Innate Immunity: Nonspecific Defenses of the Host

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1 PowerPoint Lecture Presentations prepared by Bradley W. Christian, McLennan Community College CHAPTER 16 Innate Immunity: Nonspecific Defenses of the Host 2016 Pearson Education, Ltd.

2 Big Picture: Immunity 2016 Pearson Education, Ltd.

3 Big Picture: Immunity 2016 Pearson Education, Ltd.

4 Big Picture: Immunity White blood cell (WBC) counts measure leukocytes in the blood High WBC counts may indicate bacterial infections, autoimmune diseases, or side effects of medications Low WBC counts may indicate viral infections, pneumonia, autoimmune diseases, or cancers 2016 Pearson Education, Ltd.

5 Big Picture: Immunity NORMAL RANGES AND PERCENTAGES for men and nonpregnant women Plasma White blood cells Red blood cells White blood cell count: 5,000 10,000 WBCs per cubic millimeter (mm 3 ) or x 10 9 WBCs per liter. Neutrophils: 60% to 70% Lymphocytes: 20% to 25% Monocytes: 3% to 8% Eosinophils: 2% to 4% Basophils: 0.5% to 1% 2016 Pearson Education, Ltd.

6 The Concept of Immunity Immunity: ability to ward off disease. Innate (nonspecific) immunity: defenses against any pathogen and are present at birth. Adaptive (specific) immunity: defenses that involve specific recognition of a microbe once it has breached the innate immunity defenses. Susceptibility: lack of resistance to a disease.

7 Toll-like receptors (TLRs) on host cells attach to pathogen-associated molecular patterns (PAMPs). TLRs bound to PAMPs induce the release of cytokines from the host cell that regulate the intensity and duration of immune responses.

8 First line of defense: skin and mucous membrane Physical Factors Skin: the largest organ of human body in terms of surface area. Dermis: inner portion made of connective tissue Epidermis: outer portion made of tightly packed epithelial cells containing keratin, a protective protein Figure 16.1 A section through human skin.

9 Mucous membranes: consist of an epithelial layer and an underlying connective tissue layer Lacrimal apparatus ( 淚器 ): Washes eye. Figure 16.2 The lacrimal apparatus.

10 Ciliary escalator: microbes trapped in mucus are transported away from the lungs. Earwax: prevents microbes from entering the ear. Urine: flows out. Vaginal secretions: flow out. Figure 16.3 The ciliary escalator.

11 Chemical Factors Sebum ( 油脂 ): produced by sebaceous (oil) glands of the skin one of the components is unsaturated fatty acids, which inhibit the grow of certain pathogenic bacteria and fungi low ph (3-5) is caused in partly by fatty acid and lactic acid Perspiration ( 汗 ): produced by sweat glands of the skin contain lysozyme can break peptidoglycan of cell walls of gram (+) bacteria and less gram (-) bacteria is also found in tears, saliva, nasal secretions, tissue fluids Low ph ( ) of gastric juice.

12 Normal Microbiota and Innate Immunity Microbial antagonism/competitive exclusion: Normal microbiota compete with pathogens. For example: (in Ch14) Normal microbiota vs Candida albicans in vagina E. coli vs Salmonella and Shigella in large intestine Normal microbiota vs Clostridium difficiles in large intestine

13 Second line of defense Formed Elements in Blood Cells and cell fragments suspended in plasma. Erythrocytes (red blood cells) Leukocytes (white blood cells) Platelets Created in red bone marrow stem cells via hematopoiesis.

14 Figure 16.4 Hematopoiesis Pearson Education, Ltd.

15 Leukocytes are divided into: Granulocytes: Neutrophils: highly phagocytic and motile commonly called polymorphonuclear leukocytes (PMNs), or polymorphs activate in the initial stage of an infection Basophils: produce histamine important in inflammation and allergic response Eosinophils: produce toxic proteins against parasites and some phagocytosis

16 Table 16.1 Leukocytes (White Blood Cells) 2016 Pearson Education, Ltd.

17 Agranulocytes are leukocytes with granules in their cytoplasm that are not visible with a light microscope. Monocytes: mature into macrophages in tissues where they are phagocytic Dendritic cells: found in the skin, mucous membranes, and thymus; phagocytic Lymphocytes: T cells, B cells, and NK cells; play a role in adaptive immunity

18 Agranulocytes: Monocytes: are not actively phagocytic until they leave circulating blood and mature macrophages fixed macrophages (or histiocytes) are found in lungs, liver, and bronchi etc wandering macrophages roam the tissues Dendritic cells: are belived to be derived from monocytes abundant in the epidermis of the skin, mucous membranes, the thymus and lymph nodes initiate adaptive immune response

19 Lymphocytes: include natural killer (NK) cells, T cells and B cells NK T NK cells are found in blood, spleen, lymph nodes, and red bone marrow, and attack abnormal body cells by perforins ( 穿孔素 ) and granzymes ( 顆粒溶解酶 ). B cells and T cells occur in lymphoid tissues of lymphoid system and also circulate in the blood. B

20 Table 16.1 Leukocytes (White Blood Cells) 2016 Pearson Education, Ltd.

21 The Lymphatic System The lymphatic system: Consists of lymph, lymphatic vessels, lymphoid tissue, and red bone marrow. Contains lymphocytes and phagocytic cells. Lymph carries microbes to lymph nodes where lymphocytes and macrophages destroy the pathogen.

22 Figure 16.5 The lymphatic system. Right lymphatic duct Thoracic (left lymphatic) duct Tonsil Right subclavian vein Left subclavian vein Thymus Lymph node Thoracic duct Spleen Large intestine Small intestine Peyer s patch Lymphatic vessel Red bone marrow 2016 Pearson Education, Ltd.

23 Figure 16.6 Lymphatic capillaries. Interstitial fluid (between cells) Tissue cell Lymph in lymphatic capillary Lymphatic capillary Blood capillary Venule Arteriole Flow of fluid between arteriole, blood capillaries, lymphatic capillaries, and venule Lymph in lymphatic capillary Lymphatic capillary One-way opening Interstitial fluid flow Tissue cells Lymphatic vessel Toward lymph node Lymphatic capillaries and lymphatic vein 2016 Pearson Education, Ltd.

24 Phagocytosis Phago: from Greek, meaning eat. Cyte: from Greek, meaning cell. Fixed macrophages are residents in tissues and organs. Free (wandering) macrophages roam tissues and gather at sites of infection. Figure 16.7 A macrophage engulfing rod-shaped bacteria.

25 The Mechanism of Phagocytosis Chemotaxis ( 趨化作用 ) Chemical signals attract phagocytes to microorganisms. Adherence Attachment of a phagocyte to the surface of the microorganism. Ingestion Opsonization: microorganism is coated with serum proteins, making ingestion easier. Digestion Microorganism is digested inside a phagolysosome.

26 Figure 16.8 The Phases of Phagocytosis Pearson Education, Ltd.

27 Microbial Evasion of Phagocytosis Inhibit adherence: M protein, capsules Kill phagocytes: leukocidins Lyse phagocytes: membrane attack complex Escape phagosome Prevent phagosome-lysosome fusion Survive in phagolysosome Streptococcus pyogenes, S. pneumoniae Staphylococcus aureus Listeria monocytogenes Shigella, Rickettsia HIV, Mycobacterium tuberculosis Coxiella burnetii

28 Inflammation Damage to the body s tissue triggers a defensive response called inflammation. Inflammation is usually characterized by 4 signs and symptoms: Redness Pain Heat Swelling (edema) Loss of function ( the fifth)

29 Inflammation has the following function: to destroy the injurious agent, if possible, and to remove it and its by-products from the body if destruction is not possible, to limit the effects on the body by confining or walling off the injurious agent and its by-products to repair or replace tissue damaged by the injurious agent or its by-products

30 The process of inflammation into 3 stages: 1. Vasodilation and increased permeability of blood vessels 2. Phagocyte migration and phagocytosis 3. Tissue repair

31 Vasodilation and Increased Permeability of Blood Vessels During inflammation, there is an activation and increased concentration of a group of proteins in the blood called acute-phase proteins. Histamine Kinins Prostaglandins Leukotrienes Cytokines

32 Figure 16.9a-b The process of inflammation. Tissue damage Chemical Function Bacteria Epidermis Histamine Vasodilation, increased permeability of blood vessels Blood vessel Dermis Kinins Vasodilation, increased permeability of blood vessels Nerve Subcutaneous tissue Prostaglandins Leukotrienes Intensity histamine and kinin effect Increased permeability of blood vessels, phagocytic attachment Vascular reactions and phagocytosis Chemicals such as histamine, kinins, prostaglandins, leukotrienes, and cytokines (represented as blue dots) are released by damaged cells. Blood clot forms Pearson Education, Ltd. Abscess starts to form (orange area).

33 Phagocyte Migration and Phagocytosis Margination is the sticking of phagocytes to blood vessels in response to cytokines at the site of inflammation Phagocytes squeeze between endothelial cells of blood vessels via diapedesis

34 Figure 16.9b The process of inflammation. Blood vessel endothelium Monocyte Bacterium RBC Margination phagocytes stick to endothelium. Diapedesis phagocytes squeeze between endothelial cells. Macrophage Neutrophil Phagocytosis of invading bacteria occurs Pearson Education, Ltd.

35 Tissue Repair Cannot be completed until all harmful substances are removed or neutralized Stroma is the supporting connective tissue that is repaired Parenchyma is the functioning part of the tissue that is repaired

36 Figure 16.9c The process of inflammation. (c) Tissue repair Scab Blood clot Regenerated epidermis (parenchyma) Regenerated dermis (stroma) 2016 Pearson Education, Ltd.

37 Fever Abnormally high body temperature. Hypothalamus normally set at 37 C (98.6 F). Cytokines cause the hypothalamus to release prostaglandins that reset the hypothalamus to a higher temperature Body constricts the blood vessels, and shivering occurs (which raises temperature) As body temperature falls (crisis), vasodilation and sweating occurs

38 Advantages Increase IL-1 activity Disadvantages Tachycardia 心跳過快 Acidosis 酸中毒 Dehydration 脫水

39 Antimicrobial Substances The Complement System consisting of over 30 proteins produced by liver found circulating in blood serum destroy microbes by cytolysis inflammation phagocytosis ( opsonization) are inactive until they are split into fragments are numbered C1 through C9 activated in a cascade

40 The cascade of complement proteins that occurs during an infection is called complement activation. Complement activation may occur in 3 pathways: the classical pathway the alternative pathway the lectin pathway

41 The Classical Pathway Antibodies bind to antigens, activating C1 C1 splits and activates C2 and C4 C2a and C4b combine and activate C3 C3a functions in inflammation C3b functions in cytolysis and opsonization

42 Figure 16.10a Pathways of complement activation. pathway of complement activation classical Microbe Antigen C1 Antibody C2 C4 C2b C2a C4b C4a C3 C3a C3b inflammation cytolysis opsonization 2016 Pearson Education, Ltd.

43 The Alternative Pathway C3 present in the blood combines with factors B, D, and P on microbe surface C3 splits into C3a and C3b, functioning the same as in the classical pathway

44 Figure 16.10b Pathways of complement activation. alternative Microbe Lipid carbohydrate complex Microbe B D P Factors C3 C3a C3b inflammation cytolysis opsonization 2016 Pearson Education, Ltd.

45 The Lectin Pathway Macrophages ingest pathogens, releasing cytokines that stimulate lectin production in the liver Mannose-binding lectin (MBL) binds to mannose, activating C2 and C4 C2a and C4b activate C3, which functions the same as in the classical and alternative pathways

46 Figure 16.10c Pathways of complement activation. lectin Microbe Carbohydrate containing mannose Mannose-binding lectin (MBL) C2 C4 C2b C2a C4b C4a C3 C3a C3b inflammation cytolysis opsonization 2016 Pearson Education, Ltd.

47 Outcomes of Complement Activation Cytolysis Activated complement proteins create a membrane attack complex (MAC) Opsonization ( 調理作用 ) Promotes attachment of a phagocyte to a microbe Inflammation Activated complement proteins bind to mast cells, releasing histamine

48 Figure The MAC results in cytolysis Pearson Education, Ltd.

49 Figure Outcomes of Complement Activation outcomes of complement activation C3 Splits into activated C3a and C3b cytolysis opsonization inflammation C3a C3b C3a C3b C3a C3b C5 C5 C5a C5b C5a C5b C6 Histamine C7 C8 Microbe C3a C5a C9 C3a receptor Mast cell C5a receptor Channel C3b protein Microbes Phagocytesa C6 C7 C5b C8 C9 Phagocyte Microbes burst as extracellular fluid flows in through transmembrane channel formed by membrane attack complex. Coating microbes with C3b enhances phagocytosis. Blood vessels become more permeable, and chemotactic agents attract phagocytes to area. KEY CONCEPTS The complement system is another way the body fights infection and destroys pathogens. This component of innate immunity complements other immune reactions. Complement is a group of over 30 proteins circulating in serum that are activated in a cascade: one complement protein triggers the next. The cascade can be activated by a pathogen directly or by an antibody antigen reaction. Together these proteins destroy microbes by (1) cytolysis, (2) enhanced phagocytosis, and (3) inflammation Pearson Education, Ltd.

50 Figure Inflammation stimulated by complement. C3a and C5a bound to mast cell, basophils, and platelets trigger the release of histamine C5a functions as a chemotactic factor that attracts phagocytes to the site of complement activation 2016 Pearson Education, Ltd.

51 Regulation of complement Regulatory proteins readily break down complement proteins, minimizing host cell destruction

52 Complement and disease Lack of complement proteins causes susceptibility to infections Evading the complement system Capsules prevent complement activation

53 Interferons (IFNs) IFN are a family of cytokines produced by cells; have antiviral activity. Human IFNs are of 3 principal types: Alpha IFN (IFN- ) and Beta IFN (IFN- ): produced by cells in response to viral infections; cause neighboring cells to produce antiviral proteins (AVPs) that inhibit viral replication. Gamma IFN (IFN- ): causes neutrophils and macrophages to phagocytize bacteria.

54 Figure Antiviral action of alpha and beta interferons (IFNs). New viruses replicated in host cell infect neighboring cells. Viral RNA Viral RNA Transcription Translation Transcription Translation Viral RNA Infecting virus Virus replicates Alpha and beta interferons Antiviral proteins (AVPs) Viral replication inhibited Nucleus IFN-mRNA Virus-infected host cell Neighboring cell Viral RNA from an infecting virus enters the cell. The virus induces the host cell to produce interferon mrna (IFN-mRNA), which is translated into alpha and beta interferons. Interferons make contact with uninfected neighboring host cells, where they bind either to the plasma membrane or to nuclear receptors. Interferons induce the cells to synthesize antiviral proteins (AVPs). AVPs degrade viral mrna and inhibit protein synthesis and thus interfere with viral replication Pearson Education, Ltd.

55 Iron-binding proteins Transferrin ( 運鐵蛋白 ) is found in blood and tissue fluids Lactoferrin ( 乳鐵蛋白 ) is found in milk, saliva, and mucus Ferritin ( 含鐵蛋白 ) is found in the liver, spleen and red bone marrow Hemoglobin is located within RBC Function: inhibit bacterial growth by reducing the amount of available iron siderophore

56 Antimicrobial peptides (AMPs) Short peptides produced in response to protein and sugar molecules on microbes Inhibit cell wall synthesis Form pores in the plasma membrane Broad spectrum of activity

57 Table 16.2 Summary of Innate Immunity Defenses (1 of 2) 2016 Pearson Education, Ltd.

58 Table 16.2 Summary of Innate Immunity Defenses (2 of 2) 2016 Pearson Education, Ltd.