Immune / Lymphatic System

1. phagocytic leukocyte Fighting theEnemy Within! Immune / LymphaticSystem lymphocytes attacking cancer cell lymph system

2. Avenues of attack • Points of entry • digestive system • respiratory system • urogenital tract • break in skin • Routes of attack • circulatory system • lymph system

3. Why an immune system? • Attack from outside • lots of organisms want you for lunch! • animals are a tasty nutrient- & vitamin-packed meal • cells are packages of macromolecules • animals must defend themselves against invaders (pathogens) • viruses • HIV, flu, cold, measles, chicken pox • bacteria • pneumonia, meningitis, tuberculosisLyme disease • fungi • yeast (“Athlete’s foot”…) • protists • amoeba, malaria • Attack from inside • cancers = abnormal body cells Mmmmm, What’s in your lunchbox?

4. Nonspecific vs. Specific Defenses • Three cooperative lines of defense have evolved to counter threats posed by bacteria and viruses. • Two of these are nonspecific - that is, they do not distinguish one infectious agent from another.

5. Lines of defense • 1st line: Non-specific barriers • broad, external defense • “walls & moats” • skin & mucous membranes • 2nd line: Non-specific patrols • broad, internal defense • “patrolling soldiers” • leukocytes = phagocytic WBC • 3rd line: True immune system • specific, acquired immunity • “elite trained units” • lymphocytes & antibodies • B cells & T cells Bacteria & insectsinherit resistance. Vertebratesacquire immunity.

6. 1st line: Non-specific barriers • Mechanical Barriers that physically block pathogens from entering the body. The skin is the most important mechanical barrier. • It is the single most important defense the body has.

7. 1st line: Non-specific barriers • Chemical Barriers destroy pathogens on the outer body surface, at body openings, and on inner body linings. Sweat, mucus, tears, and saliva all contain enzymes that kill pathogens. Urine is too acidic for many pathogens, and semen contains zinc, which most pathogens cannot tolerate. In addition, stomach acid kills pathogens that enter the GI tract in food or water

8. 1st line: Non-specific barriers • Biological Barriers are living organisms that help protect the body. Millions of harmless bacteria live on the human skin. Many more live in the GI tract. The harmless bacteria use up food and space so harmful bacteria cannot grow.

9. 1st line: Non-specific External defense • Barrier • skin • Traps • mucous membranes, cilia,hair, earwax Lining of trachea: ciliated cells & mucus secreting cells

10. 1st line: Non-specific External defense • Elimination • coughing, sneezing, urination, diarrhea • Unfavorable pH • stomach acid, sweat, saliva, urine • Lysozyme enzyme • digests bacterial cell walls • tears, sweat

11. 2nd line: Non-specific patrolling cells bacteria • Patrolling cells • attack pathogens, but don’t “remember” for next time • leukocytes • phagocytic white blood cells • macrophages, neutrophils, natural killer cells macrophage Phagocyte & yeast

12. 2nd line: Non-specific patrolling cells • Proteins • complement system • proteins that destroy cells • inflammatory response • increase in body temp. • increase capillary permeability • attract macrophages

13. Leukocytes: Phagocytic WBCs • Attracted by chemical signals released by damaged cells • ingest pathogens • digest in lysosomes • Neutrophils • most abundant WBC (~70%) • ~ 3 day lifespan • Macrophages • “big eater”, long-lived • Natural Killer Cells • destroy virus-infected cells & cancer cells

14. Destroying cells gone bad! • Natural Killer Cells perforate cells • release perforin protein • insert into membrane of target cell • forms pore allowing fluid to flow in & out of cell • cell ruptures (lysis) • apoptosis vesicle natural killer cell perforin cell membrane perforinpuncturescell membrane cell membrane virus-infected cell

15. Anti-microbial proteins • Complement system • ~20 proteins circulating in blood plasma • attack bacterial & fungal cells • form a membrane attack complex • perforate target cell • apoptosis • cell lysis extracellular fluid complement proteinsform cellular lesion plasma membrane of invading microbe complement proteins bacterial cell

16. Inflammatory response • Damage to tissue triggers local non-specific inflammatory response • release chemical signals • histamines & prostaglandins • capillaries dilate, becomemore permeable (leaky) • delivers macrophages, RBCs, platelets, clotting factors • fight pathogens • clot formation • increases temperature • decrease bacterial growth • stimulates phagocytosis • speeds up repair of tissues

17. Fever • When a local response is not enough • system-wide response to infection • activated macrophages release interleukin-1 • triggers hypothalamus in brain to readjust body thermostat to raise body temperature • higher temperature helps defense • inhibits bacterial growth • stimulates phagocytosis • speeds up repair of tissues • causes liver & spleen to store iron, reducing blood iron levels • bacteria need large amounts of iron to grow

18. 3rd line: Acquired (active) Immunity • Specific defense with memory • lymphocytes • B cells • T cells • antibodies • immunoglobulins • Responds to… • antigens • cellular name tags • specific pathogens • specific toxins • abnormal body cells (cancer) B cell

19. Specific Defenses: The 3rd Line of Defense • While microorganisms are under assault by phagocytic cells, the inflammatory response, and antimicrobial proteins, they inevitably encounter lymphocytes, the key cells of the immune system. • Lymphocytes generate efficient and selective immune responses that work throughout the body to eliminate particular invaders: • This includes pathogens, transplanted cells, and even cancer cells, which they detect as foreign.

20. Humoral and Cell-Mediated Immunity • The immune system can mount two types of responses to antigens: a humoral response and a cell-mediated response. • Humoral immunityinvolves B cell activation and results from the production of antibodies that circulate in the blood plasma and lymph. • Circulating antibodies defend mainly against free bacteria, toxins, and viruses in the body fluids. • In cell-mediated immunity, T lymphocytes attack viruses and bacteria within infected cells and defend against fungi, protozoa, and parasitic worms. • They also attack “nonself” cancer and transplant cells. • The humoral and cell-mediated immune responses are linked by cell-signaling interactions, especially via helper T cells.

21. B’s and T’s • The vertebrate body is populated by two main types of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells). • They are said to display specificity. • A foreign molecule that elicits a specific response by lymphocytes is called an antigen: • Including molecules belonging to viruses, bacteria, fungi, protozoa, parasitic worms, and nonpathogens like pollen and transplanted tissue or organs.

22. bone marrow Lymphocytes • B cells • mature in bone marrow • humoral response system • “humors” = body fluids • attack pathogens still circulating in blood & lymph • produce antibodies • T cells • mature in thymus • cellular response system • attack invaded cells • “Maturation” • learn to distinguish “self” from “non-self” antigens • if react to “self” antigens, cells are destroyed during maturation

23. How are invaders recognized? • Antigens • cellular name tag proteins • “self” antigens • no response from WBCs • “foreign” antigens • response from WBCs • pathogens: viruses, bacteria, protozoa, parasitic worms, fungi, toxins • non-pathogens: cancer cells, transplanted tissue, pollen “self” “foreign”

24. B cells • Attack, learn & remember pathogens circulating in blood & lymph • Produce specific antibodiesagainst specific antigen • Types of B cells • plasma cells • immediate production of antibodies • rapid response, short term release • memory cells • continued circulation in body • long term immunity

25. Antibodies • One way that an antigen elicits an immune response is by activating B cells to secrete proteins called antibodies. • This structure of a lymphocyte’s receptors is determined by genetic events that occur during its early development. • As unspecialized cells differentiate into a B or T lymphocyte, segments of antibody genes are linked together by a type of genetic recombination in the DNA, generating a single functional gene for each polypeptide of an antibody or receptor protein. • This process occurs before any contact with foreign antigens and creates an enormous variety of B and T cells in the body, each bearing antigen receptors of particular specificity. • This allows the immune system to respond to millions of antigens.

26. Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Antibodies Y Y • Proteins that bind to a specific antigen • multi-chain proteins • binding region matches molecular shape of antigens • each antibody is unique & specific • millions of antibodies respond to millions of foreign antigens • tagging “handcuffs” • “this is foreign…gotcha!” Y Y Y antigen-binding site on antibody Y antigen Y Y Y variable binding region Y Y each B cell has ~50,000 antibodies

27. Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y antigen-binding site variable region s s s s s s s s light chain s s s s s s s s s s s s s s s s heavy chains s s s s s s s s s s s s Structure of antibodies Y Y Y Y Y Y Y light chain Y Y B cell membrane

28. Y Y Y Y Y Y invading pathogens tagged with antibodies macrophageeating tagged invaders What do antibodies do to invaders? neutralize capture precipitate apoptosis

29. First Exposure to antigen: • The selective proliferation and differentiation of lymphocytes that occur the first time the body is exposed to an antigen is the primary immune response. • About 10 to 17 days are required from the initial exposure for the maximum effector cell response. • During this period, selected B cells and T cells generate antibody-producing effector B cells, called plasma cells. • While this response is developing, a stricken individual may become ill, but symptoms of the illness diminish and disappear as antibodies and plasma cells clear the antigen from the body.

30. Secondary Response • A second exposure to the same antigen at some later time elicits the secondary immune response. • This response is faster (only 2 to 7 days), of greater magnitude, and more prolonged. • In addition, the antibodies produced in the secondary response tend to have greater affinity for the antigen than those secreted in the primary response.

31. Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y invader(foreign antigen) B cells + antibodies memory cells “reserves” recognition Y capturedinvaders Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y macrophage Y Y Y Y Y Y Y Y Y Y clones 1000s of clone cells plasma cells release antibodies 10 to 17 days for full response B cell immune response tested by B cells (in blood & lymph)

32. Active Immunity • Immunity conferred by recovering from an infectious disease such as chicken pox is called active immunity because it depends on the response of the infected person’s own immune system. • Active immunity can be acquired naturally or artificially, by immunization, also known as vaccination. • Vaccines include inactivated toxins, killed microbes, parts of microbes, and viable but weakened microbes. • These no longer cause disease, but they can act as antigens, stimulating an immune response, and more important, immunological memory.

33. Vaccinations • Immune system exposed to harmless version of pathogen • stimulates B cell system to produce antibodies to pathogen • “active immunity” • rapid response on future exposure • creates immunity without getting disease! • Most successful against viruses

34. Polio epidemics 1994: Americas polio free

35. Passive immunity • Obtaining antibodies from another individual • maternal immunity • antibodies pass from mother to baby across placenta or in mother’s milk • critical role of breastfeeding in infant health • mother is creating antibodies against pathogens baby is being exposed to • Injection • injection of antibodies • short-term immunity

36. T What if the attacker gets past the B cells in the blood & actually infects (hides in) some of your cells? You need trained assassins to recognize & kill off these infected cells! Attackof the Killer T cells! But how do T cellsknow someone ishiding in there?

37. MHC protein T or Bcell MHC proteins displaying self-antigens How is any cell tagged with antigens? • Major histocompatibility (MHC) proteins • proteins which constantly carry bits of cellular material from the cytosol to the cell surface • “snapshot” of what is going on inside cell • give the surface of cells a unique label or “fingerprint” Who goes there? self or foreign?

38. MHC proteins displaying foreign antigens TH cell WANTED How do T cells know a cell is infected? • Infected cells digest some pathogens • MHC proteins carry pieces to cell surface • foreign antigens now on cell membrane • called Antigen Presenting Cell (APC) • macrophages can also serve as APC • tested by Helper T cells infectedcell T cell with antigen receptors

39. T cells • Attack, learn & remember pathogens hiding in infected cells • recognize antigen fragments • also defend against “non-self” body cells • cancer & transplant cells • Types of T cells • helper T cells • alerts rest of immune system • killer (cytotoxic) T cells • attack infected body cells • memory T cells • long term immunity T cell attacking cancer cell

40. Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y killerT cell APC:activated macrophage activatekiller T cells stimulateB cells &antibodies APC:infected cell helperT cell helperT cell helperT cell helperT cell helperT cell Y Y Y Y Y Y Y Y T cell response recognition interleukin 2 interleukin 1 or interleukin 2 clones recognition

41. Attack of the Killer T cells • Destroys infected body cells • binds to target cell • secretes perforin protein • punctures cell membrane of infected cell • apoptosis vesicle Killer T cell Killer T cellbinds toinfected cell cell membrane perforinpuncturescell membrane cell membrane infected cell destroyed target cell

42. Y Y Y Y Y Y Y Y Y Y Y Y Y Y antibodies antibodies Y Y Y Y Y Y Y Y Immune response pathogen invasionantigen exposure skin skin free antigens in blood antigens on infected cells macrophages (APC) humoral response cellular response alert alert helperT cells B cells T cells plasmaB cells memoryB cells memoryT cells cytotoxicT cells

43. HIV & AIDS • Human Immunodeficiency Virus • virus infects helper T cells • helper T cells don’t activate rest of immune system: killer T cells & B cells • also destroys helper T cells • AIDS: Acquired ImmunoDeficiency Syndrome • infections by opportunistic diseases • death usually from • “opportunistic” infections • pneumonia, cancers HIV infected T cell

44. AIDS The HIV virus fools helper T-cells into thinking its proteins are “self,” and so is able to infect the cells that trigger specific immunity. The virus forces T-cells to make more viruses, killing the T-cells when the new viruses burst out.

45. NATURAL COURSE OF HIV/AIDS

46. Short, flu-like illness - occurs one to six weeks after infection Mild symptoms Infected person can infect other people Stage 1 - Primary

47. Lasts for an average of ten years This stage is free from symptoms There may be swollen glands The level of HIV in the blood drops to low levels HIV antibodies are detectable in the blood Stage 2 - Asymptomatic

48. The immune system deteriorates Opportunistic infections and cancers start to appear. Stage 3 - Symptomatic

49. The immune system weakens too much as CD4 cells decrease in number. Stage 4 - HIV  AIDS

50. CD4<500 Bacterial infections Tuberculosis (TB) Herpes Simplex Herpes Zoster Vaginal candidiasis Hairy leukoplakia Kaposi’s sarcoma Opportunistic Infections associated with AIDS