Normal Immune System Function

1. Normal Immune System Function Karim Rafaat

2. Organs of the Immune System

3. Central lymphoid organs Central (primary) lymphoid organs are the sites for generation and early maturation of lymphocytes T cells mature in the thymus (T for thymus) B cells mature in the bone marrow B for bursa of Fabricius (a lymphoid organ in birds) [After Hieronymus Fabricius (1537-1619), Italian anatomist]

4. Lymphoid organs contain lymphocytes and non-lymphoid cells such as macrophages and dendritic cells (and epithelial cells) Lymphoid organs are important for the generation and maturation of lymphocytes, the initiation of immune responses and the perpetuation of immune responses

5. Peripheral lymphoid organs • 1. trap antigens • are the sites for initiation of most immune response • provide signals for recirculation of lymphocytes • Antigen delivery to regions of increased traffic *other stuff (not peripheral lymphoid organs)

6. Flow of lymph

7. Gut associated lymphoid tissue (GALT)(tonsils, adenoids, Peyer’s patches, appendix)

8. Immature B and T cells mature in the central lymphoid organs • Then, they circulate in the blood and through the peripheral lymphoid organs. As long as they have not encountered the specific antigen that binds their antigen receptors (BCR or TCR), the circulating lymphocytes are mature naïve lymphocytes When they encounter antigen (bind antigen in their antigen receptor), they 1. Stick in the lymph nodes (or other peripheral lymphoid organ)(they stop circulating, i.e., altered trafficking) 2. Proliferate (divide) 3. Differentiate

9. Innate and Specific immunity; Cells of the Immune System

10. Myeloid cells lymphoid cells Granulocytic Monocytic T-cells B-cells Dendritic cells? Neutrophils Macrophages Helper Cytotoxic Basophils Langerhans & Plasma Eosinophils Kupffer cells Suppressor cells Dendritic cells? Cells of the Immune System

11. Nonspecific Specific Humoral Cellular Humoral Cellular complement, interferon, TNF etc. macrophages, neutrophils antibodies T cells; other effectors cells Components of the Immune System

12. No Immunologic memory Innate Immunity Adaptive Immunity Characteristicsof Innate and Adaptive Immunity Antigen independent Antigen dependent No time lag A lag period Not antigen specific Antigen specific • Development of memory

13. Innate Immunity Adaptive Immunity Componentsof Innate and Adaptive Immunity physical barriers skin, gut Villi, lung cilia,etc none soluble factors many protein and non-protein secretions Immunoglobulins (antibody) cells phagocytes, NK cell eosinophils, K cells T and B lymphocytes

14. Site Component Functions Skin squamous cells sweat desquamation flushing, fatty acids GI tract columnar cells Peristalsis, low pH bile salts, fatty acids Lung mucociliary elevator surfactants tracheal cilia Effector mechanisms in Innate Immunity

15. Site Component Functions Effector mechanisms in Innate Immunity Nasopharynx and eye mucus, saliva, tears flushing, lysozyme Phagocytes phagocytosis and intracellular killing Blood and Lymphiod organs K, NK & LAK cells direct and antibody dependent cytolysis

16. Site Component Functions Effector mechanisms in Innate Immunity Serum and other serous fluids lactoferrin, transferrin iron deprivation interferons, TNF- antiviral proteins phagocyte activation lysozyme peptidoglycan hydrolysis opsonization, enhanced phagocytosis, inflammation Fibronectin & complement

17. George Bernard Shaw wrote: “There is at bottom only one genuine treatment for all diseases,…to stimulate the phagocytes. Drugs are a delusion. …(when) the phagocytes are stimulated; they devour the disease…” Influenced by the work of Eli Metchnikoff, Phagocytes are the Most Important Cells

18. Phagocytes:Macrophages • phagocytosis, intracellular and extra-cellular killing, tissue repair, antigen presentation for specific immune response • characteristic nucleus and CD14 membrane marker.

19. Phagocyte Response to Infection • The SOS Signals • N-formyl methionine • Clotting system peptides • Complement products • Phagocyte response • Vascular adherence • Diapedesis • Chemotaxis • Activation • Phagocytosis and killing

20. ScavengerR IgG FcR CR Toll-like R Initiation of Phagocytosis Attachment via

21. Glucose +NADP+ G-6-P-dehydrogenase Pentose-P + NADPH NADPH + O2 Cytochrome b558 NADP++ O2- 2O2- + 2H+ Superoxide dismutase H2O2 + 1O2 2O2- + H2O2 .OH + OH- + 1O2 Respiratory Burst Oxygen Dependent Myeloperoxidase Independent Reactions

22. Mediators of Oxygen Independent Killing in the Phago-lysosome Effector Molecule Function Cationic proteins (cathepsin) Damage to microbial membranes Lysozyme Hydrolyses mucopeptides in the cell wall Lactoferrin Deprives pathogens of iron Hydrolytic enzymes (proteases) Digests killed organisms

23. NK and LAK cells ADCC (K) cell Activated macrophages Eosinophils They all kill foreign and altered self targets Non-specific Killer Cells

24. also known as large granular lymphocytes (LGL) kill infected and malignant cells are identified by the presence of CD56 & CD16 and absence of CD3 activated by IL2 and IFN-γto become LAK cells Natural Killer (NK) cells

25. kills malignant cells kills transformed and malignant cells Lymphokine Activated Killer (LAK) cell IFN IFN IL2 IL2

26. Innate Immunity • The complement system

27. Complement:history Discovered in 1894 by Bordet It represents lytic activity of fresh serum

28. Complement functions • Host benefit: • opsonization to enhance phagocytosis • phagocyte attraction and activation • lysis of bacteria and infected cells • regulation of antibody responses • clearance of immune complexes • clearance of apoptic cells • Host detriment: • Inflammation, anaphylaxis

29. Proteins of the complementsystem (nomenclature) • C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9 • factors B, D, H and I, properdin (P) • mannose binding lectin (MBL), MBL associated serine proteases (MASP-1 MASP-2) • C1 inhibitor (C1-INH, serpin), C4-binding protein (C4-BP), decay accelerating factor (DAF), • C1 receptor (CR1), protein-S (vitronectin)

30. antibody independent antibody dependent Activation of C3 and generation of C5 convertase activation of C5 LYTIC ATTACK PATHWAY Pathways of complement activation LECTIN PATHWAY ALTERNATIVE PATHWAY CLASSICAL PATHWAY

31. C1r C1s C1q Ca++ Components of the Classical Pathway C4 C3 C2 C1 complex

32. C4a C1r C1s C1q b Ca++ Classical Pathway Generation of C3-convertase C4

33. C2b C1r C1s a C1q Ca++ C2 a Classical Pathway Generation of C3-convertase C2 C4a Mg++ C4b2a is C3 convertase C4b

34. C1r C3a C1s C1q Ca++ C2 a b Classical Pathway Generation of C5-convertase C2b C4a C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway Mg++ C3 C4b

35. MBL Components of mannose-binding lectin pathway C4 MASP2 C2 MASP1

36. C2a C2a C2b C4a C4b C4b MBL Mannose-binding lectin pathway C4b2a is C3 convertase; it will lead to the generation of C5 convertase C4 C2 MASP2 MASP1

37. Components of thealternative pathway D C3 B P

38. b i b C3a Spontaneous C3 activation Generation of C3 convertase D H2O B C3 C3 C3iBb complex has a very short half life

39. C3b b b C3a C3-activationthe amplification loop If spontaneously-generated C3b is not degraded D B C3

40. C3b b b Bb C3b C3a C3-activationthe amplification loop D B C3 C3a

41. Bb C3b C3b b b Bb C3b C3a C3-activationthe amplification loop D B C3 C3a C3a

42. Bb Bb C3b C3b C3b Bb C3b C3-activationthe amplification loop C3a C3a C3a

43. Bb Bb C3b C3b Bb C3b C3-activationthe amplification loop C3a C3a C3a

44. C3b DAF CR1 Autologous cell membrane Control of spontaneousC3 activation via DAF DAF prevents the binding of factor B to C3b B

45. DAF B b B b C3b C3b CR1 CR1 iC3b iC3b Control of spontaneousC3 activation via CR1 H I I DAF Autologous cell membrane

46. C3a C3b finds an activator (protector) membrane C3b b b C3b stabilization andC5 activation This is stable C5 convertase of the alternative pathway D P B C3

47. C3b regulation on self and activator surfaces C3b

48. C3b C2a C4b C5-convertase of the two pathways C5-convertase of the Classical and lectin Pathways C5-convertase of the Alternative Pathway Bb C3b C3b

49. Lytic pathway Generation of C5 convertase leads to the activation of the Lytic pathway

50. C8 C7 Components of the lytic pathway C6 C5 C 9