The Immune System

1. The Immune System P A R T A

2. Immunity: Two Intrinsic Defense Systems • Innate (nonspecific) system responds quickly and consists of: • First line of defense – skin and mucosa prevent entry of microorganisms • Second line of defense – antimicrobial proteins, phagocytes, and other cells • Inhibit spread of invaders throughout the body • Inflammation is its most important mechanism

3. Immunity: Two Intrinsic Defense Systems • Adaptive (specific) defense system • Third line of defense – mounts attack against particular foreign substances • Takes longer to react than the innate system • Works in conjunction with the innate system

4. Innate and Adaptive Defenses

5. Innate Defense - First Line • Surface Barriers: skin and mucosa • Skin, mucous membranes, and their secretions make up the first line of defense • Keratin in the skin: • Presents a physical barrier to most microorganisms • Is resistant to weak acids and bases, bacterial enzymes, and toxins • Mucosa provide similar mechanical barriers

6. Innate Defense • Epithelial membranes produce protective chemicals that destroy microorganisms • Skin acidity (pH of 3 to 5) inhibits bacterial growth • Sebum contains chemicals toxic to bacteria • Stomach mucosa secrete concentrated HCl and protein-digesting enzymes • Saliva and lacrimal fluid contain lysozyme

7. Innate Defense • Mucus traps microorganisms that enter the digestive and respiratory systems • Respiratory Tract Mucosae: • Mucus-coated hairs in the nose trap inhaled particles • Mucosa of the upper respiratory tract is ciliated • Cilia sweep dust- and bacteria-laden mucus away from lower respiratory passages

8. Innate Defense - Second Line • Cells • Mast cells and basophils • Release histamine and heparin

9. Innate Defense – Second Line • Phagocytes • Macrophages are the chief phagocytic cells • Free macrophages wander throughout a region in search of cellular debris • Kupffer cells (liver) and microglia (brain) are fixed macrophages • They derive from monocytes

10. Innate Defense – Second Line • Neutrophils become phagocytic when encountering infectious material • They also release defensins that will perforate the pathogen’s membrane • Eosinophils are weakly phagocytic. They are important against parasitic worms • They degranulate their enzymes when encountering the parasite

11. Microbe adheres to phagocyte. 1 Phagocyte forms pseudopods that eventually engulf the particle. 2 Phagocytic vesicle containing antigen (phagosome). Lysosome Phagocytic vesicle is fused with a lysosome. 3 Phagolysosome Microbe in fused vesicle is killed and digested by lysosomal enzymes within the phagolysosome, leaving a residual body. 4 Acid hydrolase enzymes Residual body Indigestible and residual material is removed by exocytosis. 5 (b) Figure 21.2b

12. Innate Defense – Second Line • Mechanism of phagocytosis: • First step for phagocytosis is adherenceof the pathogen to the phagocyte. • Adherence will be facilitated when the pathogen is coated with complement or antibodies: • Opsonization

13. Innate Defense – Second Line • Respiratory burst • It happens when the pathogen is resistant to common digestive enzymes • Neutrophils and macrophages will then release more powerful enzymes that are lethal to most bacteria.

14. Innate Defense – Second Line • Natural Killer (NK) Cells • Can lyse and kill cancer cells and virus-infected cells • Are a small, distinct group of large granular lymphocytes • They lack specificity • They are not phagocytes

15. Innate Defense – Second Line • Kill their target cells by releasing perforins to destroy virus-infected cells • They release interferons that interfere with viral replication • Secrete chemicals that enhance the inflammatory response • They can recognize self cell receptors

16. Innate Defense – Second Line • Inflammation: Tissue Response to Injury • The inflammatory response is triggered whenever body tissues are injured • Prevents the spread of damaging agents to nearby tissues • Disposes of cell debris and pathogens • Sets the stage for repair processes • The four cardinal signs of acute inflammation are redness, heat, swelling, and pain

17. Innate Defense – Second Line • Begins with a flood of inflammatory chemicals released into the extracellular fluid • Inflammatory mediators: • Kinins, prostaglandins (PGs), complement, and cytokines • Released by injured tissue, phagocytes, lymphocytes, and mast cells • Cause local small blood vessels to dilate, resulting in hyperemia

18. Innate Defense – Second Line • Vasodilation and increased vascular permeability • Chemicals liberated by the inflammatory response will • Dilate small blood vessels • Hyperemia • Increase the permeability of local capillaries • Exsudate

19. Innate Defense – Second Line • Exudate—fluid containing proteins, clotting factors, and antibodies • Exudate seeps into tissue spaces causing local edema (swelling), which contributes to the sensation of pain. • Also the bacterial toxins, prostaglandins and kinins contribute for the pain

20. Innate Defense – Second Line • The surge of protein-rich fluids into tissue spaces (edema): • Helps dilute harmful substances • Brings in large quantities of oxygen and nutrients needed for repair • Allows entry of clotting proteins, which prevents the spread of bacteria by creating a gel-like fibrin mesh • Inflammation will also release β-defensins that have antimicrobial properties

21. Innate Defense – Second Line • Mobilization of Phagocytes: • Leukocytosis- the increase of WBC in the blood. It is caused by factors released by injured cells. • Margination – neutrophils cling to the walls of capillaries in the injured area • Diapedesis – neutrophils squeeze through capillary walls and begin phagocytosis • Chemotaxis – WBC attraction to chemicals that guide them to the site of injury or inflammation after they leave the bloodstream.

22. Innate defenses Internal defenses Positive chemotaxis 4 Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents Diapedesis Neutrophils enter blood from bone marrow 3 1 Margination 2 Endothelium Basement membrane Capillary wall Figure 21.4

24. Innate Defense – Second Line • Antimicrobial Proteins • Enhance the innate defenses by: • Attacking microorganisms directly • Hindering microorganisms’ ability to reproduce • The most important antimicrobial proteins are: • Interferon • Complement proteins

25. Innate Defense – Second Line • Interferon (IFN) • Genes that synthesize IFN are activated when a host cell is invaded by a virus • Interferon molecules leave the infected cell and enter neighboring cells • Interferon stimulates the healthy cells to activate genes for an antiviral protein production • This antiviral protein nonspecifically blocks viral reproduction in the neighboring cell

26. Interferon

27. Innate Defense – Second Line • IFNs family • Family of related proteins each with slightly different physiological effects • Lymphocytes secrete gamma () interferon, but most other WBCs secrete alpha () interferon • Fibroblasts secrete beta () interferon • Interferons also activate macrophages and mobilize NKs • Some anticancer property

28. Innate Defense – Second Line • Complement • 20 or so proteins that circulate in the blood in an inactive form • Proteins include C1 through C9, factors B, D, and P (properdin), and regulatory proteins • Provides a major mechanism for destroying foreign substances in the body

29. Innate Defense – Second Line • Amplifies all aspects of the inflammatory response • Kills bacteria and certain other cell types (our cells innactivate complement) • Enhances the effectiveness of both nonspecific and specific defenses

30. Innate Defense – Second Line • Complement Pathways: • Complement can be activated by two pathways: classical and alternate (properdin) • Classical pathway is linked to the immune system • Depends on the binding of antibodies to invading organisms • Subsequent binding of C1 to the antigen-antibody complexes (complement fixation)

31. Innate Defense – Second Line • Alternative pathway is triggered by interaction among factors B, D, and P, and polysaccharide molecules present on microorganisms • Each pathway involves a cascade in which complement proteins are activated in a sequence where each step catalyzes the next • Both pathways converge on C3, which cleaves into C3a and C3b

32. Innate Defense – Second Line • C3b initiates formation of a membrane attack complex (MAC) • MAC causes cell lysis by creating pores in the cell membranes • C3b also causes opsonization, and C3a causes inflammation

33. Complement Pathways

34. Innate Defense – Second Line • C-reactive Protein (CRP) • CRP is produced by the liver in response to inflammatory molecules • CRP is a clinical marker used to assess: • The presence of an acute infection • An inflammatory condition and its response to treatment

35. Innate Defense – Second Line • Functions of C-reactive Protein: • Binds to receptor of pathogens and exposed self-antigens of damaged body cells • Targets them for disposal by macrophages and complements (classical pathway) • Activates complement by biding to C1

36. Innate Defense – Second Line • Fever • Abnormally high body temperature in response to invading microorganisms • The body’s thermostat is reset upwards in response to pyrogens, chemicals secreted by leukocytes and macrophages exposed to bacteria and other foreign substances

37. Innate Defense – Second Line • High fevers are dangerous because they can denature enzymes • Moderate fever can be beneficial, as it causes: • The liver and spleen to sequester iron and zinc (needed by microorganisms) • An increase in the metabolic rate, which speeds up tissue repair

38. Adaptive Defenses – Third Line • The adaptive (specific) immune system is a functional system that: • Recognizes specific foreign substances • Acts to immobilize, neutralize, or destroy foreign substances • Amplifies inflammatory response and activates complement

39. Adaptive Immune Defenses • The adaptive immune system is antigen-specific, systemic, and has memory • It has two separate but overlapping arms: • Humoral, or antibody-mediated immunity • Cellular, or cell-mediated immunity

40. Self-Antigens • Our cells are dotted with a variety of protein molecules (self-antigens) that are not antigenic to us but are strongly antigenic to others • One type, MHC proteins, mark a cell as self • The two classes of MHC proteins are: • Class I MHC proteins – found on virtually all body cells • Class II MHC proteins – found on certain cells in the immune response

41. Nonself Antigens • Substances that can mobilize the immune system and provoke an immune response • The ultimate targets of all immune responses are mostly large, complex molecules not normally found in the body (nonself) • They can be complete or incomplete

42. Complete Antigens • Important functional properties: • Immunogenicity – ability to stimulate proliferation of specific lymphocytes and antibody production • Reactivity – ability to react with products of activated lymphocytes and the antibodies released in response to them • Complete antigens include foreign protein, nucleic acid, some lipids, and large polysaccharides

43. Haptens (Incomplete Antigens) • Small molecules, such as peptides, nucleotides, and many hormones, that are not immunogenic but are reactive when attached to protein carriers • If they link up with the body’s proteins, the adaptive immune system may recognize them as foreign and mount a harmful attack (allergy) • Haptens are found in poison ivy, dander, some detergents, and cosmetics

44. Antigenic Determinants • Only certain parts of an entire antigen are immunogenic • Antibodies and activated lymphocytes bind to these antigenic determinants • Most naturally occurring antigens have numerous antigenic determinants that: • Mobilize several different lymphocyte populations • Form different kinds of antibodies against it • Large, chemically simple molecules (e.g., plastics) have little or no immunogenicity

45. Complete Antigens

46. HAPTENS Completeantigen Hapten Carriermolecule Antibody molecules can bind ahapten (partial antigen) once it hasbecome a complete antigen bycombining with a carrier molecule.

47. Cells of the Adaptive Immune System • Two types of lymphocytes • B lymphocytes – oversee humoral immunity • T lymphocytes – non-antibody-producing cells that constitute the cell-mediated arm of immunity • Antigen-presenting cells (APCs): • Do not respond to specific antigens • Play essential auxiliary roles in immunity

48. Lymphocytes • Immature lymphocytes formed in the bone marrow are essentially identical • Whether a lymphocyte matures into a B cell or a T cell depends on where in the body it becomes immunocompetent (ability to recognize a specific antigen) and self-tolerant • B cells mature in the bone marrow • T cells mature in the thymus

49. T Cells • T cells mature in the thymus under negative and positive selection pressures • Positive selection – selects T cells that recognize self-antigens, • Happens in the thymic cortex • Negative selection – eliminates T cells that are strongly anti-self • Happens in the inner thymic cortex • They become self-tolerant (ignore one’s self antigens)

50. T Cell Selection in the Thymus