2. Host defenses are composed of two complementary, frequently interacting systems: (1)innate (nonspecific) defenses, which protect against microorganisms in general, and (2) acquired (specific) immunity, which protects against a particular microorganism.

3. TWO TYPES OF IMMUNITY Nonspecific (innate) Physical and chemical agents Lysozyme Acute phase proteins Complement system Cytokines (chemokines) Phagocytes (granulocytes, macrophages) Natural killer (NK) cells Dendritic cells Toll-like receptors Specific (adaptive) Antibodies (B lymphocytes) T lymphocytes Present at birth Immediate protection against variety of pathogens and foreign substances

4. Immunity signifies all those properties of the host that confer resistance to a specific infectious agent. Immunity Natural Acquired or adaptive (specific) (Innate, nonspecific) Passive Active

5. Acquired ( Adaptive) Immunity Active Passive Natural Artificial (Infection) (Immunizing agents) Clinical Subclinical (Placental transfer, colostrum) (administration of immune sera)

6. First Line of Defense Epidermis Mucous membranes  Mucous  Cilia  Lacrimal apparatus of eyes  Saliva  Urine flow  Vaginal secretions  Defecation and vomiting Sebum Perspiration Lysozyme Gastric juice

7. Intact skin is the first line of defense against many organisms. In addition to the physical barrier presented by skin, the fatty acids secreted by sebaceous glands in the skin have antibacterial and antifungal activity. Innate (nonspecific) defenses Skin and Mucous Membranes

8. Mucous membranes protective covering in intestine, lungs, eyes etc., that resists penetration and traps many microbes antimicrobial secretions  Lysozyme  Lactoferrin: macrophages and PMNs, sequesters iron  Lactoperoxidase: produces superoxide radicals  mucosal-associated lymphoid tissue (MALT)

9. MUCOSAL SURFACES Gastrointestinal tract Respiratory tract Urinary tract Reproductive tract

10. Respiratory System - The mucociliary blanket of the respiratory epithelium traps microorganisms less than 10 ㎛ diameter - The bronchial-Associated Lymphoid Tissue (BALT) Gastrointestinal Tract - In the stomach : lower pH, enzymes - In the intestine : enzymes - In the large intestine : the normal microbiota ⇒ preventing the establishment of pahtogens ⇒ destroy microorganisms Genitourinary Tract - Urine kills some bacteria due to its low pH and the presence of urea and other metabolic end products The Eye - Tears contain large amount of lysozyme, lactoferrin and sIgA

11. A second important defense is the mucous membrane of the respiratory tract, which is lined with cilia and covered with mucus. The coordinated beating of the cilia drives the mucus up to the nose and mouth, where the trapped bacteria can be expelled.

12. In lacrimal fluid, sputum, saliva, blood, milk, tissues and organs lysozyme is found. It is found in some bacterial cells. Nasal mucus is bactericidal for many microbes and viruses of influenza, herpes, poliomyelitis, etc.

15. Second Line of Defense Antimicrobial proteins 1. Interferons (IFNs)  Antivirals that prevent replication of virus 2. Complement system  Enhance immune reactions 3. Transferrins  Inhibit bacterial growth by reducing available iron

16. Interferons (IFNs) are antiviral proteins produced in response to viral infection. alpha-IFN, beta-IFN, gamma-IFN. The mode of action of  -IFN and  -IFN is to induce uninfected cells to produce antiviral proteins (AVPs) that prevent viral replication. Interferons are host-cell–specific but not virus-specific. Gamma-interferon activates neutrophils and macrophages to kill bacteria. Interferons (IFNs)

18. Complement System Summary Series of  30 plasma (serum) proteins, activated in a cascade Three effects of complement system: 1. Enhances inflammatory response, e.g.: attracts phagocytes 2. Increases phagocytosis through opsonization or immune adherence 3. Creates Membrane Attack Complexes (MACs)  Cytolysis

19. Classical Pathway of Complement Activation

20. IgA and IgE cannot activate complement

21. Alternative Pathway of Complement Activation

22. Lectin Pathway of Complement Activation

24. Late Steps of Complement Activation

26. Inflammation Stimulated by Complement

27. Transferrins Transferrins Transferrins are iron-binding proteins. Inhibit bacterial growth by reducing the amounts of available iron. Transferrin transports iron from the small intestine, where the iron is absorbed, to the tissues, where the iron is used. Transferrin and lactoferrin bind iron, limiting the growth of pathogens in the blood. Lactoferrin is present in tears, semen, breast milk, bile, and nasopharyngeal, bronchial, cervical, and intestinal mucosal secretions. Transferrin is present in serum and the intercellular spaces of many tissues and organs.

29. Innate Immunity Depends on Receptor- Recognition of Common Pathogen-Associated Molecules  Pathogen-associated molecular patterns (PAMPs) help the innate immune system recognize pathogens  Toll-like receptors (TLRs) are signaling receptors on: macrophages dendritic cells endothelial cells

30. TLRs on MPhs, dendritic cells, epithelial cells Cytokines! PAMPs recognition

33. Second Line of Defense Natural killer (NK) cells  ~ 5 – 10% of lymphocytes  In spleen, lymph nodes and red bone marrow  Attack body cells displaying abnormal plasma membrane proteins  Perforin perforates cell membranes  Granzymes destroy cell proteins Phagocytes  Phagocytosis Neutrophils Macrophages  Develop from monocytes  Wandering  Fixed

34. Figure 21.8a

35. Phagocytosis

38. Killing mechanisms of phagocytes

40. SEM of macrophage engulfing E. coli cells on the surface of a blood vessel

43. Phagocytosis Phagocytes recognize the enemy either directly, by binding to components on the surface of the organism or indirectly, by binding to a foreign entity that has antibody bound to it.

44. Inhibit adherence: M protein, capsules Streptococcus pyogenes, S. pneumoniae Kill phagocytes: Leukocidins Staphylococcus aureus Lyse phagocytes: Membrane attack complex Listeria monocytogenes Escape phagosomeShigella Prevent phagosome- lysosome fusion HIV Survive in phagolysosomeCoxiella burnetti Microbial Evasion of Phagocytosis

45. Natural Killer Cells Recognize and Kill Abnormal Cells  NK cells are formed in the bone marrow, and migrate to: tonsils lymph nodes spleen  When activated, they produce cytokines that trigger response by macrophages and other cells  Then they move into blood and lymph where they kill: cancer cells virus-infected cells

47. When an NK cell recognizes a cell as “non-self” it releases cytotoxic perforins and granzymes

49. ADCC by NK Cells

50. Destruction of Virus-Infected Cells by NK Cells through Antibody-Dependent Cellular Cytotoxicity (ADCC)

52. Tissue damage triggers the inflammatory response The inflammatory response mobilizes nonspecific defense forces Tissue injury; release of chemical signals such as histamine 1 23 Dilation and increased leakiness of local blood vessels; migration of phagocytes to the area Phagocytes (macrophages and neutrophils) consume bacteria and cell debris; tissue heals Pin Skin surface Bacteria Chemical signals White blood cell Swelling Phagocytes and fluid move into area Phagocytes Red, swell, warm Non-specific defense system The inflammatory response can  disinfect tissues  limit further infection

53. Cytokines “Cytokines” are soluble protein mediators secreted by immune cells (mostly) that act on other cells to regulate their activity; many are called “interleukins” (IL-1, IL-2, etc.) Cytokines have many functions, we’ll focus on a few central functions of a few key cytokines A subfamily of cytokines primarily functions in directing migration of cells, these are called “chemotactic cytokines” or “chemokines ”

54. - monokines, lymphokines, interleukines colony stimulating factors, chemokines, interferon - The four cytokine families Function : autocrine paracrine endocrine

55. A summary of innate and acquired immunity INNATE IMMUNITY Rapid responses to a broad range of microbes ACQUIRED IMMUNITY Slower responses to specific microbes External defensesInternal defenses Skin Mucous membranes Secretions Phagocytic cells Antimicrobial proteins Inflammatory response Natural killer cells Humoral response (antibodies) Cell-mediated response (cytotoxic lymphocytes) Invading microbes (pathogens)

56. Break !