1. Libro consigliato: Immunobiology, Janeway 6th edizione Date appelli: 30 Maggio ore 9.30 14 giugno 4 luglio 13 settembre 16 novembre 14 dicembre Esame orale

2. Immune System Function Defends the body against the outside world –Microorganisms Defends the body against the inside world –Abnormal cells Functions by modulation –Highly complex up and down regulatory mechanisms

4. Types of Immunity Two major types Innate immunity or natural immunity Acquired immunity or specific immunity

5. Self Recognition Concept Immune system must recognize what is part of the body and what is not part of the body –Different classes of histocompatibility complex proteins Important in immune stimulation

6. Innate immunity first front line of defense not specific no immunologic memory (does not get stronger with more exposures)

7. Innate or Natural Immunity Mechanisms include –Mucous barriers –Natural killer cells –Polymorphonuclear and mononuclear phagocytic cells

8. Macrophage Neutrophil Phagocytosis of Bacteria by Macrophages and Neutrophils- First Line of Defense Listeria

9. Acquired Immunity It is specific and generally increases with exposure to foreign substances Two kinds of acquired immune response –Humoral immunity Immunoglobulins –Protein called antibody and substances that react with antibodies are called antigens –Cell-mediated immunity Specialized cells that destroy foreign target cells

10. Immunogen Immunogen is a substance that triggers an immune response. These include: –Proteins –Polysaccharides –Nucleic acids

11. Overview of Immune Mechanisms

12. Recognition of Self Genetic variations in specific proteins –Class I and Class II major histocompatibility complex (MHC) –Immune system develops with a concept of self

13. Cell Types Polymorphonuclear phagocytes Mononuclear phagocytes Lymphocytes Antigen presenting cells

14. Lymphocytes Cells with large nucleus and small amount of cytoplasm –Circulate in the blood and lymph systems Develop from pluripotent stem cells as the lymphoid series

15. Blood Cell

16. Two Major Types of Lymphocytes T-cells –develop in the thymus B-Cells

17. T-Lymphocytes T-lymphocytes –Initiating an immune response –Modulating an immune response T-lymphocytes have the following cluster differentiation (CD) or surface proteins –CD3 + –CD4 + T-helper cells –CD8 + T-suppressor cells T-cytotoxic cells

18. B-Lymphocytes Develop and mature in the bone marrow Produce class specific Immunoglobulins

19. Cells of the specific immune system T cellB cell Involved with cell mediated immunity Two types: helper T cells (CD4) cytotoxic T cells (CD8) Generally eliminate intracellular pathogens Involved with humoral immunity Secrete antibodies Generally eliminate extracellular pathogens

20. Immunity mediated by T cells T cells recognise and destroy cells infected with foreign antigen –e.g. viral infection, intracellular bacteria (mycobacterium tuberculosis), intracellular parasites) T cells can either: – kill infected cells themselves (CD8+ T cells also called cytotoxic T cells) or –recruit help to eliminate the infected cell by means of soluble mediators called cytokines (CD4+ T cells also called helper T cells)

21. How do T cells recognise specific antigenic epitopes?

22. CD4 and CD8 are co-receptors that serve to aid TCR signalling CD4 or CD8 co-receptor TCR CD3 signalling complex

23. How does the TCR get to see specific epitopes derived from and intracellular foreign antigen? i.e. if the infecting agent such as a virus is within its target cell how does the T cell get access?

24. Antigen Presentation

25. Professional Antigen Presenting Cells (APCs)

26. Major Histocompatibility Complex (MHC) Two types –MHC class I Expressed on the surface of all nucleated cells in your body –MHC class II Expressed on the surface of professional antigen- presenting cells e.g. macrophages and dendritic cells

27. CD4+ T cells interact with MHC class II on antigen-presenting cells CD8+ T cells interact with MHC class I which is expressed on all nucleated cells within your body

28. Processing of intracellular foreign antigen Presentation of antigen on MHC class II molecules, example: –Macrophages/Dendritic cells phagocytose bacteria which are digested into small antigen fragments –These fragments are processed in the cytoplasm and bound to MHC class II molecules –Antigen/MHC II complexes are subsequently expressed on the surface of the antigen-presenting cell

29. Presentation of antigen on MHC class I molecules, example: –Influenza virus infects a cell and becomes incorporated into the host DNA where it can replicate itself –Each cell in your body constantly screens itself by processing ‘self’ antigens and binding them to MHC class I molecules which are subsequently expressed on the cell surface –If viral protein is present it to will be processed and expressed on the cell surface in the context of MHC class I

30. Interaction between CD4+ T cells and antigen/MHC II complexes Activation and secretion of cytokines CD4 Stabilises the MHC antigen complex TCR MHC II/antigen Processing of microbial fragments onto MHC class II by macrophage

31. Interaction between CD8+ T cells and antigen/MHC I complexes CD8+ T cell kills the infected cell CD8 Stabilises the MHC antigen complex TCR MHC I/antigen Virus infects a cell

33. T Cell Development (I)- Thymus

34. T Cell Development (II)- Periphery

35. Features of the Adaptive Immune Responses DescriptionMechanismFeature Non-reactivity to self- antigens or non-pathogenic antigens Central: negative selection (T, B) Peripheral: angergy (T, B) (T) AICD, suppression Tolerance Acceleration of elimination of specific pathogens Proliferation of antigen-specific T or B cells ligation with APCs Clonal Expansion Recall of immune response is rapid and larger Differentiation of naïve to effector cells Memory Lymphocyte repertoire is extremely large DNA rearrangement in TCR and BCR genes Diversity Immune responses are specific for distinct antigens DNA rearrangement in TCR and BCR genes Specificity

36. Effector Ag elimination Memory maintenance Recognition Ag presentation Activation Differentiation Naïve T/B Activated T/B Humoral & Cellular Immunity Memory T/B Different Phases of Adaptive Immune Response Modified from Cell. Mol. Immunol. 5 th ed. Abbas et al. Days after antigen exposure 0 7 14 >30 Number of antigen- specific T/B cells Antigen challenge Clonal Expansion Apoptosis Homeostasis

37. Time Course for Induction of Antiviral Response

38. Where Pathogens Enter the Body  Skin : DC, macrophages  Gut : GALT (Gut-Associated Lymphoid Tissue)  Lung : BALT (Bronchia-Associated Lymphoid Tissue )  Blood : Spleen/lymph nodes  Genital duct: MALT (Mucosal-Associated Lymphoid Tissue)

39. Where T/B Cells Meet Foreign Antigens-Spleen and Lymph Nodes

40. Induction and Effector Phases of Cell-mediated Immunity Cell. Mol. Immunol. 5 th ed. Abbas et al.

41. Requirements for a Professional APC 1.Able to ingest and present antigens 2.Express both MHC I and MHC II 3.Express Co-stimulatory molecules

42. Molecules Involved in the Interactions of T Cells and APCs during T Cell Activation T cellAPC TCR-CD3 complexMHC-peptides CD4/CD8 (coreceptor)MHC I/II Adhesion moleculesLigands Costimulatory molecule Ligands

43. Adhesion Molecules involved in the Interactions of T Cells with APCs

44. Costimulatory Molecules of T Cells and APCs T cellAPC CD28, CTLA-4B7.1 B7.2 ICOSLICOS 4-1BB ( on CD8)4-1BBL PD-1PD-L Blue: Constitutive expression Red: Inducible expression

45. Activation of Naïve T Cells Requires Two Independent Signals- TCR + Costimulatory Signals

46. Mechanism of Peripheral Tolerance- TCR Ligation Without Costimulatory Molecules

47. Role of Costimulation and Th Cells in the Differentiation of CD8 T Cells CD8 IL-2 1. CTL differentiation without Th cells CD8 4-1BBL 4-1BB IL-2 3. Th cells enhance APCs to stimulate CTL differentiation Modified from Cell. Mol. Immunol. 5 th ed. Abbas et al. CD8 IL-2 2. Th cells produce cyto- kines to stimulate CTL differentiation

48. Distribution of Different APCs in Lymph Node

49. Features of Mature DC  Increased expression of MHC I and II  Expression of CCR7 for homing to 2 o Lymphoid organs  Expression of costimulatory molecules B7  Increased expression of DC-SIGN  Secret cytokines IL-12 and TNF   Secret DC-CK to attract naïve T cells

50. Dendritic Cells are Immature in Peripheral Tissues and Become Mature after Taking up Antigens

51. DC Take up Antigen in the Skin and Migrate to Lymphoid Organs Where They Present It to T Cells

52. Involvement of TLR in Linking Innate Immunity to Adaptive Immunity Nature Immunology 2001 2:675

53. Microbial Substances Induce Co-stimulatory Activity in Macrophages

54. B Cells Use Ig Receptor to Capture Specific Antigens

55. Summary of Different Properties of APCs

56. Naïve T Cells can Differentiate into Three Effector Cells FasL

57. Fas-FasL-mediated Apoptosis Pathway (Extrinsic Pathway) Back

58. Release of Effector Molecules is Localized on Contact Sites of T and Target Cells

59. Cytotoxic Effector Proteins Released by T Cells

60. Perforin of Cytotoxic T Cells Can Insert and Form Pores in the Membrane of Target Cells

61. Differentiation of Immature CD4 Helper T Cells In terms of cytokine production

62. Genes Dev. 2000 14:1693 Factors Involved in the Differentiation of Helper T Cells

63. Cytokine Receptor Families by Their Structures

64. Functions of Th1 Cytokines

65. Effector Functions of Th1 Cells Cell. Mol. Immunol. 5 th ed. Abbas et al.

66. Th1 Cells Activate Macrophages to Become Highly Microbicidal

67. Functions of Th2 Cytokines

68. Effector Functions of Th2 Cells Cell. Mol. Immunol. 5 th ed. Abbas et al.