Libro consigliato: Immunobiology, Janeway 6th edizione

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

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

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 cell B cell • Involved with humoral immunity • Secrete antibodies • Generallyeliminate extracellular pathogens • Involved with cell mediated immunity • Two types: helper T cells (CD4)cytotoxic T cells (CD8) • Generally eliminate intracellular 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 TCR CD4 or CD8 co-receptor 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. MHC II/antigen Activation and secretion of cytokines TCR Processing of microbial fragments onto MHC class II by macrophage CD4 Stabilises the MHC antigen complex Interaction between CD4+ T cells and antigen/MHC II complexes

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

33. T Cell Development (I)- Thymus

34. T Cell Development (II)- Periphery

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

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

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. 5th ed. Abbas et al.

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

42. Molecules Involved in the Interactions of T Cells and APCs during T Cell Activation T cellAPC TCR-CD3 complex MHC-peptides CD4/CD8 (coreceptor) MHC I/II Adhesion molecules Ligands 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-4 B7.1 B7.2 ICOS LICOS 4-1BB ( on CD8) 4-1BBL PD-1 PD-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. 4-1BBL 4-1BB IL-2 CD8 CD8 CD8 IL-2 IL-2 2. Th cells produce cyto- kines to stimulate CTL differentiation 1. CTL differentiation without Th cells 3. Th cells enhance APCs to stimulate CTL differentiation Role of Costimulation and Th Cells in the Differentiation of CD8 T Cells Modified from Cell. Mol. Immunol. 5th ed. Abbas et al.

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 2o Lymphoid organs • Expression of costimulatory molecules B7 • Increased expression of DC-SIGN • Secret cytokines IL-12 and TNFa • Secret DC-CK to attract naïve T cells

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