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Blood and Immune System.pdf

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Gordon Richardson

Blood  and  Immune  System   Lecture  1:  Intro  and  Red  blood  cells     Case  study:  Jessica   Jessica  –  newborn  baby  has  yellow  skin  and  sclera   -­‐ Condition?   -­‐ Treatment?   Functions  of  the  blood   -­‐ Transport  gases,  nutrients,  hormones  and  metabolic  wastes   -­‐ Regulates  composition  of  ISF  (pH,  ions,  water,  etc.)   -­‐ Restrict  fluid  loss  at  injury  sites  via  blood  clotting  (prevent  blood  loss)   -­‐ Defends  against  toxins  &  pathogens   -­‐ Regulates  body  temperature  by  absorbing  &  redistributing  heat  (vasoconstrict/dilate)   Constituents  of  blood   -­‐ Plasma  ~46-­‐63%  à  most  plasma  proteins  are  made  by  the  liver   o Water  ~92%   o Ions   o Organic  molecules   § Amino  acids   § Proteins   • Albumins  60%   • Globulins  35%   • Fibrinogen  4%   § Glucose   § Lipids   § Nitrogenous  waste   o Trace  elements  and  vitamins   o Gases   § CO 2   § O   2 §   -­‐ Formed  elements  37-­‐54%   o Erythrocytes  (RBC)  99.9%   o Leukocytes  (WBC)  0.1%   § Lymphocytes  20-­‐40%   § Monocytes  2-­‐8%  (phagocyte)   § Neutrophils  50-­‐70%  (phagocyte  &  granulocyte)   § Eosinophils  1.4%  (granulocyte)     § Basophils  <1%  (granulocyte)   o Thrombocytes     § Platelets   Functions  of  plasma  protein s   -­‐ General:   o Generate  colloid  osmotic  pressure   o Buffer  pH   -­‐ Specific:   o Albumins   § Colloid  osmotic  pressure;  carriers   o Globulins   § α  &  β  -­‐  Clotting  factors,  enzymes,  carriers   § γ  -­‐  Antibodies   o Fibrinogen   § Forms  fibrin  for  blood  clotting   Where  do  all  these  cells  come  from?   -­‐ In  embryo:  yolk  sac,  liver,  spleen  &  bone  marrow   -­‐ After  birth:  bone  marrow   -­‐ Adults:  pelvis,  spine,  ribs,  cranium,  proximal  end  long  bones   Hematopoiesis  (the  formation  &  development  of  blood  cells)   -­‐ Pluripotent  hematopoietic  stem  cell   o Uncommitted  stem  cell   § Committed  progenitor  cells   • Erythroblast   • Megakaryocyte   • And  other  cells…   o Lymphocyte  stem  cell   -­‐ In  bone  marrow   o 25%  developing  erythrocytes   o 75%  developing  leukocytes   What  regulates  hematopoiesis?   -­‐ Cytokines   -­‐ Colony  stimulating  factors   –  from  endothelial  cells  &  WBC   -­‐ Interleukins  –  from  WBC   -­‐ Effect:  survival,  proliferation  &  differentiation  of  different  cell  types   -­‐ Erythropoietin  (EPO)  (growth  factor,  raise  RBC  in  blood)   –  (from  kidney):  erythrocytes   -­‐ Thrombopoietin  (TPO)  –  (from  liver):  megakaryocytes  (increases  platele ts)   Clinical  connection   -­‐ G-­‐CSF  (granulocyte  colony  stimulating  factor)  injected   artificially   o Time  required  for  neutrophils  to  return  to  normal  is  less   o Can  better  withstand  chemotherapy  w/little  complications   Review  question   -­‐ Which  protein  is  most  abundant  in  plasma?   o Albumin   -­‐ List  all  the  types  of  formed  elements  that  are  found  in  the  blood   o Erythrocytes   o Neutrophils   o Monocytes   o Platelets   o Lymphocytes   o Basophils   o Eosinophils   o Natural  killer  cells   Red  blood  cells   -­‐ Essentially  bags  filled  with  hemoglobin  &  enzymes   -­‐ Anaerobic  metabolism   -­‐ No  nucleus  =  no  new  transcription   -­‐ 5x10  cells/L   -­‐ Cytoskeleton  creates  unique  shape  of  RBCs   -­‐ Moves  very  well  in  small  capillaries  (can  fold  in  half)   -­‐ Life  span  ~120  days   Hemoglobin   -­‐ RBC  jam  packed  w/hemoglobins   -­‐ 4  polypeptide  chains   o 2α  chains   o 2β  chains   -­‐ Heme  –  oxygen  carrier   Red  blood  cells  can  change  shape   -­‐ Life  span  ~120  days   -­‐ Makes  2-­‐3  million/second   -­‐ Hypotonic  sol :  less  solute  out,  water  moves  in   n -­‐ Hypertonic  sol :  more  solute  in,  water  moves  out   Erythropoiesis   -­‐ Regulated  by  erythropoietin   -­‐ Erythropoietin  synthesized  &  released  from  kidney  in  response  to  low  oxygen   -­‐ Nucleus  pinches  off  &  mitochondria  &  ER  breakdown   -­‐ Help  pts  w/kidney  failure  by  injection  of  EPO   o Stimulus=  low  O 2 ∴  ⇑RBC  &  ∴⇑O 2   Red  blood  cell  removal  ***   -­‐ Bone  marrow  formation   à  new  RBCs  released  into  circulation  (90%  to  macrophage  after  ~120  life   span,  10%  hemolysis)   à     Jaundice  (hyperbilirubinemia)   -­‐ High  turn  over  of  RBC  (excessive  breakdown)   -­‐ Liver  disease  (escaping  from  liver  to  blood  (bilirubin))   -­‐ Bile  duct  obstruction   Case  study:  Jessica   -­‐ Jessica  is  new  born  baby  who  has  yellow  skin  &  sclera   o Condition   § Neonatal  jaundice   • High  turnover  of  RBCs   • Liver  not  yet  able  to  remove  adequate  bilirubin  from  blood   • Too  much  bilirubin  reabsorbed  from  intestines   o Treatment   § If  severe:  blue  light  (420-­‐470  nm)   What  is  anemia?   -­‐ Normal  production  and  removal   -­‐ Hemoglobin  content  too  low   o Anemia  low  production  and  high  removal   § Irritability   § Fatigue   § Dizziness,  lightheadedness,  rapid  heartbeat  (b/c  try  to  pump  more  blood)   § Causes  for  low  production   • Destruction  of  stem  cells  via  drugs  &  radiation  (aplastic)   –  stem  cell  issues,  not   enough  production   • Inadequate  nutrients:  iron,  folic  acid,  Vitamin  B   12 • Low  erythropoietin  (renal)  ie.  Kidney  failure   § Causes  for  high  removal   • Genetic:  defects  in  RBC  proteins  (e.g.  hemog lobin)   • Parasitic  infections   • Drugs  (some  antibiotics  &  anti -­‐seizure  drugs_   • Autoimmune  reactions  (hemolytic)   • Excessive  blood  loss  (hemorrhagic)   • Sickle  cell  anemia  –  destruction  of  RBCs   What  is  polycythemia?   -­‐ Normal  production  and  removal   -­‐ Hematocrit  too  high   o Polycythemia  high  production  and  low  removal   § High  blood  viscosity   § Leukemia  of  precursor   § Causes   • Primary:  abnormal  erythrocyte  precursors   • Secondary:  low  oxygen  delivery  to  tissues   • Injection  of  EPO   Lecture  2:  Pathogens  and  Innate  Immunity   What  does  our  immune  system  do?   -­‐ Destroy  pathogens  &  our  own  cells  that  become  cancerous   -­‐ Detects  &  kills  abnormal  cells   -­‐ Remove  cell  debris  from  body   -­‐ Pts  w/HIV  more  prone  to  certain  cancer   What  kinds  of  pathogens  are  there?   -­‐ Parasitic  worms   -­‐ Fungi   -­‐ Protozoa   -­‐ Bacteria   -­‐ Viruses   o Located  intracellular  &  extracellular   Viruses   -­‐ Has  DNA  or  RNA  coated  w/lipid  protein  coat   -­‐ Require  cells  to  replicate   -­‐ Specific  cold  viruses  will  bind  to  respiratory  tract   How  do  we  defend  against  pathogens?   -­‐ Physical  barriers   o Skin,  mucous,  acid,  lysozyme  (castle  walls  &  moat)   o Protective  surfaces  –  critical,  traps  viruses   -­‐ Innate  Immunity   o Rapid,  non-­‐specific  (Guards)   o Attack  anything  that  is  foreign   o Cells  &  chemical  in  body  fluids   -­‐ Acquired  Immunity   o Specific  response  (Army)   o Cells  are  specific  to  pathogens   o Lymphocytes  (T  cells  and  B  cells)   What  are  the  components  of  the  immune  system?   -­‐ Tonsils  are  diffuse  lymphoid  tissue   -­‐ Thymus  produces  T  lymphocytes   -­‐ Lymph  nodes  &  spleen  (encapsulated  lymphoid  tissues)   -­‐ Gut-­‐associated  lymphoid  tissue  (GALT)  is  diffuse  lymphoid  ti ssue   -­‐ Bone  marrow  produces  most  blood  cells   -­‐ Lymphatic  vessels   Lymphatics   -­‐ Return  excess  tissue  fluid  to  the  blood  (venous  circulation)   -­‐ Transport  pathogens/dendritic  cells  to  lymph  nodes   -­‐ Transport  fat  from  digestive  system  to  blood   -­‐ Lymphatic  capillary   o Very  small   o Near  blood  vessels   o Cells  can  engulf  bacteria  here  &  travel  to  lymph  nodes   Specialized  lymphoid  organs   -­‐ Lymph  node  (lymph-­‐monitors  lymph)  &  spleen  (monitors  blood)   o Both  contain  mature  immune  cells  that  interact  w/pathogens  &  initiate  immune  response   Immune  cells  found  in  blood,  lymph  and  tissues   -­‐ Lymphocytes   o B  lymphocytes   o T  lymphocytes   o Natural  killer  (NK)  cells   -­‐ Monocytes   o Macrophages   -­‐ Neutrophils   -­‐ Eosinophils   -­‐ Basophils   Three  lines  of  defense   -­‐ Physical  barriers   o Skin,  mucous,  acid,  lysozyme  (castle  walls  &   moat)   o Protective  surfaces  –  critical,  traps  viruses   -­‐ Innate  Immunity   o Rapid,  non-­‐specific  (Guards)   o Attack  anything  that  is  foreign   o Cells  &  chemical  in  body  fluids   -­‐ Acquired  Immunity   o Specific  response  (Army)   o Cells  are  specific  to  pathogens   o Lymphocytes  (T  cells  and  B  cells)   How  does  the  innate  immune  system  work?   -­‐ 1.  Phagocytes   o Neutrophils  –  50-­‐70%  WBC   § Release  cytokines  (cause  fever  &  inflammation)   o Macrophages  &  dendritic  cells  (derived  from  monocytes  &  reside  in  tissues)   -­‐ 2.  Natural  killer  (NK)  cells   -­‐ 3.  Antimicrobial  proteins   -­‐ 4.  Inflammation   -­‐ 5.  Fever   1.  Phagocytes   -­‐ Diapedesis  (extravasation)   o Roll  across  endothelial  cells  (basal  lamina)  &  enters   -­‐ Chemotaxis  stimulates  chemotaxis  =  e.g.  bacterial  toxins,  products  of  tissue  injury,  cytokines   Phagocytosis  of  pathogens   -­‐ Phagocytes  have  different  surface  receptors   o Toll  receptors  (recognizes  pathogen)   § Phagocyte  w/toll  receptors  à  pathogen  à  engulfs  pathogen   o F c  receptors  (antibody  receptors)   § Phagocyte  w/antibody  receptors  à  pathogen  (polysaccharide  capsule)   à  antibody   molecules  attach  to  pathogen  à  engulfs  pathogen   o Antibody  is  an  example  of  an  opsonin  (marks  pathogen  for  phaygocytosis)   o Coating  substance  w/an  opsonin  =  opsonization  (makes  pathogen  more  likely  to  be   phagocytized  &  pathogen  more  tasty  for  phagocyte)   Macrophages  &  dendritic  cells  display  antigen  fragments   -­‐ Macrophage   à  macrophage  digests  antigen  in  lysosomà  antigen-­‐presenting  macrophage  displays   antigen  fragments  on  surface  receptors   Review   -­‐ What  is  the  function  of  opsonin?   o Mark  pathogens  for  phagocytosis   2.  Natural  killer  (NK)  cells   -­‐ Kill  cells  when  the  cells  are  infected  w/a  virus  or  cancerous   -­‐ Recognize  cells  that  appear  abnormal   -­‐ Cytokines  –  sometimes  release  perforins  ***   -­‐ ***   3.  Antimicrobial  proteins       -­‐ Interferons:     o α  &  β  -­‐  Prevents  viral  replication  in  cells   o γ  -­‐  Activate  macrophages  &  other  immune  cells   -­‐ Complement:   o ~25  plasma  proteins  (all  inactive  form  until  required)   o Destroy  target  cell  membranes   o Stimulate  inflammation   o Attract  phagocytes  (act  as  opsonin  &  chemotaxin)   o Enhance  phagocytosis   o Complement  à  attaches  to  pathogen  à  lysed  pathogen   Complement     -­‐ Three  pathways   o Classical  pathway  (antigen -­‐antibody  complex)   o Lectin  pathway  (microorganism’s  cell  wall  polysaccharide)   o Alternative  pathway  (no  inhibitors  on  microbe  surface)   o Classical  pathway  &  lectin  pathway  &  alternative  pathway  à  cleaves  C3  à  C3b  &  C3a     o C3b  à  bind  to  bacteria  à  opsonization   § C3b  gets  cleaved  again  à  C5b,  C5a,  C6,  C7,  C8,  C9  à  membrane  attack  complex   (forms   a  pore  just  to  allow  ions  to  flow  then  cell  will  die   o C3a  &  C5aà  causes  inflammation   Complement:  Details  ***   Review   -­‐ Which  of  the  following  is  NOT  a  role  for  complement  proteins   o Activate  apoptosis  in  host  cells   4.  Inflammation   -­‐ Localized  tissue  response  to  injury  producing:  swelling,  redness,  heat  and  pain   -­‐ Roles   o Slowing  the  spread  of  pathogens   o Mobilization  of  local,  regional,  &  systemic  defenses   o Sets  the  stage  for  repair   Inflammatory  response   -­‐ Tissue  damage  à  chemical  change  in  interstitial àl  mast  cells  release  histamine  &  heàri    ( attraction  of  phagocytes,  especially  neutrophils à   activation  of  specific  defenses  &  removal  of  debris  by   neutrophils  &  macrophages;  stimulation  of  repair à   tissue  repaà)  dilation  of  blood  vessels,  increase   blood  flow,  increase  vessel  permeability  (antibody,  complement,  kinins,  clotting  factors  move  into  ISF)   ( à  clot  formation) à   area  becomes  red,  swollen,  warm,  and  painful   -­‐ Kinin  cascade  leads  to  formation  of  bradykinin   –  vasodilator  &  stimulates  pain  receptors   5.  Fever     -­‐ Body  temp.  >  37.2 °C   -­‐ Cause:     o Pyrogens  change  the  thermoregulatory  set  point  in  the  hypothalamus   -­‐ Roles:     o Speed  up  metabolic  activity  of  host   o Inhibits  some  pathogens   -­‐ Pathogens:  e.g.  bacterial  components,  interleukin -­‐1  released  from  activated  macrophages   Innate  Immunity  Summary  ***   Review   -­‐ Which  is  the  first   cell  to  exit  the  bloodstream  during  inflammation?   o Neutrophils     Lecture  3:  Acquired  Immunity   -­‐ Recall:  Innate  immunity  ***   o Bacteria  enter  extracellular  fluid  à  activate  complement  proteins  à  act  as  opsonins  à  which   coats  bacteria   Three  lines  of  defense   -­‐ Physical  barriers   o Skin,  mucous,  acid,  lysozyme  (castle  walls  &  moat)   o Protective  surfaces  –  critical,  traps  viruses   -­‐ Innate  Immunity   o Rapid,  non-­‐specific  (Guards)   o Attack  anything  that  is  foreign   o Cells  &  chemical  in  body  fluids   -­‐ Acquired  Immunity   o Specific  response  (Army)   o Cells  are  specific  to  pathogens   o Lymphocytes  (T  cells  and  B  cells)   What  are  the  4  features  of  acquired  immunity?   -­‐ Specificity  –  activated  by  &  responds  to  a  specific  antigen   (T  cells  &  B  cells)   -­‐ Versatility  –  ready  to  confront  any  antigen  at  anytime   -­‐ Memory  –  “remembers”  any  antigen  it  has  encountered  (very  imp.  for  acquired  immune  system)   -­‐ Tolerance  –  responds  to  foreign  substances  but  ignores  normal  tissues   How  are  these  features  achieved?   -­‐ 1.  Specificity  –  responds  to  a  specific  antigen   o Both  B  &  T  cells  have  receptors  that  recognize  specific  shapes/antigen  (B  cell  recognize  what  T   cell  cannot  &  vice  versa)   -­‐ 2.  Versatility  –  ready  to  confront  any  antigen  at  anytime   o Different  B  &  T  cells  have  different  receptors   -­‐ 3.  Memory  –  “remembers”  any  antigen  it  has  encountered   o Some  activated  B  &  T  cells  are  long  lasting   o Remain  in  memory  for  a  long  time   à  activate  &  reactivate   -­‐ 4.  Tolerance  –  response  to  foreign  substances  but  ignores  normal  tissues   o B  &  T  cells  w/receptors  that  recognize  self  are  deleted  or  not   activated   o Not  activated  by  own  protein   o Fail  =  autoimmune  disease  (i.e.  type  I  diabetes   –  tolerance  fail)   (1)  Specificity  &  (2)  versatility  of  B  &  T  cell  receptors   -­‐ Within  B  cell  &  T  cell  are  specific  antigen  receptors   -­‐ One  cell  will  bind  to  one  shape,  others  will  bind  to  other   -­‐ Antibody  shape  different   ∴  versatility   B  cell  receptors  bind  to  extracellular  antigen   -­‐ Membrane  bound  antibody   -­‐ Extracellular  antigen   -­‐ Receptors  are  Immunoglobulin -­‐like  molecule   T  cell  receptors  bind  to  antigens  displayed  on  the  surface  of  the  cells   -­‐ T  cell  receptor  must  bind  to  viral  antigen  &  MHC   T  and  B  cells  circulate  throughout  the  body  searching  for  antigen   -­‐ Encounter  antigen  in  secondary  lymphoid  tissues   -­‐ Sees  antigen  =  activated   Clonal  selection  and  expansion   Pr-­‐ry Antigen  à I  Naïve  lymphocytes  reproduce  (many  of  them  will  only  live  for  short  period  of  time  others   i.e. (3) Memory will  be  memory) à  clonal  expansion à   short-­‐lived  effector  carry  out  the  immediate  responà   memory  cells  are  long  lived  and  continue  to  reproduce   Primary  and  Secondary  Immune  Respons es  (3)  Memory     B  and  T  lymphocytes  originate  in  the  bone  marrow   –  Need  to  be  educated  (4)  Tolerance   -­‐ T  cells  undergo  positive  and  negative  selection  in  the  thymus   Focus: B cells and Humoral Immunity  positive  and  negative  selection  in  the  bone  marrow   -­‐ Appropriate  receptors  that  will  act  positively   -­‐ Delete  ones  that  work  with  self  proteins   Focus:  B  cells  and  Humoral  Immnunity  Antibodies   Figure 24.12   -­‐ 4  polypeptide  chains   Every human has between 10 and 10 different shaped Fabs 9 How is B cell diversity (versatility) o Joined  by  disulfide  bonds   -­‐ Every  human  has  been  between  10  and  10  different  shaped  Fabs   -­‐ Antigen-­‐binding  site  is  the  most  variable  region   How  is  B  cell  diversity  (versatility  generated?     -­‐ Somatic  rearrangement   -­‐ DNA  rearrangement   -­‐ Variable  depending  on  cell   –  1  selected  for  V,  D ,  J   Somatic  rearrangement  (recombination)   Somatic rearrangement How are B cells activated?   How  are  B  cells  activated?   See ani-­‐iB  cells  start  to  become  activated  when  they  encounter  a ntigen  html B cell MHC B cells start to receptor become activated when they encounter antigen B cell Antigen is internalized, combined with MHC and then transported to cell surface Antigen   Antigen  is  internalized,  combined  with  MHC  and  then  transported  to  cell  surface   B cell MHC receptor Modified figure from Interactive Physiology B cell Antigener T cell recognizes antigen and MHC — becomes activated and secretes cytokines   Helper  T  cell  recognizes  antigen  and  MHC   –  becomes  activated  and  secretes  cytokines   T cell receptor MHC B cell receptor CD40 CD40L Modified figure from Interactive Physiology B cell Helper T cell Antigen + cytokines (IL-4, IL-5,  ) Modified figure from Interactive Physiology -­‐ Activated  B  cells  divide   -­‐ Some  become  plasma  cells  and  secrete  antibodies,  others  become  memory  B  cells   Activated B cells cytokines divide. Some become plasma cells and secrete antibodies, others become memory B cells   Summary Figure from Martini (2006) Fundamentals of Anatomy and Physiology Summary Figure from Martini (2006) Fundamentals of Anatomy and Physiology   Antigen  in  à  bind  to  B  cell  à  sensitize     Review  –  The  following  are  steps  in  the  activation  of  B  cells   1. Antigen  binds  to  the  B  cell  receptor   2. Antigen  is  internalized  by  the  B  cell   3. T  cell  secretes  cytokines   4. T  cell  recognizes  antigen  on  B  cells   5. T  cell  secretes  cytokines   6. Some  B  cells  differentiate  into  plasma  cells   7. Plasma  cells  secrete  antibody     How do antibodies protect us? How  do  antibodies  protect  us?   Antigen 1 6 Activates binding Activates B complement site lymphocytes to antibodyds Complement Triggers mast cell 5 degranulation Antibody Memory Plasma cells cells Secrete NK cell or eosinophil antibodies 2 Acts as 4dependent cellular- opsonins activity Bacterial toxins 3 Causes antigen clumping and inactivation of
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