Immunology- Welcome!

1. Immunology- Welcome! Where we’re headed today Get a feel for what immunology covers A bit of history Some coverage of Chapter 1 & 2

2. The Broad Overview • The question is not: why to we get sick and die? But “how do we manage to survive at all??” • Observations: • We get sick, often recover • Some illnesses impart immunity • We sometimes get “reactions” to things • Some people get sick more than others

3. Immunology addresses these observations • How we respond to become immune • Recognize self from non-self • Why we have allergies- rxns to things • Why some people are prone to illness • Practical areas: • Vaccines, immunotherapy against cancer, allergy treatments, transplants, etc.

4. Characteristics of the Immune System (BRIEF!) • Some parts are non-specific- indeed some things that help do so incidentally. • Others are specific: • Recognize self from non-self • React to non-self, thus we tolerate self. • There’s a MEMORY of the reaction

5. A bit of history • Ancient observations • Chinese- 1100 AD- use mild forms of smallpox to infect infants- “variolation” • Lady Mary Montagu- from Turkey to England, 1718 • Edward Jenner- cowpox-smallpox- 1799 • Pasteur- vaccines against anthrax and rabies (why you should take vacation)

6. More history • Emil Von Behring, Shisaburo Kitasato: Immune serum- specific killing of microbes, passive immunization against diphtheria, tetanus developed • Jules Bordet: complement (Nobel Prize 1919) • Metchnikoff, 1882- phagocytosis

7. More History • Koch- Major early microbiologist- discovered causative agent for TB, TB rxn (Mantoux) test • Peter Medawar, MacFarlane Burnet, Niels Jerne, 1950’s- clonal selection theory • Susumu Tonegawa- generation of antibody diversity

8. On to the broad overview • Innate immunity- broad topic • Adaptive immunity

9. Die, you worm!

10. Specific and non-specific responses (5e)

14. Immunology Chapter 1&2- the Broad Overview Adaptive Immunity- Humoral and cellular Characteristics The players: Humoral Response: Fig 1-10 STUDY THIS FIGURE!!!!!!

15. Characteristics • Antigenic specificity  • Diversity: respond to LOTS of different antigens • two types: antibody, or humoral, and cellular responses. •  memory- faster & stronger 2nd time  • self/non-self-no inappropriate responses; we tolerate ourselves.

16. The players • lymphocytes and antigen presenting cells. •  Lymphocytes: round little cells in blood and lymph nodes; white blood cells; 2 types: •   B lymphocytes: Antibody production • Mature in the bone marrow. Have membrane-bound antibody, that reacts with a particular antigen.

17. T lymphocytes: arise in the bone marrow, mature in the thymus. • Surface molecules that react with antigen- T-cell receptors. • Need the action of a second molecule/cell type that presents Ag – MHC proteins on Antigen Presenting Cells- APCs

18. The Players (cont’d) • APC's: B cells, macrophages, dendritic cells; have MHC II on surface to be recognized by Th cells. •  Antigen is internalized and reexpressed- recognized along with the MHC II. Also provides a costimulatory signal. • Finally- a virally infected cell also presents Ag - MHCI

19. Production by clonal selection (1-10)

21. Cell Mediated Response: • Activation of Th and Tc cells • Exogenous and endogenous Ag presentation • Think VIRUSES • Th cells help lots of other cells- B cells, Macrophages, Tc cells- help is direct and by cytokines.

23. When Things go wrong: • Allergies • Autoimmune disease • Transplantation problems • Cancer?? • Immunodeficiency- natural and acquired

24. Chapter 2: Cells and Organs of the immune system • Where we’re going: • Lots of details- see learning objectives! • Types of cells- functions, and some surface proteins • Phagocytosis details • Primary and secondary lymphoid organs • Structure of a lymph node- some terms

25. The war metaphor (unapologetic) • Cells- soldiers • Primary lymphoid organs: training camp • Secondary lymphoid organs: war zone. • Capture/destroy some antigens • Present antigen to the proper cells • Stimulate the proper cells (usually B cells) • Produce the proper antibody • The cells: Hematopoiesis, toti, multi, uni-potent cells

26. Differentiation is a matter of cytokine environment, and stromal cells (later)

27. Control is Complicated • We make 3.7 X 10^11 WBC’s a DAY!!!!! • The right types • Production can change 10-20X upon bleeding or infection!!! • One factor: apoptosis: • Neutrophils programmed to live 1-3 days • B cells- life span determined by stimulation.

29. Bcl-2 inhibits apoptosis, so we’re lowering an inhibitor; counteracted by increased sensitivity to cytokines, /cause receptors are up. B cell lymphomas when BCL-2 is overactive!

30. Stem Cells- we can find them! Remove the differentiated cells

31. Lymphoid cells • T, B, null; small- naïve; large- stimulated-lymphoblasts • Can’t tell by looking! We differentiate by the surface molecules Table 2-5, but don’t bother

32. Lymphoid cells- Proteins to learn • B cells: surface antibody- 10^5/cell • MHC II- capable of exogenous Ag presentation • Ligands to Tcells • Th and Tc: • TCR • Th: CD4 • Tc: CD8 • Molecules for cell-cell interactions

33. NK Cells • No B or T-cell receptor • Naturally kill tumor cells/virally infected cells: • Low MHCI levels • ADCC- antibody-dependent cell-mediated cytotoxicity

34. Macrophages! • Phagocytic, long-lived, Ag-presenting, secretory • AKA: • blood: monocytes- precursor • connective tissue- histiocytes • liver-Kupffer cells • brain: microglea • lungs: alveolar Mphages • kidneys: mesangial cells

35. Activated by LPS, IFN gamma

37. Chemotaxis Adherance/opsonization Ingestion, digestion Exocytosis

38. Killing the bacteria: 3 ways: Oxygen Dependent Killing: Respiratory burst- NADPH oxidase- NADPH +202 ---> NADP+ + H++ 202-. This is superoxide. turns into H202 w/ superoxide dismutase: 202- +2H+---> H2O2 + O2 this can then react with myeloperoxidase to make hypochlorite. H2O2 + Cl- ----H2O + H+ + OCl- uses up lots of oxygen and NADPH the cell sometimes goes anaerobic, making lactic acid- which helps the process. Pentose phosphate shunt repenishes NADPH Nitrogen products: mphages respond to LPS, muramyl di-peptide- the building block of bacterial membranes- and IFN gamma, which comes from T cells, and start making NO and other reactive N products. NO is a byproduct of arginine metabolism Oxygen independent killing: lysozyme defensins: peptides that poke holes in membranes. various hydrolytic enzymes- break up proteins, lipids, etc.

39. Other Myeloid cells • Neutrophils- other major phagocyte • Short lived (1-3 days), no Ag presentation • Better phagocytes than m-phages • Chemotactic- leave the blood by extravasation • Inflammatory upon death • Eosinophils: Also phagocytic, less important, granules important for parasite killing • Basophils- like mast cells; degranulate in an allergic response.

40. Dendritic cells • Multiple lineages (fig 2-11) • Langerhans cells: skin • Interstitial: organs • Interdigitating: thymus

41. Organs of the Immune System • Primary: Bone Marrow and Thymus- the “training camp”- competent B and T cells produced here. • Secondary: Lymph nodes, MALT, Spleen, various cells lurking under our skin.

43. Positive and – selection: +: MHC I or II ; -: loss of self-reactive cells The thymus

44. Secondary Lymph organs • Various levels of organization • Follicles, primary and secondary • Lymph nodes • Spleen • Peyer’s patches • Langerhans cells lurking beneath your skin • Catch, trap, present ag; stimulate B cells & Th cells; produce antibody, including memory response.

45. Primary follicles- unstimuated; Dendritic & naïve B cells Ag activated: differentiation, affinity maturation (memory, improved Ab producing cells)

47. Ag meets Dendritic cells in the marginal zone; brought to the PALS; T cells are activated, B cells are activated, The primary follicles become secondary Processing RBC’s

48. MALT • LOTS of surface area!- 20X 20M- > 2X the size of my house! • MALT- tonsils, appendix, Peyer’s patches • Same pattern- trap, present, stimulate B& Tcells, produce Ab in primary and secondary response. • We massively tolerate gut bacteria- ????