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Gilead -Topics in Human Pathophysiology Fall 2009 Drug Safety and Public Health White Blood Cells • Granulocytes – Neutrophils – Eosinophils – Basophils • Agranulocytes – Monocytes – Lymphocytes White Blood Cells Lymphatic System • Functions: – Drains excess tissue fluid (interstitial fluid) – Transports fats and fat-soluble vitamins absorbed from digestive system – Defends against infection Figure 9.3a Figure 9.3b 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 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 Second Line of Defense (Nonspecific) • • • • • • Phagocytosis Inflammatory response Complement system Interferons Natural killer cells Fever Figure 9.6a Phagocytosis Figure 9.7 Inflammation Figure 9.8 (1/2) Complement Figure 9.8 (2/2) Interferon Figure 21.5 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 Figure 9.9 B lymphocytes – •Recognition •Activation •Attack (cloning and antibody production) Antibody functions Figure 21.14 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 Figure 9.13 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 Figure 9.12 Macrophages act as antigen presenting cells •Helper T cells are presented with antigen by specialized WBCs •When activated these helper T cells clone themselves into memory cells and active cells Figure 21.17 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 Figure 21.19 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 Figure 9.15 Figure 21.12 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 Figure 9.19 Immunobiology – HIV infection copyright GarlandSciences • http://www.blink.biz/immunoanimations/ind ex1.html Figure 9.20 Reverse transcriptase required Protease required HIV Transmission 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 Figure 9.21 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 Figure 9.20 Reverse transcriptase Inhibitors work here Protease inhibitors work here Gilead Anti-HIV drugs AIDS Progression • Phase III – Full blown AIDS – T cell count falls below 200/mm3 – Opportunistic infections or cancer associated with AIDS set in – Pneumonia, meningitis, tuberculosis, encephalitis, Kaposi’s sarcoma, non-Hodgkins lymphoma – Nearly always fatal if untreated Additional Information • NRTI mechanism and drug resistance • http://www.youtube.com/watch?v=qYUnDzD O-Ic How HIV Testing Works From: http://www.clinical-virology.org/graphic/elisa_principle.jpg