Advanced Cell Biology // Molecular Biology of Cells Fall 2002 Immunity (Dec 5th) Liza Raggatt Ph.D

1. Advanced Cell Biology // Molecular Biology of Cells Fall 2002 Immunity (Dec 5th) Liza Raggatt Ph.D

2. What is Immunity? Ability to defend ourselves against potentially harmful things (PATHOGENS) that invade us. Examples of pathogens / invaders include: Bacteria, Fungi, Viruses and Parasites What advantage do they have over humans? Short life span / short reproductive time

3. The Immune System What are Features of the Immune System ? Fast acting Mobile Specific Memory

4. Over view of the Immune System Innate Adaptive Protective Barriers phagocytosis Antibody response Cell-mediated response Pathogen recognition

5. Components of the Innate Immune System 1. Protective Barriers & chemicals Skin Tight junctions between cells Mucus Defensins 2. Recognition of pathogens 3. Phagocytosis

6. Components of the Innate Immune System continued……. 2. Recognition of Pathogens “Self vs non-self recognition” Recognize molecules common to pathogens but not found on host/self cells. Pathogen-associated immuno stimulants (PAIS)

7. Examples of Pathogen associated immuno stimulant (PAIS) A. Prokaryote proteins use formylated methionine potent chemoattractant for neutrophils B. Outer surface of pathogens contain many non- self proteins that act as immuno stimulants C. Bacterial DNA can also be an immuno stimulant How does host detect PAIS ?

8. Pattern Recognition Receptors Soluble receptors in blood Aid in phagocytosis and direct killing Initiate Phagocytosis Membrane-bound receptors Simulate a program of gene expression in the host cell for stimulating the innate immune responses

9. Example of a membrane bound pattern recognition receptor system (Troll Like Receptors) Inflammatory response Adaptive Immune response

10. Troll like receptors have related molecules which are involved in the innate immune system of all multicellular organisms………ie plants. Evolutionary conservation indicates the importance of these innate immune responses to the host defense system.

11. Components of the Innate Immune System continued……. This component of the innate immune system is not present in plants only found in vertebrates and invertebrates 3. Phagocytic cells Macrophages Neutrophils

12. Many pathogens have developed strategies to avoid the innate immune system or use it to their advantage Example The Salmonella bacteria induces an inflammatory response at the site of infection (gut) and thus macrophages are recruited. The bacteria then invades the macrophages and hitch a ride to other body tissues To destroy such pathogens the adaptive immune system is required

13. Immune System Features of the Immune System Innate Adaptive  Fast acting  Mobile Specific Memory

14. Adaptive Immune System Functions are performed by white blood cells (Lymphocytes) 2 classes of responses Antibody Responses (B-cells responses) Cell-mediated Responses (T-cell responses)

15. Types of adaptive immune responses Called a B-cell response as the cells involved are derived from bone marrow Called a T-cell response as the cells involved are derived from the thymus

16. Human Lymphoid Organs Approximately 2x1012 lymphocytes in human body. Comparable cell mass to that of the brain or liver

17. The classic experiment showing that lymphocytes are required for adaptive immune responses to foreign antigens

18. Acquired Immune Tolerance The adaptive immune system can respond to approximately 106 different foreign antigens in a very specific way but doesn’t (usually) react with self antigens. Why?

19. Adaptive Immune System Functions are performed by white blood cells (Lymphocytes) 2 classes of responses Antibody Responses (B-cells responses) Cell-mediated Responses (T-cell responses)

20. Antibody Responses (B-cells responses) With out this response vertebrates would eventually die

21. Antibodies

22. Antibodies consists of 4 polypeptide chains 2 identical light chains 2 identical heavy chains Antigen binding domain usually required both light and heavy chains 5 classes of Ab in mammals each has a different class of heavy chain IgM, IgD, IgG, IgA, IgE

23. The diversity of antigen binding domains is dependent on the variable regions of the light and heavy chains

24. Light and heavy chains are composed of repeating segments that fold independently to form functional units called immunoglobulin (Ig) domains

25. Organization of the DNA sequences that encode the constant regions of an Ab heavy chain

26. Generation of Antibody Diversity At rest or in the absence of pathogen assault, the immune system can likely make 1012 different antibodies How can an animal make more Antibodies than there are genes in the genome? Answer lies in the variable regions of the antigen binding site on Antibodies. Eg if have 1000 different light chains and 1000 different heavy chain genes 1000 x 1000 = 1,000,000 different antigen binding sites

27. Antibody Diversification Rearrangement of DNA during B cell development

28. Site specific recombination is involved in generating Ab light chain diversity

29. Adaptive Immune System Functions are performed by white blood cells (Lymphocytes) 2 classes of responses Antibody Responses (B-cells responses) Cell-mediated Responses (T-cell responses)

30. Similarities and Differences between T-cell and B-cell responses SimilaritiesHighly Antigen specific DifferencesT-cells require antigens to be displayed on the surface of cells Effector or activated T-cells can only act at short range as they require contact with the infected cell.

31. T-cells T-cells are activated by antigen-presenting cells (dendritic cells, macrophaqes and B-cells) Dendritic cells found through out the body where they encounter foreign microbes endocytose them or their products and transport them to local lymph glands where they activate cytotoxic or helper T-cells

32. Importance of Co-stimulatory Proteins in T cell activation MHC signal Co-stimulatory signal

33. The importance of MHC proteins to T cell activation

34. Cytotoxic T cells Once activated cytotoxic T cells act on target cells infected with the same pathogen and kill them by apoptosis This stops intracellular pathogens reproducing and further infecting host cells

36. Helper T cells Are essential for the defense of both intracellular and extracellular pathogens.

37. Immune System Features of the Immune System Innate Adaptive  Fast acting   Mobile  Specific Memory

38. Immunological Memory

39. Immunological memory is due to clonal expansion of memory cells

40. Immune System Features of the Immune System Innate Adaptive  Fast acting   Mobile  Specific  Memory

41. The Innate and Adaptive Immune Systems work together