophage uses a pseudopod to engulf nearby bacteria. Pseudopods Phagocyte Cytoplasm 1 CHEMOTAXIS and ADHERENCE of phagocyte to microbe 2 INGESTION of microbe by phagocyte Microbe or other particle Details of adherence 3 Formation of phagosome (phagocytic vesicle) 4 Fusion of phagosome with a lysosome to form a phagolysosome Lysosome PAMP (peptidoglycan in cell wall) Digestive enzymes Partially digested microbe 5 DIGESTION of ingested microbes by enzymes in the phagolysosome Indigestible material 6 Formation of the residual body containing indigestible material TLR (Toll-like receptor) Plasma membrane 7 DISCHARGE of waste materials © 2013 Pearson Education, Inc.

Oxidative Burst 4 Superoxide dismutase converts 5 H 2 O 2 burst superoxide to hydrogen peroxide (H 2 O 2) kills bacterium 3 NADPH oxidase 1 Bacterium adheres to membrane of neutrophil. Insert art from Clinical Case on Superoxide p. 463 dismutase O 2 • H 2 O 2 Plasma membrane Neutrophil If possible on this slide, include title: Oxidative Burst O 2 NADPH oxidase Pentose phosphate pathway 2 NADPH is produced © 2013 Pearson Education, Inc. uses electron from NADPH to produce superoxide (O 2 • ) NADP+ NADPH

Microbial Evasion of Phagocytosis Inhibit adherence: M protein, capsules Streptococcus pyogenes, S. pneumoniae Kill phagocytes: Leukocidins Staphylococcus aureus Lyse phagocytes: Membrane attack complex Listeria monocytogenes Escape phagosome Shigella, Rickettsia Prevent phagosome– lysosome fusion HIV, Mycobacterium tuberculosis Survive in phagolysosome Coxiella burnettii © 2013 Pearson Education, Inc.

Inflammation § Activation of acute-phase proteins (complement, cytokine, and kinins) § Vasodilation (histamine, kinins, prostaglandins, and leukotrienes) § Redness § Swelling (edema) § Pain § Heat © 2013 Pearson Education, Inc.

Chemicals Released by Damaged Cells Histamine Kinins Prostaglandins Leukotrienes © 2013 Pearson Education, Inc. Vasodilation, increased permeability of blood vessels Intensify histamine and kinin effect Increased permeability of blood vessels, phagocytic attachment

Figure 16. 8 a-b The process of inflammation. Bacteria entering on knife Epidermis Bacteria Blood vessel Dermis Nerve Subcutaneous tissue (a) Tissue damage 1 Chemicals such as histamine, kinins, prostaglandins, leukotrienes, and cytokines (represented as blue dots) are released by damaged cells. 2 Blood clot forms. 3 Abscess starts to form (orange area). (b) Vasodilation and increased permeability of blood vessels © 2013 Pearson Education, Inc.

Figure 16. 8 c The process of inflammation. Blood vessel endothelium Monocyte 4 Margination— phagocytes stick to endothelium. 5 Diapedesis— phagocytes squeeze between endothelial cells. Insert Fig 16. 8 c 6 Phagocytosis of invading bacteria occurs. Red blood cell Macrophage (c) Phagocyte migration and phagocytosis © 2013 Pearson Education, Inc. Bacterium Neutrophil

Figure 16. 8 d The process of inflammation. Scab Blood clot Regenerated epidermis (parenchyma) Insert Fig 16. 8 d (d) Tissue repair © 2013 Pearson Education, Inc. Regenerated dermis (stroma)

Fever § Abnormally high body temperature § Hypothalamus is normally set at 37°C § Gram-negative endotoxins cause phagocytes to release interleukin-1 (IL-1) § Hypothalamus releases prostaglandins that reset the hypothalamus to a high temperature § Body increases rate of metabolism, and shivering occurs, which raise temperature § Vasodilation and sweating: body temperature falls (crisis) © 2013 Pearson Education, Inc.

The Complement System § Serum proteins activated in a cascade § Activated by § Antigen–antibody reaction § Proteins C 3, B, D, P and a pathogen ANIMATION Complement: Overview ANIMATION Complement: Activation © 2013 Pearson Education, Inc.

The Complement System § C 3 b causes opsonization § C 3 a + C 5 a cause inflammation § C 5 b + C 6 + C 7 + C 8 + C 9 cause cell lysis ANIMATION Complement: Results © 2013 Pearson Education, Inc.

Figure 16. 9 Outcomes of Complement Activation. 1 Inactivated C 3 splits into activated C 3 a and C 3 b. 2 C 3 b binds to microbe, resulting in opsonization. C 3 b C 3 a C 3 b proteins 3 C 3 b also splits C 5 into C 5 a and C 5 b 5 C 3 a and C 5 a cause mast cells to release histamine, resulting in inflammation; C 5 a also attracts phagocytes. opsonization C 5 Enhancement of phagocytosis by coating with C 3 b C 5 a C 5 b Histamine C 5 a Insert Fig 16. 9 Mast cell 4 C 5 b, C 6, C 7, and C 8 bind together sequentially and insert into the microbial plasma membrane, where they function as a receptor to attract a C 9 fragment; additional C 9 fragments are added to form a channel. Together, C 5 b through C 8 and the multiple C 9 fragments form the membrane attack complex, resulting in cytolysis. C 5 a receptor C 6 C 3 a receptor C 3 a inflammation C 7 C 8 Increase of blood vessel permeability and chemotactic attraction of phagocytes C 9 Microbial plasma membrane Channel C 6 C 7 C 5 b C 8 C 9 Formation of membrane attack complex (MAC) C 6 C 5 b C 7 C 8 C 9 Cytolysis cytolysis © 2013 Pearson Education, Inc. Bursting of microbe due to inflow of extracellular fluid through transmembrane channel formed by membrane attack complex

Effects of Complement Activation § Opsonization, or immune adherence: enhanced phagocytosis § Membrane attack complex: cytolysis § Attract phagocytes © 2013 Pearson Education, Inc.

Figure 16. 10 Cytolysis caused by complement. Insert Fig 16. 10 © 2013 Pearson Education, Inc.

Figure 16. 11 Inflammation stimulated by complement. C 5 a receptor Histamine Phagocytes Neutrophil Histaminecontaining granule Insert Fig 16. 11 Histaminereleasing mast cell © 2013 Pearson Education, Inc. C 3 a receptor C 5 a Macrophage

Figure 16. 12 Classical pathway of complement activation. Microbe Antigen C 1 is activated by binding to antigen–antibody complexes. Antibody C 1 Activated C 1 splits C 2 into C 2 a and C 2 b, and C 4 into C 4 a and C 4 b. C 4 C 2 Insert Fig 16. 12 C 2 b C 2 a and C 4 b combine and activate C 3, splitting it into C 3 a and C 3 b (see also Figure 16. 9). Opsonization C 4 a C 3 b Cytolysis © 2013 Pearson Education, Inc. C 4 b C 3 a Inflammation

Figure 16. 13 Alternative pathway of complement activation. Lipid-carbohydrate complex Microbe C 3 combines with factors B, D, and P on the surface of a microbe. B D P C 3 Insert Fig 16. 13 This causes C 3 to split into fragments C 3 a and C 3 b C 3 a Inflammation Opsonization Cytolysis Key: © 2013 Pearson Education, Inc. B B factor D D factor P P factor

Figure 16. 14 The lectin pathway of complement activation. Microbe Carbohydrate containing mannose Lectin binds to an invading cell. Bound lectin splits C 2 into C 2 b and C 2 a and C 4 into C 4 b and C 4 a. C 2 b C 4 C 2 a and C 4 b combine and activate C 3 (see also Figure 16. 9). Opsonization C 4 b C 2 a C 3 b Cytolysis © 2013 Pearson Education, Inc. C 4 a C 3 a Inflammation

Some Bacteria Evade Complement § Capsules prevent C activation § Surface lipid–carbohydrate complexes prevent formation of membrane attack complex (MAC) § Enzymatic digestion of C 5 a © 2013 Pearson Education, Inc.

Interferons (IFNs) § IFN- and IFN- : cause cells to produce antiviral proteins that inhibit viral replication § IFN- : causes neutrophils and macrophages to phagocytize bacteria © 2013 Pearson Education, Inc.

Figure 16. 15 Antiviral action of alpha and beta interferons (IFNs). 1 Viral RNA from an infecting virus enters the cell. 2 The infecting virus 5 New viruses released by replicates into new viruses. Viral RNA the virus-infected host cell infect neighboring host cells. 3 The infecting virus also induces the host cell to produce interferon m. RNA (IFN-m. RNA), which is translated into alpha and beta interferons. Infecting virus Viral RNA Nucleus Translation Insert Fig 16. 15 Transcription IFN-m. RNA 4 Interferons released by the virus-infected host cell bind to plasma membrane or nuclear membrane receptors on uninfected neighboring host cells, inducing them to synthesize antiviral proteins (AVPs). These include oligoadenylate synthetase and protein kinase. © 2013 Pearson Education, Inc. Alpha and beta interferons Translation Virus-infected host cell Neighboring host cell Antiviral proteins (AVPs) 6 AVPs degrade viral m. RNA and inhibit protein synthesis—and thus interfere with viral replication.

Innate Immunity § Transferrins § Bind serum iron © 2013 Pearson Education, Inc. § Antimicrobial peptides § Lyse bacterial cells