Section 2 Slides

Section 2 Slides - 9/12/11 How Research Is Done...

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

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 ...
View Full Document

Ask a homework question - tutors are online