Section 2 Slides

Section 2 Slides - How Research Is Done...

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Unformatted text preview: 9/12/11 How Research Is Done Epidemiological Studies (Medical Detec;ves) • Observa;on and Repor;ng of Cases • Iden;fy Common Factors • Iden;fy PaEerns • Note Anomalies • Iden;fy the Cause How Research Is Done In vitro Studies • Cell cultures PBMCs –  (Peripheral Blood Mononuclear Cell cultures) –  infec;on monitored in cell lines • Disease models –  other retroviruses –  course of infec;on in cells How Research Is Done Turning to the Lab Tes;ng of Hypotheses •  Iden;fica;on of Possible Candidate Causes •  Match the Epidemic to Experimental Data •  Iden;fy Mechanisms –  Connec;ng molecular interac;ons to physiological effects How Research Is Done In vivo Studies • Animal models –  primates e.g. •  infec;on of model animals •  study naturally occurring infec;ons • Disease models –  SCID  ­ severe combined immunodeficiency • Clinical Data and Studies –  Lab tests: monitor clinical effects –  clinical trials: drug trials and effects Overview of Cell Func;ons •  Metabolism –  Protein synthesis –  RNA synthesis –  Enzyma;c processes •  Replica;on –  DNA synthesis •  Cell communica;on/ responses/ specializa;on –  Receptors Overview of Cell Structures •  Cytoplasm – RNA and Proteins –  Ribosomes: Protein synthesis –  Endoplasmic re;culum: protein trafficking –  Enzymes: synthesis, degrada;on, conversion •  Nucleus – DNA –  Chromosomes: physical loca;on of genes •  Cell membrane – Protein Receptors –  Selec;ve barrier: specific entry allowed –  Receptors: specific binding 1 9/12/11 Cells Maintain / Replicate Using Mul;ple Organelles, Compartments and Environments Key processes are Two general effects: •  Gene transcrip;on: DNA ⇒ RNA (nucleus) •  Protein synthesis: RNA ⇒ proteins (cytoplasm) •  Protein localiza;on: protein targeted to correct cellular structure (ER) •  Cell signaling: Response to OR release of signaling molecules (cell membrane) Cell Membrane and Cell Surface An;gens • Surface proteins crossing cell membrane • Usually glycosylated – (have short sugar branches aEached to proteins) • Play many func;onal roles – Receptors, enzymes, signaling, iden;fica;on, aEachment, mo;lity Immune System •  Involves cells and molecules that circulate through the body •  Circulatory system •  Lympha;c system Pathogens Like HIV Must U;lize and Subvert Those Processes 1.  Because cells no longer func;on in normal role, body loses func;onal role of cells 2.  Cells become damaged, body must respond to damage An;gens Molecules that are iden;fying characteris;cs of a cell. They can be inside cells or on the cell surface Epitopes Small sec;ons of an;gens Immune System Response Consists of •  A generalized response to all foreign maEer in the body (the inflammatory response) –  Mediated largely by phagocy;c cells and other myeloid cells •  A Specific Immune Response 2 9/12/11 The Immune System Response Consists of Immune System Response Overview •  PRIMARY DEFENSE –  INTACT SKIN AND HEALTHY MUCOSA 1.  Generalized responses This clears many infec;ons, but if not … 2.  Specific response Slow to develop Targets specific pathogen Enhanced response Basis of immunological memory •  •  •  •  •  SECONDARY DEFENSE –  BLOOD CELLS, PROTEINS –  INNATE IMMUNE SYSTEM –  NON ­SPECIFIC •  THIRD DEFENSE –  BLOOD CELLS –  ACQUIRED IMMUNE SYSTEM –  SPECIFIC Immune System Response Details •  PRIMARY DEFENSE –  PHYSICAL MECHANISMS •  Skin: dry, low pH, sheds •  Mucosa: mucus, sheds –  CHEMICAL MECHANISMS •  Lysozyme •  SLPI Secondary Defense SLPI •  Saliva •  Secre;ons –  Inhibits HIV infec;on in vitro. –  Appears to block HIV/cell interac;on. •  Breast milk – decreases aaer parturi;on. Higher measured infant saliva levels associated with lower transmission risk through breast milk. •  Increases in HIV+ individuals; posi;vely correlates with viral load Innate Immune System Response  ­ Details •  SECONDARY DEFENSE •  Innate Immune System Response •  A generalized response to all foreign maEer in the body (the inflammatory response) –  INNATE IMMUNE SYSTEM –  MYELOID LINEAGE OF WBCs –  Blood proteins –  Innate immunity resides primarily in circulatory system •  Phagocy;c cells: neutrophils, monocytes/ macrophages (Mφ) and dendri;c cells 3 9/12/11 Innate Immune System  ­ Macrophages •  Develop from circula;ng monocytes •  Resident in ;ssues •  Engulf and digest foreign material –  Fragments of material brought to Mφ cell surface •  Ag fragments displayed on Mφ surface by class II MHC molecules An;gen Presen;ng Cells •  Macrophages •  Dendri;c cells •  B cells Innate Immune System  ­ Dendri;c Cells •  Circula;ng and resident in ;ssues •  Engulf foreign maEer and display an;gens on surface with class II MHC •  Aaer engulfment, DCs *ac;vated* •  Become mobile  migrate to regional lymph node, deliver Ag Cell Membrane and Cell Surface An;gens • Surface proteins crossing cell membrane • Usually glycosylated – (have short sugar branches aEached to proteins) • Play many func;onal roles – Receptors, enzymes, signaling, iden;fica;on, aEachment, mo;lity Immune System Response  ­ Lympha;c System •  •  •  •  •  Second Circulatory system Lymph vessels Lymph nodes Lymph ducts Collects fluid from ;ssues Majority of lymphocytes reside in lympha;c system Immune System Response  ­ Lympha;c System •  Major organs include –  Bone marrow –  Thymus –  Spleen –  Peyer’s patches –  Tonsils –  Appendix –  Mucosal linings •  Dendri;c cells (and Mφ) bring Ags to lymph ;ssues/nodes/organs 4 9/12/11 Lymph nodes At junc;on of lympha;c vessels Filter lymph Have Mø, dendri;c cells and lymphocytes Most lymphocytes are here HIV infected Langerhans cells ac;vate T cells here; produce HIV which infects T cells coming through the node •  Foreign an;gen enters body •  Picked up by, or brought to, lympha;c system by dendri;c cells •  Trapped in network of phagocy;c and dendri;c cells in paracortex –  T cell ac;va;on occurs here –  B cell ac;va;on occurs here Lymph node func;on •  •  •  •  •  Lymph node func;on Lymph node func;on •  Paracortex – ac;va;on •  Cortex  ­ primary follicle, secondary follicle with germinal center (plasma cells) •  Medulla  ­ Plasma cells, CTLs •  Ac;vated TH and B cells migrate to primary follicle of cortex, then to germinal center of secondary follicle •  B cells and Plasma cells formed in germinal centers •  Plasma cells go to medulla and produce an;bodies •  CTLs migrate to medulla and exit Acquired Immunity  ­ development of B lymphocytes Specific Immune Response •  Acquired Immunity – Mediated by lymphocytes •  Humoral response •  Cell ­mediated response I.  II.  III.  IV.  Naïve B lymphocytes enter circula;on B cell receptor (BCr) binds its specific Ag Signals B cell *ac;va;on* B cell undergoes clonal expansion –  Popula;on of B cells with same receptor structure to respond to specific Ag V.  B cell popula;on undergoes differen;a;on –  Plasma B cells •  Most cells enlarge, extensive endoplasmic re;culum, increase receptor synthesis but secreted as Ab –  Memory B cells •  Some cells do not produce Ab, are long ­lived 5 9/12/11 Acquired Immunity  ­ role of B lymphocytes •  •  •  •  Plasma B cells produce Ab  ­ secreted BCrs Approximately 2,000 Ab/sec Live up to two weeks Ab bind to foreign Ag a)  b)  c)  •  Opsonize Neutralize Triggers MAC Rids body of extracellular pathogens Acquired Immunity  ­ role of T lymphocytes •  CD4+ T lymphocytes ac;vate other classes of lymphocytes and immune cells –  CD8+ cells require cytokine ac;va;on from CD4+ T lymphocytes –  B cells s;mulated by cytokine ac;va;on for clonal expansion –  Mφ have ⇑⇑ phagocy;c/an;microbial ac;vity •  *ac;vated* CD8+ cells ⇒ cytotoxic T lymphocytes (CTLs) aEack infected body cells •  CTLs rid body of intracellular pathogens Immune System Response •  Orchestrated by the CD4+ T ­lymphocytes (helper cells) •  These helper cells need to be ac;vated for them to do their job. –  An;gen Presen;ng Cells (APCs) are required for this ac;va;on Acquired Immunity  ­ development of T lymphocytes •  Par;ally differen;ated T lymphocytes migrates to thymus •  Further differen;ate into two popula;ons  ­ CD4+ and CD8+ cells •  Released into circula;on •  T cell receptor (TCr) binds specific epitope from specific Ag •  Further signaling results in clonal expansion and complete ac;va;on Integra;on of Innate and Acquired Immune Responses •  CD4+ T cells unable to directly respond to Ag •  APCs (dendri;c cells, macrophages or B cells) display Ag •  Pathogen engulfed by APC, then migrates to lymph node •  CD4+ cell binds and Ag displayed by APC  ­ occurs in lymph node Two subsets of CD4+ TH cells •  CD4+ T cells ac;vated by APCs in lymph nodes •  CD4+ T cells develop into two popula;ons of TH cells •  TH cells release chemical mediators that s;mulate other immune cells •  The two popula;ons of TH cells nega;vely regulate each other 6 9/12/11 TH 1 subset •  Cytokines –  IL ­2 –  TNF ­β  ­ IFN ­ γ •  Biological Ac;vity Cell mediated Immunity –  Mø ac;va;on –  delayed ­type hypersensi;vity –  Tc Ac;va;on –  Inhibits TH2 •  Combats intracellular parasites, viruses and tumor cells Acquired Immunity CD8+ T lymphocytes •TH 2 subset   Cytokines –  IL ­4  ­ IL ­10 –  IL ­13 Biological Ac;vity •  B cell ac;va;on “Humoral Response” –  allergic reac;ons –  Inhibits TH1 •  Combats extracellular organisms •  Ac;va;on (MHC I) •  Prolifera;on (IL ­2) •  Effector CD8+ T cells = cytotoxic T lymphocytes (CTLs) •  Memory CD8+ T cells •  CTLs rid body of intracellular pathogens Integra;on of Innate and Acquired Immune Responses •  •  •  •  APCs + Ag (MHC II) CD4+ T cells  Thelper cells B cells  plasma cells CD8+ T cells  CTLs HIV u;lizes this relay of informa;on •  Dendri;c cells (DCs) carry pathogens to lymph ;ssue using several mechanisms •  One mechanism  ­ using DC ­SIGN  ­ allows very efficient infec;on of lymph nodes to occur DC ­SIGN can infect CD4+ cells •  Surface molecules (gp120) binds to DC ­SIGN •  Dendri;c cell in lymph ;ssue makes contact with mul;ple CD4+ cells •  Allows for HIV to bind to CD4+ cells •  Infec;on cycle begins Apoptosis vs Necrosis •  •  •  •  •  •  •  •  Programmed cell death Controlled, regulated death Ac;va;on of enzymes that degrade DNA Shrinkage of cell, no damage to system vs Rapid death Cell enlargement Unregulated process Releases damaging cell components 7 ...
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