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Lesson 10: Innate Immunity/ Nonspecific Defenses of the Host March 24, 2015.

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Presentation on theme: "Lesson 10: Innate Immunity/ Nonspecific Defenses of the Host March 24, 2015."— Presentation transcript:

1 Lesson 10: Innate Immunity/ Nonspecific Defenses of the Host March 24, 2015

2 Overview Our bodies are constantly being attacked by microbes – Susceptible—the inability to ward off disease – Immunity—ability to fight off a disease Immune system—is a set of biological structures and systems that protect an organisms from invading pathogens – Innate Immunity – Adaptive Immunity

3 Innate Immunity—refers to defenses that are present at birth – The body’s first line of defense against invading microorganisms – Always present to provide a rapid response to protect against disease – No memory response present Multiple infections with same organism would produce similar response

4 Components of Innate Immunity – First line of defense Skin and mucous membranes – Lacrimal glands (eye), saliva, urine, vaginal secretions – Mucous is secreted by goblet cells in epithelial lining – Second line of defense Natural killer cells Phagocytes Inflammation Fever Antimicrobial substances

5 Serves as the body’s early-warning system – Designed to prevent microbes from gaining access into the body – The microbes that slip past the skin and mucous membranes usually are eliminated by the innate immune system Also referred to as “non-specific immunity”

6 Responses of the innate system are activated by protein receptors (Toll-like receptors) on the plasma membrane of defensive cells Toll-like receptors (TLRs) recognize various components found on/in pathogens (pathogen- associated molecular patterns) Examples of PAMPs – Lipopolysaccharide (LPS) – Peptidoglycan – Flagella – DNA

7 Each TLR can recognize a specific PAMP – Multiple TLRs can be used to bind one PAMP – 13 TLRs have been identified. Function of two are unknown Binding of TLR to PAMP induces a chemical response – Cytokines—proteins released by the cell to signal an infection has taken place – Cytokines regulate the intensity and duration of an immune response – One role of cytokines is to recruit other immune cells to the site of the infection

8 Cytokines function in both Innate and Adaptive immunity – Cytokines recruits macrophages and dendritic cells to the site of the infection – Cytokines activate T-cells and B-cells involved in adaptive immunity. (stimulates antibody production)

9 Adaptive immunity—the portion of the immune system that “remembers” an attacking pathogen – Activated when innate immunity fails to stop an invading microbe – Slower activation than innate immunity but contains a memory component – Specific immunity “Particular response for a specific microbe”

10 Components of adaptive immunity – T-cells (T-lymphocytes) – B-cells (B-lymphocytes) Lymphocytes are a type of white blood cell

11 First line of defense Intact skin Mucous membranes and their secretions Normal microbiota Second line of defenseThird line of defense Specialized lymphocytes: T cells and B cells Antibodies Phagocytes, such as neutrophils, eosinophils, dendritic cells, and macrophages Inflammation Fever Antimicrobial substances Figure 16.1 An overview of the body’s defenses.

12 Innate Immunity The first line of defense against an invading pathogen is the skin and mucous membranes – Physical factors—provide a physical barrier Skin Mucous membranes – Chemical factors—secrete chemicals that inhibit growth or eradicates the bacteria

13 Physical Factors Skin – Largest organ in the body – Dermis—skin’s inner, thicker portion. Composed of connective tissue – Epidermis—skin’s outer, thinner layer. Direct contact with the external environment Keratin—protective layer of protein epidermis w/ keratin epidermis dermis

14 Anti-microbial properties of the skin – Shedding of the top layer of epidermis aids in the removal of microbes (sloughing) – Dryness of the skin prevents microbial colonization Populations in humid climates have a greater incidence of skin infections Athletes Foot Fungus (Trichophyton spp) – Compactness of the cells prevents pathogen passage (tight junctions) – pH of skin is between 3-5

15 Mucous membranes – Consists of epithelial layer and connective tissue – Line the gastrintestinal, respiratory, and genitourinary tracts – Goblet cells secretes mucous (slightly viscous glycoprotein) Prevents colonization Connective Tissue Epithelial Layer Mucus

16 Other Physical Barriers Lacrimal apparatus (tear ducts) washes microbes and other particulates from the eyeball Saliva dilutes the numbers of microbes and washes them from the teeth and mucous membranes of the mouth Hair aids in filtering the inhaled air by trapping microbes, dust, and pollutants

17 Other Physical Barriers Cilia are hair-like structures on cells that help propel particulates out of the lower respiratory tract (ciliary escalator) – Toxins in cigarette smoke impair cilia function

18 B. pertussis Cilia Figure 24.7 Ciliated cells of the respiratory system infected with Bordetella pertussis. © 2013 Pearson Education, Inc.

19 Other Physical Barriers Cilia are hair-like structures on cells that help propel particulates out of the lower respiratory tract (ciliary escalator) – Toxins in cigarette smoke impair cilia function Epiglottis is a small flap of cartilage in the larynx Earwax traps microbes in the external ear

20 Other Physical Barriers Urine/vaginal secretions functions by mechanically cleaning the urethra and vagina, respectively Peristalsis, defecation, vomiting, diarrhea all act to remove microbes and toxins from the body – Contraction of gastrointestinal muscles is an effort of the body to remove toxins (stomach pains)

21 Chemical Factors Sebaceous (oil) glands secretes sebum that forms a protective film over the skin surface – Sebum contains unsaturated fatty acids that prevents the growth of certain pathogens – Contributes to acidic pH (3-5) of the skin Perspiration (sweat) eliminates certain wastes and microbes from the body – Also contains lysozyme—enzyme that breaks down the cell wall of Gram (+) bacteria and some Gram (-) bacteria Found in tears, saliva, nasal secretions, tissue fluids, & urine PEPTIDOGLYCAN!!!!

22 Earwax is a mixture of secretions rich in fatty acids (lowers pH) – Sebaceous glands – Sweat glands Saliva contains lysozyme, urea, and uric acid that inhibit microbial growth – Immunoglobin A (antibody) that prevents microbial attachment to cells

23 Gastric juice – Produced by stomach glands. – Very acidic (pH 1.2-3.0) – Destroys microbes and their toxins Vaginal Secretions – Contains glycogen that is digested by Lactobacillus acidophilus, resulting in lactic acid (pH 3-5) Urine – Contains lysozyme that lowers pH thus inhibiting microbial growth

24 Normal Microbiota The normal flora also acts as a first line of defense against invading pathogens – Microbial antagonism Changes in pH – Prevents Candida albicans growth in the vagina Oxygen availability Production of bacteriocins that inhibit growth of pathogens – E. coli production of bacteriocins prevent Shigella and Salmonella growth Competition for nutrients

25 Probiotics—live microbial cultures applied to or ingested to exert a beneficial effect – Prebiotics (chemicals that selectively promote growth of beneficial bacteria) – Studies have shown that the introduction of certain lactic acid bacteria can prevent the growth by Salmonella enterica

26 Innate Immunity: Nonspecific Defenses of the Host

27 Second Line of Defense If a microbe escapes the first line of defense, the body begins mounting a second wave of defense – Production of phagocytes – Inflammation – Fever – Antimicrobial substances

28 Formed Elements in Blood Blood consists of plasma (fluid) and formed elements (cells and cell fragments) Cells of the blood – Erythrocytes – Leukocytes (white blood cells) Granulocytes Agranulocytes During an infection, the number of leukocytes can increase (leukocytosis) or decrease (leukopenia)

29 Insert Table 16.1 If possible, break into multiple slides Table 16.1 Formed Elements in Blood (Part 1 of 2)

30 Insert Table 16.1 If possible, break into multiple slides Table 16.1 Formed Elements in Blood (Part 2 of 2)

31 Percentage of each type of white cell in a sample of 100 white blood cells Neutrophils60–70% Basophils0.5–1% Eosinophils2–4% Monocytes3–8% Lymphocytes (NK cells, T and B cells) 20–25% Differential White Cell Count

32 Lymphatic System Is part of the circulatory system that functions by carrying a clear liquid (lymph) towards the heart Transports leukocytes and antigen-presenting cells to and from lymph nodes Lymph nodes are organized collection of lymphoid tissue through which lymph passes before circulating back into the blood Lymph nodes are primarily found in the neck, chest, armpit, pelvis, groin, and intestines

33 Right lymphatic duct Right subclavian vein Left subclavian vein Thoracic (left lymphatic) duct Tonsil Thymus Lymphatic vessel Large intestine Red bone marrow Heart Thoracic duct Spleen Small intestine Peyer’s patch Lymph node (a) Components of lymphatic system Figure 16.5a The lymphatic system.

34 Lymphatic capillary Lymph Interstitial fluid (between cells) Blood Arteriole Blood capillary Blood Tissue cell Venule Relationship of lymphatic capillaries to tissue cells and blood capillaries Figure 16.5b-c The lymphatic system. Lymph Tissue cell Lymphatic capillary Interstitial fluid One-way opening Details of a lymphatic capillary

35 Phagocytosis Ingestion of microbes or particles by a cell, performed by phagocytes – Phago: from Greek, meaning eat – Cyte: from Greek, meaning cell Neutrophils and eosinophils function in phagocytosis Monocytes mature into macrophages – Fixed macrophages – Wandering (circulating) macrophages

36 Pseudopods Bacterium Macrophage Figure 16.6 A macrophage engulfing rod-shaped bacteria.

37 Mechanism of Phagocytosis 1.Chemotaxis—chemical attraction of phagocytes to microbes 2.Adherence—attachment of the phagocyte’s plasma membrane to the microbe or other foreign particle – Action is enhanced with opsonins 3.Ingestion—uptake of microbe into the cell 4.Digestion—breakdown of microbe via digestive enzymes in lysosomes

38 Pseudopods Phagocyte Cytoplasm Microbe or other particle Details of adherence PAMP (peptidoglycan in cell wall) TLR (Toll-like receptor) Lysosome Digestive enzymes Indigestible material Plasma membrane Partially digested microbe CHEMOTAXIS and ADHERENCE of phagocyte to microbe 1 INGESTION of microbe by phagocyte 2 Formation of phagosome (phagocytic vesicle) 3 Fusion of phagosome with a lysosome to form a phagolysosome 4 DIGESTION of ingested microbes by enzymes in the phagolysosome 5 Formation of the residual body containing indigestible material 6 DISCHARGE of waste materials 7 A phagocytic macrophage uses a pseudopod to engulf nearby bacteria. Figure 16.7 The Phases of Phagocytosis. Pg. 461 of textbook

39 Inhibit adherence: M protein, capsules Streptococcus pyogenes, S. pneumoniae Kill phagocytes: LeukocidinsStaphylococcus aureus Lyse phagocytes: Membrane attack complex Listeria monocytogenes Escape phagosomeShigella, Rickettsia Prevent phagosome– lysosome fusion HIV, Mycobacterium tuberculosis Survive in phagolysosomeCoxiella burnettii Microbial Evasion of Phagocytosis

40 Inflammation Damage to the body’s tissues triggers a local defensive response called inflammation – Not only generated by microbes Inflammation is characterized by four signs/symptoms – Redness – Swelling (edema) – Pain – Heat Binding of microbial structures stimulate the Toll-like receptors of macrophages and they begin producing TNF-alpha Activation of acute-phase proteins (complement, cytokine, and kinins) Vasodilation (histamine, kinins, prostaglandins, and leukotrienes)

41 HistamineVasodilation, increased permeability of blood vessels KininsVasodilation, increased permeability of blood vessels ProstaglandinsIntensify histamine and kinin effect LeukotrienesIncreased permeability of blood vessels, phagocytic attachment Chemicals Released by Damaged Cells

42 Bacteria entering on knife Epidermis Dermis Subcutaneous tissue (a) Tissue damage Bacteria Blood vessel Nerve Figure 16.8a-b The process of inflammation. Chemicals such as histamine, kinins, prostaglandins, leukotrienes, and cytokines (represented as blue dots) are released by damaged cells. (b) Vasodilation and increased permeability of blood vessels Blood clot forms. Abscess starts to form (orange area). 123

43 Insert Fig 16.8c Margination— phagocytes stick to endothelium. Diapedesis— phagocytes squeeze between endothelial cells. Phagocytosis of invading bacteria occurs. (c) Phagocyte migration and phagocytosis Macrophage Bacterium Neutrophil Red blood cell Blood vessel endothelium Monocyte 654 Figure 16.8c The process of inflammation.

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

45 The Complement System 30+ proteins produced by the liver and are located in blood serum throughout the body – Serum proteins are activated in a cascade Activated by – Antigen–antibody reaction (Classical) – Complement C3 binds the factors B, D, P on a pathogen (Alternative) – Liver produces Lectins that bind to carbohydrates

46 Effects of Complement Activation Opsonization, or immune adherence: enhanced phagocytosis – C3a and C5a Membrane attack complex: cytolysis – C5b, C6, C7, C8, C9 (multiple copies) Attract phagocytes – C5a (chemoattractant)

47 Insert Fig 16.9 Inactivated C3 splits into activated C3a and C3b. C3b binds to microbe, resulting in opsonization. C3b proteins opsonization Enhancement of phagocytosis by coating with C3b C5b, C6, C7, and C8 bind together sequentially and insert into the microbial plasma membrane, where they function as a receptor to attract a C9 fragment; additional C9 fragments are added to form a channel. Together, C5b through C8 and the multiple C9 fragments form the membrane attack complex, resulting in cytolysis. C3 C3bC3a C5 C5bC5a C6 C7 C8 C9 Mast cell C3a receptor Microbial plasma membrane Channel C9 C6 C7 C8 C5b C5a C5a receptor Histamine inflammation Increase of blood vessel permeability and chemotactic attraction of phagocytes C9 C8 C7 C6 C5b Cytolysis Formation of membrane attack complex (MAC) C3a C3a and C5a cause mast cells to release histamine, resulting in inflammation; C5a also attracts phagocytes. 123 4 5 C3b also splits C5 into C5a and C5b Bursting of microbe due to inflow of extracellular fluid through transmembrane channel formed by membrane attack complex cytolysis Figure 16.9 Outcomes of Complement Activation. © 2013 Pearson Education, Inc. Pg. 468 of textbook

48 Insert Fig 16.10 Figure 16.10 Cytolysis caused by complement.

49 Insert Fig 16.11 C5a receptor C5a Histamine- containing granule Histamine- releasing mast cell C3a receptor Histamine C3a Neutrophil Phagocytes C5a Macrophage Figure 16.11 Inflammation stimulated by complement.

50 Insert Fig 16.12 C1 is activated by binding to antigen–antibody complexes. Activated C1 splits C2 into C2a and C2b, and C4 into C4a and C4b. C2a and C4b combine and activate C3, splitting it into C3a and C3b (see also Figure 16.9). C3 Opsonization Inflammation Cytolysis C3bC3a C2 C4 C1 Microbe Antibody C4a C2b C2a C4b Antigen Figure 16.12 Classical pathway of complement activation.

51 Insert Fig 16.13 Microbe Lipid-carbohydrate complex Opsonization BDP C3b C3a Inflammation C3 Cytolysis B B factor D D factor P P factor Key: C3 combines with factors B, D, and P on the surface of a microbe. This causes C3 to split into fragments C3a and C3b. Figure 16.13 Alternative pathway of complement activation.

52 C3 Opsonization Inflammation Cytolysis C3b C3a C2C4 C4aC2b C2a C4b Microbe Carbohydrate containing mannose Lectin Bound lectin splits C2 into C2b and C2a and C4 into C4b and C4a. Lectin binds to an invading cell. C2a and C4b combine and activate C3 (see also Figure 16.9). Figure 16.14 The lectin pathway of complement activation.

53 Some Bacteria Evade Complement Capsules prevent C activation – Disallows Ab from binding to bacteria thus preventing C1 binding Surface lipid–carbohydrate complexes prevent formation of membrane attack complex (MAC) – Modification of sugars on the bacterial membrane abrogates C5b-C9 from binding to surface Neisseria gonorrhoeae Enzymatic digestion of C5a – Gram positive cocci (Streptococcus pyogenes)

54 Interferons (IFNs) Interferons—class of similar anti-viral proteins produced by certain animal cells and function to abrogate viral multiplication – Host cell specific and not viral specific IFN-  and IFN-  : produced by virally-infected cells and causes neighboring cells to produce anti-viral proteins that inhibit viral replication – Oligoadenylate synthetase—degrades viral mRNA – Protein kinase—inhibits protein synthesis IFN-  : produced by lymphocytes and causes neutrophils and macrophages to phagocytize bacteria – Produce iNOS (nitric oxide) that inhibits ATP production

55 Insert Fig 16.15 Viral RNA from an infecting virus enters the cell. The infecting virus also induces the host cell to produce interferon mRNA (IFN-mRNA), which is translated into alpha and beta interferons. Viral RNA Infecting virus Viral RNA Transcription Nucleus Translation IFN-mRNA Alpha and beta interferons Virus-infected host cell Translation Transcription Neighboring host cell AVPs degrade viral mRNA and inhibit protein synthesis—and thus interfere with viral replication. Antiviral proteins (AVPs) New viruses released by the virus-infected host cell infect neighboring host cells. The infecting virus replicates into new viruses. 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. 12 34 5 6 Figure 16.15 Antiviral action of alpha and beta interferons (IFNs). Pg. 471 of textbook

56 Innate Immunity Iron-binding proteins – Bind free-iron in serum – Siderophores— proteins that microbes secrete to bind iron Antimicrobial peptides – Chain of 15-20 amino acids – Lyse bacterial cells – Production triggered by protein and sugar molecules on surface of microbes KNOW TABLE ON PAGE 474

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