1. Gilead -Topics in Human Pathophysiology Fall 2009 Drug Safety and Public Health

2. White Blood Cells Granulocytes – Neutrophils – Eosinophils – Basophils Agranulocytes – Monocytes – Lymphocytes

3. White Blood Cells

4. Lymphatic System Functions: – Drains excess tissue fluid (interstitial fluid) – Transports fats and fat-soluble vitamins absorbed from digestive system – Defends against infection

5. Figure 9.3a

6. Figure 9.3b

7. First Line of Defense Skin – barrier, sloughs, acidic pH Tears- Lubricate and wash eye, contain lysozyme Saliva - Lubricates and rinses teeth, contains lysozyme Earwax – waterproof, prevents water (and bacteria) entry Digestive acids – kills pathogens that enter stomach

8. First Line of Defense Mucus – traps pathogens for WBCs to kill, cilia sweeps Vomiting – removes toxins and pathogens from stomach Urination – slightly acidic, cleanses urinary tract Defecation – removes bacteria from GI tract Resident bacteria – outcompete harmful organisms

10. Second Line of Defense (Nonspecific) Phagocytosis Inflammatory response Complement system Interferons Natural killer cells Fever

11. Figure 9.6a Phagocytosis

12. Figure 9.7 Inflammation

13. Figure 9.8 (1/2) Complement

14. Figure 9.8 (2/2)

15. Figure 21.5 Interferon

16. Third Line of Defense (Specific Immunity) B lymphocytes – Mature in bone marrow, responsible for antibody mediated immunity – When they recognize a pathogen (antigen) and are activated, develop into plasma cells and memory cells – Plasma cells produce 1000s of antibodies (immunoglobulins) per second

17. Figure 9.9 B lymphocytes – Recognition Activation Attack (cloning and antibody production)

18. Figure 21.14 Antibody functions

19. Third Line of Defense (Specific Immunity) T lymphocytes – 3 types: helper T cells, cytotoxic T cells, suppressor T cells – When recognize a pathogen and are activated, these attack the pathogen and create a cadre of memory cells

20. Figure 9.13

21. Helper T cells Recognize pathogen presented by other WBCs Are activated by cytokines by other WBCs “Clone”themselves to form active cells and memory cells Release cytokines to activate and stimulate other WBCs, including B cells and phagocytes

22. Figure 9.12 Macrophages act as antigen presenting cells

23. Figure 21.17 Helper T cells are presented with antigen by specialized WBCs When activated these helper T cells clone themselves into memory cells and active cells

24. Cytotoxic T cells AKA killer T cells Recognize pathogen (antigens) in virally infected cell or cancer cells Activated by cytokines from helper T cells “Clone” themselves into attack cells and memory cells Attack by producing proteins that open holes in infected cells

25. Figure 21.19

26. Immunologic Memory Memory cells circulate, sometimes for a lifetime, scanning for that pathogen they recognize A second infection by the same pathogen will yield a stronger, faster immune response that prevents illness

27. Figure 9.15

28. Figure 21.12

29. HIV A retrovirus that infects host cells macrophages and helper T cells Its RNA is reverse transcribed into DNA, then inserted into host chromosomes Protein synthesis of viral DNA makes components of new HIV The components are assembled into new virus and released from host

30. Figure 9.19

31. Immunobiology – HIV infection copyright GarlandSciences http://www.blink.biz/immunoanimations/inde x1.html http://www.blink.biz/immunoanimations/inde x1.html

32. Figure 9.20 Reverse transcriptase required Reverse transcriptase required Protease required

33. HIV Transmission

34. AIDS Progression Three phases: Phase I – weeks to years – Virus levels spike briefly – Flulike symptoms – fever, chills, fatigue, body aches, swollen lymph nodes – T cell count may drop then rebound – Antibodies to HIV in the blood allow diagnosis

35. Figure 9.21

36. AIDS Progression Phase II – Average length about 10 years – Virus is replicating and bursting out of helper T cells, killing them – T cell count declines, opportunistic infections may occur – This phase may be symptomatic or symptom free – Left untreated 95% of patients will move on to phase III (AIDS) – HAART - Highly Active AntiRetroviral Therapy – 3 drug cocktail with at least 2 classes of antiretrovirals

37. Figure 9.20 Reverse transcriptase Inhibitors work here Reverse transcriptase Inhibitors work here Protease inhibitors work here

38. Gilead Anti-HIV drugs

39. AIDS Progression Phase III – Full blown AIDS – T cell count falls below 200/mm 3 – Opportunistic infections or cancer associated with AIDS set in – Pneumonia, meningitis, tuberculosis, encephalitis, Kaposi’s sarcoma, non-Hodgkins lymphoma – Nearly always fatal if untreated

40. Additional Information NRTI mechanism and drug resistance http://www.youtube.com/watch?v=qYUnDzD O-Ic http://www.youtube.com/watch?v=qYUnDzD O-Ic

41. How HIV Testing Works From: http://www.clinical-virology.org/graphic/elisa_principle.jpg