THE IMMUNE SYSTEM: INNATE AND ADAPTIVE BODY DEFENSES

1. THE IMMUNE SYSTEM:INNATE AND ADAPTIVEBODY DEFENSES

2. INNATE (NONSPECIFIC) DEFENSES • Includes two lines of defense: • First Line of Defense: • External Surface Barriers: Skin and Mucosae • Second Line of Defense: • Antimicrobial proteins • Phagocytes • Inflammation

3. Adaptive (Specific) Defense System • Third Line of Defense: • Takes considerably more time to mount than the innate response • Attacks particular foreign substances (antigens)

4. INNATE (NONSPECIFIC) DEFENSES • External Surface Barriers: Skin and Mucosae • Skin, a highly keratinized epithelial membrane, represents a physical barrier to most microorganisms and their enzymes and toxins • Mucous membranes line all body cavities open to the exterior and function as an additional physical barrier • Secretions of the epithelial tissues include: • Acidity of the skin secretions (pH 3 to 5) • Inhibits bacterial growth • Sebum contains chemicals that are toxic to bacteria • Vaginal secretions of adult female are also very acidic • Stomach: • Mucosa secretes a concentrated hydrochloric acid solution and protein-digesting enzyme (both kill microorganisms) • Saliva: • Cleanses the oral cavity and teeth • Lacrimal fluid of the eye contain lysozyme • Enzyme that destroys bacteria • Mucus (sticky): • Traps many microorganisms that enter the digestive and respiratory passageways (hairs, cilia)

5. INTERNAL DEFENSES: CELLS AND CHEMICALS • Nonspecific cellular and chemical devices to protect itself: • Recognize surface carbohydrates, proteins unique to infectious organisms (bacteria, viruses, and fungi) • Phagocytes, natural killer cells, antimicrobial proteins, and fever • The inflammatory response enlists macrophages, mast cells, all types of white blood cells, and dozens of chemicals that kill pathogens and help repair tissue • Fever

6. PHAGOCYTES • Confront microorganisms that branch the external barriers • Macrophages are the main phagocytes of the body • Derive form white blood cells called monocytes that leave the bloodstream, enter the tissues, and develop into macrophages • Free macrophages (alveolar macrophages of the lungs and dendritic cells of the epidermis) wander throughout the tissue spaces • Fixed macrophages (Kupffer cells in the liver and microglia of the brain) are permanent residents of particular organs • All macrophages are similar structurally and functionally

7. PHAGOCYTES • Neutrophils: • Most abundant type of white blood cell • Become phagocytic on encountering infectious material in the tissues • Are the first responders and become phagocytes when they encounter infectious material • Eosinophils: • Another type of white blood cell • Are weakly phagocytic but are important in defending the body against parasitic worms • Mast cells: • Role in allergies • Have the ability to bond with, ingest, and kill a wide range of bacteria • Normally not included as a phagocyte but they share their capabilities

8. Mechanism of Phagocytosis • A phagocyte engulfs particulate matter much the way an amoeba ingests a food particle • The phagosome thus formed is then fused with a lysosome to form a phagolysosome

9. Mechanism of Phagocytosis • Pathogens can sometimes elude capture because phagocytes cannot bind to their capsules (example: pneumococcus) • Adherence is both more probable and more efficient when complement proteins and antibodies coat foreign particles, a process called opsonization • Coating provides sites to which the phagocytes receptors can bind • Exception: Neutrophils produce antibiotic-like chemicals (defensins) that pierce the pathogen’s membrane • Unhappily, the neutrophils also destroy themselves in the process, whereas macrophages, which rely only on intracellular killing, can go on to kill another day

10. PHAGOCYTOSIS BY MACROPHAGES

11. Natural Killer Cells (NK) • Are able to lyse and kill cancer cells and virally infected cells before the adaptive immune system has been activated • Are a small group of large granular lymphocytes • UNLIKE lymphocytes of the adaptive immune system, which recognize and react only against specific virus-infected or tumor cells, Natural Killer cells are far less picky • Detect the lack of “SELF” cell surface receptors and by recognizing certain surface sugars on the target cell • Name “natural” reflects this non-specificity of these cells • Are not phagocytic • Mode of killing involves an attack on the target cell’s membrane and release of cytolytic chemicals called perforins • Shortly after perforin release, channels appear in the target cell’s membrane and its nucleus disintegrates • Also secrete potent chemical that enhance the inflammatory response

12. Inflammation: Tissue Response to Injury • Occurs any time the body tissues are injured by physical trauma, intense heat, irritating chemicals, or infection by viruses, fungi, or bacteria: • The four cardinal signs of acute inflammation are redness, heat, swelling, and pain • Chemicals cause dilation of surrounding blood vessels to increase blood flow to the area and increase permeability, which allows fluid containing clotting factors and antibodies to enter the tissues • Soon after inflammation the damaged site is invaded by neutrophils and macrophages

13. Inflammation Process • Begins with a flood of inflammatory chemicals released into the extracellular fluid • Toll-like receptors (TLRs): • Macrophages and certain cells lining the gastrointestinal tract and respiratory tracts bear these surface membrane receptors • Ten types have been identified: • Each recognizing a specific class of attacking microbe • Example: • One type response to glycolipid in cell walls of tuberculosis bacterium • One type response to a component of gram-negative bacteria such as salmonelle • Triggers release of cytokines that promote inflammation and attracts WBCs • Injured and stressed tissue cells, phagocytes, lymphocytes, mast cells, and blood proteins are all sources of inflammatory mediators • Histamine, kinins, prostaglandins

14. Inflammation Process • All chemicals produced cause small blood vessels in the injured area to dilate • Local hyperemia results (accounting for the redness and heat of an inflamed region) • Swelling presses on adjacent nerves contributing to pain • Pain also results from the release of bacterial toxins, lack of nutrition to cells in the area, and the sensitizing effects of released prostaglandins and kinins • Aspirin and some other anti-inflammatory drugs produce their analgesic (pain-reducing) effects by inhibiting prostaglandin synthesis • Increases the permeability of local capillaries • Exudate fluid: • Contains clotting factors (gel like substances that isolate the area, preventing the spread of harmful agents) and antibodies • Dilutes the harmful substances • Brings in large quantities of oxygen and nutrients needed for repair

15. EVENTS IN INFLAMMATION

16. PHAGOCYTE MOBILIZATION • Soon after inflammation begins, the damaged area is invaded by more phagocytes—neutrophils lead, followed by macrophages • If inflammation was provoked by pathogens • A group of plasma proteins is activated • Lymphocytes and antibodies invade the injured site

17. PHAGOCYTE MOBILIZATION • 1.Leukocytosis: • Chemicals called leukocytosis-inducing factors released by injured cells promote: • Rapid release of neutrophils from red bone marrow • Within a few hours the number of neutrophils in blood increases 4 to 5 fold • Increase in WBCs • Characteristic of inflammation

18. PHAGOCYTE MOBILIZATION • 2.Margination (pavementing): • Neutrophils adhesion molecules (CAMs) help them cling to the inner walls of the capillaries and post-capillary venules

19. PHAGOCYTE MOBILIZATION • 3.Diapedesis (emigration): • Continued chemical signaling prompts the neutrophils to squeeze through the capillary walls

20. PHAGOCYTE MOBILIZATION • 4.Chemotaxis: • Neutrophils usually migrate randomly, but inflammatory chemicals act as homing devices (chemotactic agents) • Attract the neutrophils and other WBCs to the site of the injury • Within an hour after the inflammatory response has begun, neutrophils have collected at the site and are devouring any foreign material present

21. PHAGOCYTE MOBILIZATION

22. PHAGOCYTE MOBILIZATION • Monocytes follow neutrophils into the injured area: • Develop large numbers of lysosomes with insatiable appetites • Replace the neutrophils in the battlefield • Central actors in the final disposal of cell debris as an acute inflammation subsides, and they predominate at suites of prolonged, or chronic, inflammation

23. PHAGOCYTE MOBILIZATION • The ultimate goal of an inflammatory response is to clear the injured area of pathogens, dead tissue cells, and any other debris so that tissue can be repaired • Once this is accomplished, healing usually occurs quickly

24. HOMEOSTATIC IMBALANCE • In severely infected areas, the battle takes a considerable toll on both sides, and creamy, yellow pus, a mixture of dead or dying neutrophils, broken-down tissue cells, and living and dead pathogens, may accumulate in the wound • If the inflammatory mechanism fails to clear the area of debris, the sac of pus may be walled off by collagen fibers, forming an abscess • Surgical drainage of abscesses is often necessary before healing can occur

25. HOMEOSTATIC IMBALANCE • Tuberculosis bacilli: • Some escape resistant to digestion by macrophages • Escape the effects of antibiotics by remaining enclosed within the macrophage host (infectious granulomas) • Tumorlike growth can develop • Central region of infected macrophages surrounded by uninfected macrophages encased by an outer fibrous capsule • Could harbor these pathogens for years without symptoms • Could break out and become active

26. Antimicrobial proteins • Enhance the innate defenses by attacking microorganisms directly or by hindering their ability to reproduce • Interferon • Complement proteins

27. Interferon • Virally infected cells can do little to save themselves, some can secrete small proteins to help protect cells that have not yet been infected • Small proteins produced by virally infected cells that help protect surrounding healthy cells • Interferon diffuses to nearby cells, where they stimulate synthesis of a protein known as PKR, which then “interferes” with viral replication in the still-healthy cells by blocking protein synthesis at the ribosomes • Not virus specific • Produced against a particular virus—protects against a variety of other viruses

28. INTERFERON MECHANISM

29. Interferon • Family of related proteins, produced by a variety of body cells, each having a slightly different physiological effect • Lymphophytes secrete gamma (immune) interferon • Most other leukocytes secrete alpha interferon • Used to treat genital warts and hepatitis C (spread by blood and sexual intercourse) • Fibroblasts secrete beta interferon • Active in reducing inflammation • Besides anti-viral effects, activates Macrophages and Natural Killer Cells

30. COMPLEMENT • Complement (fills up or completes) refers to a group of about 20 plasma proteins that provide a major mechanism for destroying foreign pathogens in the body • Normally circulate in the blood in an inactive state • C1 through C9 • B, D, and P, plus several regulatory proteins • Activation unleashes chemical mediators that amplify virtually all aspects of the inflammatory process • Non-specific defense mechanism

31. COMPLEMENT • Can be activated by two pathways: • Classical: involves antibodies, water-soluble protein molecules that the adaptive immune system produces to fight off foreign invaders • Alternative: triggered when factors B, D, and P interact with polysaccharide molecules present on the surface of certain microorganisms • Each mechanism involves a cascade

32. EVENTS AND RESULTS OF COMPLEMENT ACTIVATION

33. Fever • Abnormally high body temperature, is a systemic response to microorganisms • Systemic (whole body rather than to one of its parts) response to invading microorganisms • The hypothalamus (body temperature) is reset in response to chemicals called pyrogens, secreted by leukocytes and macrophages exposed to foreign substances in the body • High fevers are dangerous • Denature proteins

34. Innate/Adaptive Defenses • Unlike the innate system, which is always ready and able to react, the adaptive system must “meet” or be primed by an initial exposure to a specific foreign substance (antigen) before it can protect the body against that substance, and this priming takes precious time

35. ADAPTIVE (SPECIFIC) DEFENSES • Aspects of the Adaptive Immune Response • It is specific: • Recognize and destroy the specific antigen that initiated the response • It is systemic: • Not limited (restricted) to the initial infection site • It has “memory”: • After an initial exposure the immune response is able to recognize the same antigen and mount a faster and stronger defensive attack

36. ADAPTIVE DEFENSES • Humoral (humors: fluids) immunity: • Antibody-mediated immunity • Provided by antibodies present in the body’s “humors” or fluids • Produced by B lymphocytes • Circulate freely in the blood and lymph • Mark bacteria, bacterial toxins, viruses for destruction by phagocytes or complement

37. ADAPTIVE DEFENSES • Cellular (cell-mediated) immunity: • Protective factor is a living cell • Cellular targets: • Virus-infected tissue cells • Parasite-infected tissue cells • Cancer cells of foreign graft • Lymphocytes act either: • Directly by lysing the foreign cells • Indirectly by releasing chemical mediators that enhance the inflammatory response or activate other lymphocytes or macrophages • Associated with T lymphocytes and has living cells as its protective factor

38. ANTIGENS • Substances that can mobilize the immune system and provoke an immune response • Ultimate targets of all immune responses • Most are large, complex molecules (both natural and synthetic) that are not normally present in the body (NONSELF) • Can be complete or incomplete

39. COMPLETE ANTIGENS • Two important functional properties are: • 1. Immunogenicity: • ability to stimulate the proliferation of specific lymphocytes and antibodies • 2. Reactivity: • Ability react with the activated lymphocytes and produced antibodies • Limitless variety: • All foreign proteins, nucleic acids, some lipids, and many large polysaccharides • Proteins are the strongest antigens • Pollen, microorganisms, fungi, viruses

40. ANTIGENS • Haptens are incomplete antigens that are not capable of stimulating the immune response, but if they interact with proteins of the body they may be recognized as potentially harmful • Small peptides, nucleotides, and many hormones—are NOT immunogenic • Certain chemicals: antibiotics, chemicals in poison ivy, animal dander, detergents, cosmetics, etc.—NOT immunogenic • BUT, if they link up with the body’s own proteins, the adaptive immune system may recognize the combination as foreign and mount an attack that is harmful rather than protective (allergies) • Have reactivity but NOT immunogenicity

41. ANTIGENIC DETERMINANTS • Specific part of an antigen that has immunogenic properties: • Bind to free antibodies or activated lymphocytes in much the same manner as an enzyme binds to a substrate

42. ANTIGENIC DETERMINANTS • Large proteins have hundreds of chemically different antigenic determinants, which accounts for their high immunogenicity and reactivity • Large simple molecules such as plastics, which have many identical, regularly repeating units, have little or no immunogenicity • Such substances are used to make artificial implants

43. ANTIGENIC DETERMINANTS

44. Self-Antigens: MHC Proteins • The external surface of all our cells are dotted with a huge variety of protein molecules • These self-antigens are not foreign or antigenic to us, BUT they are strongly antigenic to other individuals • MHC proteins: major histocompatibility complex • Group of glycoproteins: surface proteins that mark a cell as SELF • Coded for by genes • Only identical twins have the same gene code • Two major groups: • Class I: found on virtually all body cells • Class II: found only on certain cells that act in the immune response

45. ADAPTIVE (SPECIFIC) DEFENSES • Cells of the Adaptive Immune System • Three cell types: • Two types of lymphocytes: • B lymphocytes (B cells) • Oversees humoral immunity • T lymphocytes (T cells) • Non-antibody-producing • Constitute the cell-mediated arm of adaptive immunity • Antigen-presenting cells (APCs) • Do not respond to specific antigens but instead play essential auxiliary roles

46. LYMPHOCYTES • Originate in the red bone marrow from hematopoietic stem cells • When released from bone marrow, the immature lymphocytes are essentially identical • Maturation (into T cells / B cells) depends on where in the body they become immunocompetent, that is, able to recognize a specific antigen by binding to it

47. LYMPHOCYTES • T cells mature in the Thymus under direction of thymic hormone • Positive selection produces self-MHC restricted T cells • Those cells that are able to recognize SELF are allowed to continue the maturation process • Those that fail undergo apoptosis (programmed death of cells) • Negative selection identifies T cells that are self-tolerant • Those that react too vigorously with self MHC are selected against and eliminated • This ensures that the T cells surviving this second screening process exhibit self tolerance (relative unresponsiveness to self antigens)

48. T CELL SELECTION IN THE THYMUS

49. LYMPHOCYTES • B cells become immunocompetent and self-tolerant in bone marrow • Mechanism is not completely understood but appears to be very similar to the thymus

50. Lymphoid Organs • Location where lymphocytes become immunocompetent • Primary lymphoid organs: • Thymus • Bone marrow • Secondary lymphoid organs: • All other organs