Introduction to the immune system Innate immunity the “front line” of defense non specific Acquired immunity mechani

1. Introduction to the immune system Innate immunity the “front line” of defense non specific Acquired immunity mechanisms- antigen specificity immunological memory principles of vaccination

2. Important features of the immune system Must be able to distinguish foreign antigens from self antigens (what is an antigen?) Must have memory (responds slowly to first exposure, but more rapidly to subsequent exposures TO THE SAME ANTIGEN)

3. What does the immune system actually do? Phagocytes- kill and remove foreign or damaged cells Antibodies- “tag” invading cells or viruses for destruction Cytotoxic cells- killed altered cells Regulate the immune response

4. What/where is the immune system? Barriers Circulating blood cells Tissue-fixed cells Lymphatic system

5. p. 375, physical barriers to infection

6. p. 377, origin of lymphoid cells

7. Cells with immune function (p. 378) Granulocytes Neutrophils most common leukocyte (50-70%) most potent phagocyte Eosinophils (2-4%) probably phagocytic involved in allergic responses, parasitic infections Basophils (0-1%) mostly found in tissues (mast cells) release inflammatory molecules

8. Agranulocytes Monocytes (5-10%) more common in tissues In tissues: macrophages- phagocytes; help regulate immune response (“antigen presenting cells”) dendritic cells- present antigen to lymphocytes Lymphocytes (20-40%) B cells- make antibodies T cells- some are cytotoxic, some are regulatory

9. Where are the lymphoid cells? In the blood In the tissues In the lymphoid system Can be recruited to site of injury or infection

10. p. 396, the lymphoid system

11. The lymphoid system parallels the circulatory system Primary lymphoid organs- where lymphoid cells develop bone marrow (ALL blood cells) thymus- T cells mature there (become cytotoxic or helper T cells) and then circulate

12. Secondary lymphoid organs Purpose: to trap antigen and present it to lymphocytes Most lymphocytes actually reside in these tissues Lymph nodes- “filter” antigen from lymph Spleen- “filters” antigen from blood Lymphoid tissue in mucosa, gut and skin

13. Innate defenses If they are “non-specific” how are they actually activated-appropriately?? Barriers skin antimicrobial chemicals lysozyme (in tears and saliva stomach acid oxygen metabolites normal flora (“healthy competition”)

14. If barrier is breached- then what? Pattern recognition- something is perceived as abnormal Damaged tissue Structures associated with bacteria (peptidoglycan, LPS, etc.) toll-like receptors on phagocytes, endothelial cells- some recognizes viruses, too Cell is then activated in response

15. Toll-like receptors, p. 381

16. Complement proteins- circulate in blood Are normally inactive, but become active when binding to antigen, or antigen-antibody complexes What happens next? A series of reactions, resulting in: destruction of antigen inflammation enhanced phagocytosis of antigen

17. Complement system, p. 382

18. Phagocytosis; how do the cells know whence to engulf? detectors of microbes and/or damaged cells (pattern recognition) response to cytokines (produced by damaged cells and other immune cells complement receptors What happens in phagocytosis?

19. Process of phagocytosis, p. 384

20. Neutrophils are more potent killers, but die quickly Macrophages can present antigen; amplify immune response can prolong activity by regenerating lysosomes Both contribute to inflammatory response to infection and/or damage

21. What is the inflammatory process? What triggers the inflammatory process? What are the outcomes of inflammation? What is apoptosis, and how does it prevent inflammation?

22. Inflammatory process, p. 387

24. Inflammation is triggered by infection or injury Purpose: to contain damage (and response) repair damage “Cardinal signs of inflammation”: swelling, redness, heat, pain

25. Why swelling? Chemical signals are released by damaged tissue Neutrophils, monocytes recruited to the site and enter tissues fluid enters tissues, too Why redness? Chemicals promote vasodilation Blood vessel walls relax; more blood (and therefore more blood cells) can be brought to the region

26. Why heat? Chemicals raise temperature at the spot (pyrogens) Increased temperature kills microbes phagocytes are more active more cells are formed Effect can be systemic (fever) Why pain? Chemicals effect free nerve endings (pain receptors) Pain inhibits mobility; can help localize damage

27. Inflammation can cause a lot of “bystander damage” Ideally, damaged is confined to the site of injury Some sites are more sensitive to damage than others Damage can be systemic (septic shock, due to blood infections: loss of blood volume, tissue damage, excess clot formation

28. Not all cell death causes inflammation Apoptosis: programmed cell death Under genetic control (In immune response a large number of cells are formed to fight the infection- what happens to them after the infection is cleared?)

30. Summary Innate defense consists of barriers, phagocyte surveillance, and mechanisms to detect infection or damage Inflammation is the first line response to infection Lymphocytes may be activated during this process which will respond more rapidly and inten- sively to subsequent infections

31. Adaptive immunity Specificity Memory Distinguishes self from non-self Components of adaptive immunity: Humoral Cell-mediated Principles of vaccination Immune deficiency and its consequences

32. Adaptive immunity takes several days to develop (to first exposure to antigen) Cells proliferate Antibodies are produced Cytokines (signaling molecules) are produced Meanwhile, innate mechanisms act Adaptive mechanisms respond if infection has not been eliminated

33. What are the adaptive mechanisms? Humoral immunity against “extracellular” antigens (bacteria, free viruses, toxins, etc.) antibodies and other molecules Cell-mediated against “intracellular” antigens (virus-infected cells; tumor cells) Responses are orchestrated by helper T cells

34. p. 395 (be sure to come back to this slide)

35. How does humoral immunity work? B cells proliferate (in lymphatic tissues) and make antibodies Antibodies circulate and bind to antigen Neutralization; immobilization Immune complexes Facilitates phagocytosis Facilitates complement-mediated lysis B cells are activated clonally

36. p. 401 How antibodies work

37. Clonal selection theory In bone marrow In the system Applies to T cells, too (p. 403)

38. Antibodies have certain features in common but different classes (isotypes) have different properties. p. 398

39. Variable region is unique, because each binds to a different antigen Constant regions fall into five classes (table 16.1, p. 399)

41. What happens in the primary response that leads to antibody production? T cells respond to antigen; produce cytokines These cause B cells to proliferate and become plasma cells (antibody-producing cells) They become more able to react with antigen Class-switching (for appropriate response) from IgM to IgA, IgG, IgE (unclear about IgD) Memory cells- more of them; they respond faster in subsequent responses

42. p. 405

43. What about the memory cells? • There are more of them in the circulation • Antigen specificity does not change • They have already gone through development so can become active right away (note the secondary response on previous slide) • Both T and B memory cells have been identified • Memory cells can live for years

44. T cells also have an antigen-specific receptor Receptor is NOT released T cell must come in direct contact with antigen- presenting cell Major antigen-presenting cells: macrophage dendritic cell B cell How do these cells present antigen (and where)?

45. What are the different types of T cells CD4(helper) and CD8 (cytotoxic) Both have antigen-specific receptors CD4 and CD8 molecules help with antigen presentation CD4 cells “see” antigen + MHC Class II (helper T cells) CD8 cells “see” antigen + MHC Class I (cytotoxic T cells)

46. What is MHC? (major histocompatibility complex) Groups of cell- surface proteins, inherited When cells process antigen they return fragments (peptides) to the surface, bound to either MHC Class I or Class II MHC Class I is found on most cells MHC Class II on antigen-presenting cells (and levels can vary)

47. How do cells present antigen? Class II-bearing cells take up and “process” antigen, then antigen is expressed on cell surface bound to MHC Class II Remember, only certain cell types express MHC Class II- so not all cells can do this Lots of antigen-presenting cells in lymphoid tissues! Class I-bearing cells (remember, virtually all cells), if infected or transformed, will express antigen bound to MHC Class I

48. When T cells are activated they proliferate and produce cytokines Dozens of cytokines have been identified (and other cells can produce them, too) Cytokines bind to neighboring cells and activate them Recall that immune response is characterized by rapid proliferation and activation of cells! (And: you don’t want cells activated all the time)

49. What do T cells actually do? T helper cells- cytokine production (Some are engaged in “delayed-type hypersen- sitivity) Cytotoxic T cells- cause apoptosis in targets What about natural killer cells? similar targets as CTLs no antigen-specific receptor no memory response have antibody receptors probably immune surveillance

50. Natural killer cells vs cytotoxic T cells • Natural killer cells part of innate immune system • Early protection against transformed cells or virus-infected cells (Same targets as cytotoxic T cells) • Cytotoxic T cells become activated if natural killer cells cannot eliminate these cells