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Gordon Richardson

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Lecture  1  Page  547-­‐557     Lecture  2   The  Immune  System   -­‐ Key  features  of  the  immune  system:  specificity  and  memory   –  together  these  processes  enable  body  to  distinguish  “self”   from  “non-­‐self”  and  mount  a  targeted  response  to  specific  invaders   -­‐ Immune  system  serves  three  major  functions:   o Protects  body  from  disease -­‐causing  invaders  known  as  pathogens.  Microorganisms  (microbes)  that  act  as   pathogens  (bacteria,  viruses,  fungi  and  one -­‐celled  protozoans).  Larger  pathogens  include  multicellular   parasites   (hookworms  and  tapeworms)   § Virtually  any  exogenous  molecular  or  cell  has  potential  to  elicit  an  immune  response.  Pollen,  chemicals   and  foreign  bodies  are  examples  of  substances  to  which  body  may  react.  Substances  that  trigger  body’s   immune  response  and  can  react  with  products  of  that  response  are  known  as   antigens   o It  removes  dead  or  damaged  cell  as  well  as  old  RBC.  Scavenger  cells  of  immune  system  patrol  extracellular   compartment,  gobbling  up  and  digesting  dead  or  dying  cells   o Tries  to  recognize  and  remove  abnormal  cell s  created  when  normal  cell  growth  and  development  go  wrong   -­‐ When  body’s  immune  system  fails  to  perform  its  normal  functions.  Pathologies  of  immune  system  generally  fall  into  one  of   three  categories:   o Incorrect  responses  if  mechanisms  for  distinguishing  self  from  non-­‐self  fail  and  immune  system  attacks  body’s   normal  cells  (autoimmune  disease)   o Overactive  response  allergies  are  conditions  in  which  immune  system  creates  a  response  that  is  out  of  proportion   to  the  threat  posed  by  antigen   o Lack  of  response  –  Immunodeficiency  disease  arise  when  some  components  of  immune  system  fails  to  work   properly.  Primary  immunodeficiency  is  a  family  of  genetically  inherited  disorders  that  range  from  severe  to  mild.   Acquired  immunodeficiencies   may  occur  as  a  result  of  infection  (AI DS  caused  by  HIV)     Pathogens  of  the  human  body   Bacteria  and  viruses  require  different  defense  mechanisms   -­‐ Bacteria  and  viruses  differ  from  each  other  in  several  ways   -­‐ These  differences  require  body  to  have  variety  of  immune  response   o Structure  –  bacteria  are  cell  with  cell  membrane  usually  surrounded  by  cell  wall.  Some  encapsulated  bacteria  also   produce  additional  protective  outer  layer  (capsule).  Viruses  are  not  cells   –  they  consist  of  nucleic  acid  (DNA  or   RNA)  enclosed  in  coat  of  viral  proteins  (capsid).  Som e  viruses  add  an  envelop  of  phospholipid  and  protein  made   from  host’s  cell  membrane  and  incorporate  viral  proteins  into  envelop   o Living  conditions  and  reproduction  –  most  bacteria  can  survive  and  reproduce  outside  a  host  if  required  nutrients,   temperature,  pH…  are  present.  Viruses  must  use  intracellular  machinery  of  host  to  replicate.  Location  of   pathogens  in  both  major  compartments  of  body  requires  different  defense  mechanisms  for  each  compartment   o Susceptibility  to  drugs  most  bacteria  can  be  killed  by  drugs  (antibiotics).  These  drugs  act  directly  on  bacteria  and   destroy  them  or  inhibit  their  growth.  Viruses  cannot  be  killed  by  antibiotics  some  viral  infections  can  be  treated   with  antiviral  drugs  which  target  specific  stag es  of  viral  replication     Viruses  can  replicate  only  inside  host  cells   -­‐ Replication  cycle  of  virus  begins  when  virus  invades  host  cell   -­‐ To  cross  human  cell  membrane,  virus  binds  to  membrane  receptors  triggering  endocytosis  of  entire  virus  particle   -­‐ Or  virus  envelope  fuses  with  host  cell  membrane  allowing  core  of  virus  to  enter  cytoplasm   -­‐ Once  inside  host  cell  and  free  of  capsid,  virus’s  nucleic  acid  takes  over  host  cel l  resources  to  make  new  viral  nucleic  acid  and   viral  protein   -­‐ These  components  assemble  into  a dditional  virus  particles  that  are  released  from  host  cell  to  infect  other  cells   -­‐ Viruses  can  be  released  from  host  cell  in  two  ways   o Virus  can  cause  host  cell  to  rupture  releasing  virus  particles  into  ECF   o Virus  particles  surround  themselves  with  layer  of  ho st  cell  membrane  and  then  bud  off  from  surface  of  host  cell   -­‐ Viruses  do  other  kind  of  damage  to  host  cell   –  may  disrupt  cell’s  metabolism  so  cell  dies   –  some  causes  cold  sores  and   chicken  pox     The  Immune  Response   -­‐ Body  has  two  lines  of  defense   –  physical  and  chemical  barriers  (skin,  mucus,  stomach  acid)  first  try  to  keep  pathogens  out  of   body’s  internal  environment   -­‐ If  first  line  of  defense  fails  then  internal  immune  response  takes  over   -­‐ Internal  immune  response  includes  same  basic  steps   o Detection  and  identific ation  of  foreign  substance   o Communication  with  other  immune  cells  to  rally  an  organized  response   o Recruitment  of  assistance  and  coordination  of  the  response  among  all  participants   o Destruction  or  suppression  of  invader   -­‐ Not  all  invaders  can  be  destroyed  by  bod y’s  immune  system  –  some  cases  body  can  only  control  damage  and  keep  invader   from  spreading   -­‐ Antibodies  –  proteins  secreted  by  certain  immune  cells  bind  antigens  and  make  them  more  visible  to  immune  system   -­‐ Cytokines  are  protein  messengers  released  by  one  cell  that  affect  growth  or  activity  of  another  cell   -­‐ Human  immune  response  general  divided  into  two  categories:  nonspecific  innate  immunity  and  specific  acquired  immunity   -­‐ Innate  immunity  present  from  birth  and  is  body’s  nonspecific  immune  response   to  invasion   -­‐ Immune  cell  membrane  receptors  that  mediate  innate  immunity  have  broad  specificity  and  response  to  range  of  molecular   signals  that  are  unique  and  common  to  pathogenic  microorganisms   -­‐ Nonspecific  innate  respon se  does  not  target  particular  pathogen   –  it  begins  within  minutes  to  hours   -­‐ Inflammation  apparent  on  skin  as  red,  warm,  swollen  area   –  hallmark  reaction  of  innate  immunity   -­‐ Acquired  immunity  directed  at  specific  invaders  and  for  this  reason  is  the  body’s   specific  immune  response   -­‐ The  immune  cell  membrane  receptors  that  mediate  acquired  immunity  are  highly  specific  and  can  distinguish  between   different  pathogens   -­‐ One  characteristic  of  acquired  immunity  is  that  specific  immune  response  to  first  exposure  to  a  path ogen  may  take  days  –   with  repeated  exposures,  the  immune  system  “remembers”  prior  exposure  to  pathogen  and  reacts  more  quickly   -­‐ Acquired  immunity  can  be  divided  into  cell -­‐mediated  immunity  and  humoral  immunity   o Cell-­‐mediated  immunity  uses  contact-­‐dependent  signaling  in  which  an  immune  cell  receptor  binds  to  a  receptor   on  its  target   o Humoral  immunity  (or  antibody-­‐mediated  immunity )  uses  the  secreted  proteins  (antibodies)  to  carry  out  the   immune  response   -­‐ Innate  response  is  more  rapid  but  does  not  target  specific  invader     -­‐ It  is  reinforced  by  antigen-­‐specific  acquired  response  which  amplifies  the  efficacy  of  innate  response     Anatomy  of  the  immune  system   -­‐ The  immune  system  has  two  anatomical  components:  lymphoid  tissues  and  cells  responsible   for  immune  response     Lymphoid  tissues  are  everywhere   -­‐ Two  primary  lymphoid  tissues  are:   thymus  gland  and  bone  marrow   -­‐ Both  have  an  outer  wall  formed  from  fibrous  collagenous  capsules   -­‐ Spleen  contains  immune  cells  positioned  so  thy  monitor  blood  for  foreign  in vaders   -­‐ Phagocytic  cells  in  spleen  also  trap  and  remove  aging  RBC   -­‐ Lymph  nodes  associated  with  lymphatic  circulation   –  this  filtered  fluid  is  picked  up  by  lymph  capillaries  and  passes  through   encapsulated  lymph  nodes  on  its  journey  back  from  circulation   -­‐ Inside  lymph  nodes,  clusters  of  immune  cells  intercept  pathogens  that  have  entered  ISF  through  breaks  in  skin  or  mucus   membranes   -­‐ Once  these  microbes  have  been  swept  into  lymph,  immune  cells  in  nodes  hep  prevent  their  spread  throughout  body   -­‐ Unencapsulated  diffuse  lymphoid  tissues  are  aggregations  of  immune  cells  that  appear  in  other  organs  of  the  body   –  they   include:   o Tonsils  at  posterior  nasopharynx   o Gut-­‐associated  lymphoid  tissue  (GALT)  which  lies  just  under  epithelium  of  esophagus  and  intestines   o Clusters  of  lymphoid  tissue  associated  with  kin  and  respiratory,  urinary  and  reproductive  tract   o These  tissues  contain  immune  cells  positioned  to  intercept  invading  pathogens  before  they  get  into  general   circulation     Leukocytes  mediate  immunity   -­‐ Leukocytes  (WBC)  primary  cells  responsible  for  immune  responses  of  body   -­‐ Most  are  larger  than  RBC  but  not  as  numerous   -­‐ Most  leukocytes  circulate  blood  but  usually  leave  capillaries  and  function  extravascularly     -­‐ Some  types  can  live  out  of  tissue  for  several  months  but  others  only  few  hours  or  days   -­‐ Leukocytes  are  divided  into  six  basic  types   o Eosinophils   o Basophils  (in  blood  and  related  mast  cells  in  tissues)   o Neutrophils   o Monocytes  and  their  derivatives  macrophages   o Lymphocytes  and  their  derivatives  plasma  cells   o Dendritic  cells   -­‐ They  can  be  distinguished  by  stained  tissue  samples  by  size  and  shape  of  nucleus     Immune  cell  names   -­‐ Granulocytes    -­‐  WBCs  whose  cytoplasm  contains  prominent  granules   –  names  of  different  cell  types  come  from  staining   properties  of  granules   -­‐ Basophils  granules  stain  dark  blue  with  basic  (alkaline)  dye   -­‐ Eosinophils  granules  stain  dark  pink  with  the  acid  due  eosin   -­‐ In  all  three  types  of  granulocytes  the  granule  contents  are  relased  from  cell  by  exocytosis  ( degranulation)   -­‐ Neutrophil  granules  do  not  stain  da rkly  with  standard  blood  stains  and  are  therefore  “neutral”   -­‐ Three  functional  groups:   o Phagocytes  WBC  that  engulf  and  ingest  their  targets  by  phagocytosis  (neutrophils,  eosinophils,  macrophages  and   monocytes  (macrophages  precursor)   o Cytotoxic  cells  named  because  they  kill  cells  they  attack   o Antigen-­‐presenting  cells  (APCs)  includes  macrophages,  monocytes,  certain  lymphocytes  and  dendritic  cells   -­‐ Basophils     o Rare  in  circulation  but  are  easily  recognized  in  stained  blood  smear  by  large  dark  blue  granules  in  cytoplasm     o Very  similar  to  mast  cells  of  tissues  and  both  cell  types  release  mediators  that  contribute  to  inflammation   o Granules  of  these  cells  contain  histamine   heparin  (an  anticoagulant  that  inhibits  blood  clotting),  cytokines  and   other  chemicals  involved  in  allergic  and  immune  response   o Mast  cells  are  concentrated  in  CT  of  skin,  lungs  and  GI  tract   o Ideally  situated  to  intercept  pathogens  that  are  inhaled  or  ingested  or  that  enter  though  breaks  in  epidermis   -­‐ Neutrophils   o Phagocytic  cells  that  typically   ingest  and  kill  5-­‐20  bacteria  during  programmed  life  span  of  one  or  two  days   o Most  abundant  WBC  (50 -­‐70%)  and  most  easily  identified  by  segmented  nucleus  material   o Form  in  bone  marrow  and  released  into  circulation   o Most  remain  in  blood  but  can  leave  circulatio n  if  attracted  to  an  extra vascular  site  of  damage  or  infection   o In  addition  to  ingesting  bacteria  and  foreign  particles,  neutrophils  release  a  variety  of  cytokines  including  fever -­‐ causing  pyrogens  and  chemical  mediators  of  inflammatory  response   -­‐ Eosinophils     o Easily  recognized  by  bright  pink -­‐staining  granules  in  cytoplasm   o These  immune  cells  are  associated  with  allergic  reactions  and  parasitic  di seases   o Few  found  in  peripheral  circulation  where  the  account  for  1 -­‐3%  of  all  leukocytes   o Lifespan  in  blood  ~6-­‐12  hours   o Most  functioning  eosinophils  found  in  digestive  tract,  lungs,  urinary  and  genital  epit  a  and  CT  of  skin o These  location  reflect  their  role  in  defense  against  parasitic  invaders   o They  are  known  to  attach  to  large  antibody -­‐coated  parasites  and  release  substances  from  their  granules  that   damage  or  kill  parasites     o Because  they  kill  pathogens,  they  are  classified  as  cytotoxic  cells   o Can  participate  in  allergic  reaction   –  the  contribute  to  inflammation  and  tissue  damage  by  releasing  toxic  enzymes,   oxidative  substances  and  protein  called  eosinophil-­‐derived  neurotoxin   -­‐ Monocytes  and  macrophages   o Monocytes  are  precursor  cells  of  tissue  macrophages   o Not  very  common  in  blood  (1 -­‐6%)   o Only  spend  8  hours  in  transit  from  bone  marrow  to  permanent  positions  in  tissue   o Once  out  of  blood,  monocyte  enlarge  and  differentiate  into  phagocytic   macrophages   o Some  tissue  macrophages  patrol  tissues  creeping  along  by  amoeboid  motion   o Others  find  location  and  remain  fixed  in  place   o Macrophages  are  primary  scavengers  within  tissue   o Large  and  more  effective  than  neutrophils,  ingesting  up  to  100  bacteria  during  lifespan   o They  also  remove  larger  particles  such  as  old  RBC  and  dead  neutrophils   o Because  they  are  APCs,  macrophages  play  an  important  role  in  development  of  acquired  immunity   o After  they  ingest  and  digest  molecular  or  cellular  antigens,  fragments  of  processed  antigen  are  inserted  into   macrophage  membrane  as  part  of  surface  protein  complexes   o In  addition,  dendritic  cells  and  lymphocytes  known  as  B  lymphocytes  also  act  as  APCs     -­‐ Lymphocytes   o Lymphocytes  and  their  derivatives  are  key  cells  that  mediate  acquired  immune  response  of  body   o Around  a  trillion  lymphocytes  at  one  time   –  only  5%  are  found  in  circulation  where  they  constitute  20 -­‐35%  of  all   WBC   o Most  lymphocytes  found  in  lymphoid  tissues  wh ere  they  most  likely  encounter  invaders   o Three  major  sub-­‐types  with  significant  differences  in  function  and  specificity   § B  lymphocytes  and  their  derivatives  are  responsible  for  antibody  production   § T  lymphocytes  and  natural  killer  cells  (NK  cells)  play  important  roles  in  defense  against  intracellular   pathogens  (IE  viruses)   -­‐ Dendritic  cells   o APCs  characterized  by  long,  thin  processes  that  resemble  neuronal  dendrites   o Found  in  skin  (Langerhans  cells)  and  various  organs   o When  they  recognize  and  capture  antigens,  they  migrate  to  secondary  lymphoid  tissues  where  they  present   antigen  to  lymphocytes   o Antigen  binding  activates  lymphocytes         Innate  immunity:  nonspecific  responses   -­‐ Body’s  first  line  of  defense  is  to  exclude  pathogens  by  physical  and  chemical  barriers   -­‐ If  barriers  fail  to  keep  invaders  out,  innate  immune  system  consists  of  patrolling  and  stationary  leukocytes  that  attack  and   destroy  invaders   -­‐ These  leukocytes  programmed  to  response  to  broad  range  of  material  that  they  recognize  as  foreign  which  is  why  innate   immunity  considered  nonspecific   -­‐ Innate  immunity  either  clears  infection  or  contains  it  until  acquired  immune  system  is  activated     Barriers  are  body’s  first  line  of  defense   -­‐ Physical  barriers  of  body  include  skin,  protective  mucous  lining  of  GI  and  genitour inary  tracts  and  ciliated  epithelium  of   respiratory  tract   -­‐ Digestive  and  respiratory  systems  are  most  vulnerable  to  microbial  invasion  because  these  regions  have  extensive  areas  of   thin  epithelium  in  direct  contact  with  external  environment   -­‐ In  women,  reproductive  tract  also  vulnerable   -­‐ In  respiratory  system,  inhaled  particulate  matter  is  trapped  by  mucus  lining  upper  respiratory  system   -­‐ Mucus  is  then  transported  upward  on  mucociliary  escalator  to  be  expelled  or  swallowed   -­‐ Swallowed  pathogens  may  be  disabled  by  acidity  of  stomach   -­‐ In  addition,  respiratory  tract  secretion  contain  lysozyme  an  enzyme  with  antibacterial  activity   -­‐ Lysozyme  attacks  cell  wall  components  of  unencapsulated  bacteria  and  breaks  them  down   –  but  cannot  digest  capsules  of   encapsulated  bacteria         Phagocytes  ingest  foreign  material   -­‐ Pathogens  that  get  past  physical  barriers  of  skin  and  mucus  are  dealt  with  first  by  innate  immune  response   -­‐ Key  element  of  innate  immune  response  is  ability  of  certain  leukocytes  to  recognize  molecules  that  are  unique  to   microorganisms  (pathogen -­‐associated  molecular  patterns  or  PAMPs)  and  initiate  an  appropriate  response   -­‐ PAMPs  bind  to  leukocyte  pattern  recognition  receptors  (PRRs)  that  activate  nonspecific  immune  response   -­‐ Initial  response  of  these  immune  cells  to  invaders  is  to  kill  them  or  ingest  them   -­‐ First,  patrolling  and  stationary  phagocytes  are  attracted  to  areas  of  invasion  by  chemical  signals  known  as   chemotaxins   -­‐ Chemotaxins  include  bacterial  toxins  or  cell  wall  components  that  act  as  PAMPs  as  wel l  as  products  of  tissue  injury  (fibrin   and  collagen  fragments)  that  mark  a  site  that  needs  defending   -­‐ Once  on  site,  activated  leukocytes  fighting  invaders  secrete  their  own  chemotaxins  to  bring  additional  leukocytes  to   infection  site   -­‐ If  pathogen  in  tissue,  circulating  phagocytes  leave  blood  (extravasation)  by  squeezing  through  pores  in  capillary   endothelium   -­‐ If  an  area  of  infection  attracts  large  number  of  phagocytes,  material  we  call  pus  may  form   o This  thick  whitish  to  greenish  substance  is  collection  of  livi ng  and  dead  neutrophils  and  macrophages  along  with   tissue  fluid,  cell  debris  and  other  remnant  of  immune  process   -­‐ Tissue  macrophages  and  neutrophils  are  primary  phagocytic  cells  responsible  for  defense   -­‐ Phagocyte  membranes  contain  receptors  that  recognize  ma ny  different  types  of  foreign  particles,  both  organic  and   inorganic   -­‐ In  macrophages,  pattern  recognition  receptors  known  as  toll-­‐like  receptors  (TLRs)  activate  cell  to  secrete  inflammatory   cytokines   -­‐ Phagocytes  ingest  unencapsulated  bacteria,  cell  fragments,  carbon  and  asbestos  particles  among  other  materials   -­‐ Phagocytosis  is  receptor-­‐mediated  event,  which  ensures  that  only  unwanted  particles  are  ingested   -­‐ In  simplest  phagocytic  reactions,  surface  molecules  on  pathogen  act  as  ligands  t hat  bind  directly  to  PRRs  on  phagocyte   membrane   -­‐ In  a  sequence  reminiscent  of  zipper  closing,  the  ligands  and  receptors  combine  sequentially,  so  that  the  phagocyte   surrounds  unwanted  foreign  particle   -­‐ The  process  is  aided  by  actin  filaments  that  push  arms  of  phagocytic  cell  around  invader   -­‐ The  ingested  particle  ends  up  in  cytoplasmic  vesicle  called   phagosome   -­‐ Phagosomes  fuse  with  intracellular  lysosomes  which  contain  powerful  chemicals  that  destroy  ingested  pathogens   -­‐ Lysosomal  contents  include  enzymes  and  oxidizing  agents  such  as  hydrogen  peroxide,  nitric  oxide  and  superoxide  anion   -­‐ Phagocytes  cannot  instantly  recognize  all  foreign  substances  because  pathogens  lack  markers  that  react  with  phagocyte   receptors   -­‐ The  antibodies  that  tag  encapsulated  bacteria  along  with  additional  plasma  proteins  are  known  collectively  as   opsonins   -­‐ In  body,  opsonins  convert  unrecognizable  particles  into  “food”  for  pathogens   -­‐ Opsonins  act  as  bridges  between  pathogens  and  phagocytes  by  binding  to  receptors  on  phagocytes       NK  cells  kill  infected  and  tumor  cells   -­‐ One  class  of  lymphocyte   –  natural  killer  cells  or  NK  cells  participates  in  innate  response  against  viral  infections   -­‐ NK  cells  act  more  rapidly  than  other  lymphocytes  in  a  response  that  can  be  measured  within  hours  of  primary  viral  infection   -­‐ NK  cells  recognize  virus -­‐infected  cells  and  induce  them  to  commit  suicide  by  apoptosis  before  virus  can  replicate   -­‐ Complete  elimination  of  the  virus  requires  activation  of  a  specific  immune  response   -­‐ NK  cells  also  attack  some  tumor  cells   -­‐ NK  cells  and  other  lymphocytes  secrete  various  antiviral  cytokines  including   interferons  which  were  named  for  their  ability   to  interfere  with  viral  replication   -­‐ Interferon-­‐alpha  (IFN-­‐α)  and  interferon-­‐beta  (IFN-­‐β)  target  host  cells  and  promote  synthesis  of  antiviral  proteins  to  prevent   viral  replication   -­‐ Interferon-­‐gamma  (IFN-­‐γ)  activates  macrophages  and  other  immune  cells     Cytokines  create  the  inflammatory  response   -­‐ Inflammation  is  hallmark  reaction  of  innate  immunity   -­‐ Inflammation  has  three  important  roles  in  fighting  infection  in  damaged  tissue   o Attracting  immune  cells  and  chemical  mediators  to  the  site   o Producing  a  physical  barrier  to  retard  the  spread  of  infection   o Promoting  tissue  repair  once  infection  is  under  control  (a  non -­‐immunological  function)   -­‐ Inflammatory  response  is  created  when  activated  tissue  macrophages  release  cytokines   -­‐ These  chemicals  attract  other  immune  cells,  increase  capillary  permeability  and  cause  fever   -­‐ Immune  cells  attracted  to  site  in  turn  release  their  own  cytokin es     Acute-­‐phase  proteins   -­‐ Time  following  injury  or  pathogen  invasion  (acute  phase)  body  responds  by  increasing  concentration  of  various  plasma   proteins   -­‐ Some  proteins  are  produced  mostly  by  liver  are  given  general  name   acute-­‐phase  proteins  –  they  include  molecules  that  act   as  opsonins,  antiprotease  molecules  that  help  prevent  tissue  damage  and  C -­‐reactive  protein  (CRP)   -­‐ Normally  level  of  acute -­‐phase  proteins  decline  to  normal  as  immune  response  proceeds  but  in  chronic  inflammation   diseases,  elevated  levels  of  a cute-­‐phase  proteins  may  persist     Histamine   -­‐ Found  primarily  in  granules  of  mast  cells  and  basophils  an  it  is  active  molecule  that  helps  initiate  inflammatory  response   when  mast  cells  degranulate   -­‐ Histamine’s  actions  bring  more  leukocytes  to  injury  site  to  ki ll  bacteria  and  remove  cellular  debris   -­‐ Histamine  opens  pores  in  capillaries  allowing  plasma  proteins  to  escape  into  interstitial  space  (local  edema  or  swelling)   -­‐ In  addition,  histamine  dilates  blood  vessels  increasing  blood  flow  to  area   -­‐ Result  of  histamine  release  is  hot,  red,  swollen  area  around  wound  or  infection  site   -­‐ Mast  cell  degranulation  triggered  by  different  cytokines  in  immune  response   -­‐ Because  mast  cells  are  concentrated  under  mucous  membranes  that  line  airways  and  digestive  tract,  inhalation  or   ingestion   of  certain  antigens  can  trigger  histamine  release   -­‐ Resultant  edema  in  nasal  passages  leads  to  symptom  of  seasonal  pollen  allergies   -­‐ Antihistamine  blocks  histamine     Interleukins   -­‐ Are  cytokines  initially  thought  to  mediate  communication  among  body’s   different  types  of  leukocytes   -­‐ Interleukin-­‐1  (IL-­‐1)  secreted  by  activated  macrophages  and  other  immune  cells   -­‐ Its  main  role  is  to  mediate  inflammatory  response  but  also  has  widespread  systemic  effects  on  immune  function  and   metabolism   -­‐ IL-­‐1  modulates  immune  response  by   o Altering  blood  vessel  endothelium  to  ease  passage  of  WBCs  and  proteins  during  inflammatory  response   o Stimulating  production  of  acute -­‐phase  proteins  by  liver   o Inducing  fever  by  acting  on  hypothalamic  thermostat.  IL-­‐1  is  a  known  pyrogen   o Stimulating  cytokine  and  endocrine  secretion  by  a  variety  of  other  cells     Bradykinin   -­‐ Kinins  are  a  group  of  inactive  plasma  proteins  that  participate  in  cascade  similar  to  coagulation  cascade   -­‐ The  end  product  of  kinin  cascade  is   bradykinin  a  molecule  that  has  same  vasod ilator  effect  as  histamine   -­‐ Bradykinin  also  stimulates  pain  receptors  creating  a  tenderness  associated  with  inflammation   -­‐ Pain  draws  brain’s  attention  to  injury     Complement  proteins   -­‐ Complement  is  a  collective  term  for  a  group  of  more  than  25  plasma  proteins   and  cell  membrane  proteins   -­‐ Complement  cascade  is  similar  to  blood  coagulation  cascade   -­‐ Various  intermediates  of  complement  cascade  act  as  opsonins ,  chemical  attractants  for  leukocytes  and  agents  that  cause   mast  cell  degranulation   -­‐ Complement  cascade  terminat es  with  formation  of  membrane  attack  complex  a  group  of  lipid-­‐soluble  proteins  that  insert   themselves  into  cell  membrane  of  pathogens  and  virus -­‐infected  cells  and  form  pores   -­‐ These  pores  allow  ions  to  enter  pathogen  cells  and  water  follows  by  osmosis  thus  c ells  swell  and  lyse           Lecture  3   Acquired  immunity:  antigen -­‐specific  responses   -­‐ Acquired  immune  responses  are  antigen -­‐specific  responses  which  body   recognizes  a  particular  foreign  substance  and  selectively  reacts  to  it   -­‐ Acquired  immunity  is  mediated   primarily  by  lymphocytes   -­‐ Three  main  types  of  lymphocytes:  B  lymphocytes,  T  lymphocytes  and  natural   killer  (NK)  cells   -­‐ Activated  B  lymphocytes  develop  into  plasma  cells  which  secrete  antibodies   -­‐ Activated  T  lymphocytes  develop  either  into  cells  that  attack  an d  destroy   virus-­‐infected  cells  or  into  cells  that  regulate  other  immune  cells   -­‐ NK  cells  attack  and  destroy  virus-­‐infected  cells  and  tumor  cells   -­‐ All  lymphocytes  secrete  cytokines  that  act  on  immune  cells,  on  non -­‐immune   cells  and  sometimes  on  pathogens   -­‐ Process  of  acquired  immunity  overlaps  with  process  of  innate  immunity   -­‐ Cytokines  released  by  inflammatory  response  attract  lymphocytes  to  site  of   an  immune  reaction   -­‐ Lymphocytes  release  additional  cytokines  that  enhance  inflammatory   response   -­‐ Acquired  immunity  can  be  subdivided  into  active  immunity  and  passive   immunity   -­‐ Active  immunity     o Occurs  when  body  is  exposed  to  pathogen  and  produces  its  own   antibodies   o Occurs  naturally  when  pathogen  invades  body  or  artificially  (vaccinations  containing  dead  or  disabled   pathogens)   -­‐ Passive  immunity   o Occurs  when  we  acquire  antibodies  made  by  another  animal   o The  transfer  of  antibodies  from  mother  to  fetus  across  placenta  or  injections  containing  antibodies       Lymphocytes  mediate  acquires  immune  response   -­‐ Cells  can  be  distinguished  from  one  another  by  membrane  receptors  which  make  each  lymphocyte  specific  for  particular   ligand   -­‐ All  lymphocytes  that  are  specific  for  given  ligand  form  a  group  known  as   clone   -­‐ At  birth,  each  clone  of  lymphocytes  represented  by  only  few  cells   naïve  lymphocytes   -­‐ Because  small  number  of  cells  in  each  naïve  clone  is  not  enough  to  fight  off  foreign  invaders   –  first  exposure  to  an  antigen   activates  appropriate  clone  and  stimulates  it  to  divide   -­‐ Clonal  expansion  creates  additional  cells  in  clone     -­‐ Naïve  cells  continue  to  be  generated  throughout  an  individual’s  lifetime   -­‐ Newly  formed  lymphocytes  in  clone  differentiate  into  effector  cells  and  memory  cells   -­‐ Effector  cells   o Carry  out  immediate  response  and  then  die  within  a  few  days   -­‐ Memory  cells   o Long  lived  and  continue  reproducing  themselves   -­‐ Second  and  subsequent  exposures  to  antigen  activate  memory  cells  and  cause  rapid  clonal  expansion  creating  quicker  and   stronger  secondary  response  to  antigen     B-­‐lymphocytes  become  plasma  cells  and  memory  cells   -­‐ B-­‐lymphocytes  (B  cells)  develop  in  bone  marrow   -­‐ Activated  B  lymphocytes  differentiate  primarily  into  specialized  cells  that   secrete  antibodies   -­‐ Antibodies  also  called  immunoglobulins  –  globular  proteins  that   participate  in  humoral  immune  response   -­‐ Mature  B  lymphocytes   insert  antibody  molecules  into  cell  membranes  so   that  antibodies  become  surface  receptors  marking  members  of  each  clone   -­‐ When  clone  of  B  cells  activates  in  response  to  antigen  exposure,  some  cells   differentiate  into  plasma  cells   –  effects  cells  for  B  lymphocytes   -­‐ Plasma  cells  do  not  have  antibody  proteins  bound  in  their  membrane   –   instead  they  synthesize  and  secrete  additional  antibody  molecules   -­‐ Plasma  cell  antibodies  form  humoral  immunity   –  the  soluble  antibodies  of   plasma   -­‐ After  each  invader  successfully  rep ulsed,  few  memory  cells  of  clone   remain  behind  waiting  to  respond  to  next  exposure  to  same  antigen   -­‐ Primary  immune  response     o Occurs  after  initial  exposure   –  slower  and  lower  in  magnitude   because  body  has  not  encountered  antigen  previously   -­‐ Secondary  immune  response   o Takes  place  after  second  and  subsequent  exposures   –  quicker  and   larger  because  it  is  enhanced  by  lymphocytes  that  carry  molecular  memory  of  first   exposure  to  antigen   -­‐ Existence  of  secondary  immune  response  is  what  makes  vaccinations  work   –  vaccine  contains  altered  pathogen  that  no  longer  harms  host  but  can  be   recognized  as  foreign  by  immune  cells   -­‐ Altered  pathogen  triggers  creation  of  memory  cells   specific  to  that  particular  pathogen   -­‐ If  vaccinated  person  is  later  infected  by  pathogen,  a  stronger  and   more  rapid  secondary  immune  response  results         Antibodies  are  proteins  secreted  by  plasma  cells   -­‐ Antibodies  or  immunoglobulins  (Ig)  are  divided  into  five  general  classes:  IgG,  IgA,  IgE,  IgM  and  IgD   -­‐ Antibodies  are  collectively  referred  to  as   gamma  globulins   -­‐ IgGs     o Make  up  75%  of  plasma  antibody  in  adults  because  they  are  produced  in  secondary  immune  responses   o Maternal  IgGs  cross  plac ental  membrane  and  give  infants  immunity  in  first  few  month  of  life     o IgGs  activate  complement   -­‐ IgA     o Found  in  external  secretions  (saliva,  tears,  intestinal  and  bronchial  mucus  and  breast  milk   o They  disable  pathogens  before  they  reach  internal  environment   -­‐ IgEs   o Associated  with  allergic  responses   o Mast  cell  receptors  bind  with  IgEs  and  antigen,  mast  cell  degranulate  and  release  chemical  mediators  (IE   histamine)   -­‐ IgM   o Associated  with  primary  immune  responses  and  with  antibodies  that  react  to  blood  group  antigens   o IgMs  activate  complement   -­‐ IgD   o Proteins  appear  on  surface  of  B  lymphocytes  along  with  IgM       -­‐ Antibody  proteins   o Has  four  polypeptide  chains  linked  into  Y  shape   o Two  sides  of  Y  are  identical  with  one   light  chain  attached  to  one  heavy  chain   o Two  arms  or  Fab  regions  form  antigen  binding  sites  that  confer  antibody’s  specificity   o Stem  of  Y-­‐shaped  antibody  molecule  known  as  Fc  region   o Fc  region  determines  Ig  class  to  which  antibody  belongs   o Hinge  region  between  arms  and  stem  allows  flexible  positioning  of  arms   o In  any  given  antibody  molecule,  two  light  chains  are  identical  and  two  heavy  chains  are  identical  –  however  chains   vary  widely  among  different  antibodies  and  are  specific  for  clone  from  which  antibody  comes   o Two  classes  of  immunoglobulins  (IgM  and  IgA)  secreated  as  polymers:  IgM  made  up  for  five  Y -­‐shaped  antibody   molecules  and  IgA  has  from  one  to  four  antibody  molecules   -­‐ Antibody  functions   o Most  antibodies  found  in  blood  (~20%  of  plasma  proteins)     o Most  effective  against  extracellular  pathogens  (bacteria),  some  parasites,  antigenic  macromoleciules  and  viruses   that  have  not  yet  invaded  host  cells   o Antibodies  are  not  toxic  and  can not  destroy  antigens  but  can  make  antigens  more  visible  to  immune  system  in   three  ways:   § Acting  as  opsonins  –  soluble  antibodies  coat  antigens  to  facilitate  recognition  and  phagocytosis  by   immune  cells   § Making  antigens  clump  –  antibody-­‐caused  clumping  of  antigens  enhances  phagocytosis   § Inactivating  bacterial  toxins  –  antibodies  bind  to  and  inactivate  some  toxins  produced  by  bacteria   o Antibodies  also  enhance  inflammation  by  acting   in  another  two  way:   § Activating  complement  –  antigen-­‐bound  antibodies  use  Fc  end  of  antibody  molecule  to  activate   complement   § Activating  mast  cells  –  Mast  cells  have  IgE  antibodies  attach  to  surface   –  when  antigens  or  complement   proteins  bind  to  IgE,  mast  cells  degranulate,  releasing  chemicals  that  mediat e  inflammatory  response   o Final  role  of  antibodies  is  to  activate  immune  cells   § Antigen-­‐bound  antibody  activates  immune  cells   -­‐  In  first  three  functions  listened,  antibody  binds  first  to   antigen  then  to  receptors  on  immune  cells.  Phagocytic  and  some  cytotoxic  cells  have  membrane   receptors  that  attract  Fc  region  of  antigen -­‐bound  antibodies.  Presence  of  single  Fc  receptors  to  recognize   different  antigens.  Instead  with  one  type  of  receptor  the  immune  cells  are  activated  by  any  antibody -­‐ bound  antigen   o If  immune  cell  is  phagocyte,  Fc  binding  initiates  phagocytosis   o If  immune  cell  is  cytotoxic  cell  (eosinophils  and  NK  cells)  Fc  binding  initiates  responses  that  kill  antibody -­‐bound  cell   o Nonspecific  response  of  cytotoxic  cells  is  called   antibody-­‐dependent  cell-­‐mediated  cytotoxicity   o In  the  case  of  B  lymphocytes,  antibodies  are  already  an  integral  part  of  lymphocyte   –  in  this  case,  antigen  binding   plus  cytokines  from  other  immune  cells  activate  cell  to  produce  memory  and  plasma  cells     -­‐ B  cell  activation   o Surface  of  each  B  lymphocyte  is  covered  with  many  antibody  molecules  whose  Fc  ends  are  inserted  into   lymphocyte  membrane   o Fab  regions  of  antibodies  are  then  free  to  bind  to  free -­‐floating  extracellular  antigens  (viruses  or  bacterial  toxins)   o B  cell  binding  neutralizes  pathogen  or  toxin   o Some  B  cells  then  differentiate  into  memory  cells  that  await  subsequent  invasion   -­‐ T  lymphocytes  use  contact-­‐dependent  signaling   o Antibodies  only  effective  against  extracellular  pathogens   o Once  pathogen  enters  host  cell,  it  can  no  longer  be  “seen”  by   humoral  immune  system   o Defending  body  against  intracellular  pathogens  is  role  of  T  lymphocytes  which  carry  out   cell-­‐mediated  immunity   o In  this  process,  T  cells  bind  to  cells  that  display  foreign  antigen  fragments  as  part  of  a   major  histocompatibility   complex  (MHC)  on  surface   o T  lymphocytes  develop  in  thymus  gland  from  immature  precursor  cells  that  migrate  from  bone  marrow   o Mature  T  cells  bind  to  MHC -­‐APCs  with  help  of  T-­‐cell  receptors  on  T-­‐cell  membrane   o T-­‐cell  receptors  are  not  antibodies  (as  B -­‐cell  receptors  are)  although  proteins  of  two  receptor  types  are  closely   related   o Also,  T  cells  cannot  bind  to  free -­‐floating  antigens  as  B  cells  do   o Instead  T  cells  can  only  bind  to  MHC-­‐antigen  complexes  on  surface  of  target  cell         Lecture  4   -­‐ MHC  and  antigen   o Major  histocompatibility  complexes  are  a  family  of  membrane  protein  complexes  encoded  by  specific  set  of  genes   o Every  nucleated  cell  of  body  has  MHC  on  its  membrane   o MHC  proteins  combine  with  fragments  of  antigens  that  have  been  digested  within  cell -­‐antigens  complex   is  inserted  into  cell  membrane  by  exocytosis   o Free  antigen  in  ECF  cannot  simply  bind  to  unoccupied  MHC  receptors  on  cell  surface   o There  are  two  types  of  MHC  molecules   § MHC  class  I  molecules     • Found  on  all  nucleated  host  cells   • When  viruses  and  bacteria   invade  cell,  they  are  digested  into  peptide  fragments  and  loaded  onto   MHC-­‐I  “platforms”   • If  cytotoxic  T  cCll  (T  cell)  encounters  host  cell  with  foreign  antigen  fragmenC  on  its  MHC -­‐I,  T  cell   recognizes  target  as  either  virus-­‐infected  cell  or  as  tumor  cell  and  kills  it  to  prevent  reproduction   § MHC  class  II  molecules   • Found  primarily  on  APCs:  macrophages,  B  lymphocytes  and  dendritic  cells   • When  immune  cell  engulfs  and  digests  an  antigen,  fragments  are  returned  to  immune  cell   membrane  combined  with  MHC -­‐II  proteins   • If  helper  T  Hell  (T  cell)  encounters  an  APC  with  foreign  antigen  fragment H on  its  MHC -­‐LL,  T  cell   responds  by  secreting  cytokines  that  enhance  immune  response   o All  MHC  proteins  are  related  but  vary  from  person  to  person  due  to  variable  alleles  a   person  can  inherit   o MHC  are  one  reason  tissue  cannot  be  transplanted  from  one  person  to  another  without  first  establishing   compatibility   -­‐ Cytotoxic  T  cells   o Cytotoxic  T  (T )  cells  attack  and  destroy  cells  that  display  MHC -­‐I-­‐antigen  complexes   C o This  may  be  extreme  response,  but  it  presents  reproduction  of  intracellular  invaders  (viruses,  some  parasites  and   some  bacteria)   o Kill  targets  by     § First  releasing  a  cytotoxic  pore -­‐forming  molecule  called  perforin  along  with  granzymes,  enzymes  related   to  digestive  enzymes  trypsin  and  chymotrypsin.  When  gramzymes  enter  target  cell  through  perforin   channels,  they  activate  enzyme  cascade  that  induces  cell  to  commit  suicide  (apoptosis)   § Second,  cytotoxic  T  cells  can  induce  apoptosis  by  activating   Fas  a  “death  receptor”  protein  on   target  cell   membrane  that  is  linked  to  enzyme  cascade   -­‐ Helper  T  (TH)  cells   o Do  not  directly  attack  pathogens  and  infected  cells  but  play  essential  role  in  immune  response  by  secreting   cytokines  that  influence  other  cells   o Cytokines  secreted  by  T Hinclude   § Interferon-­‐gamma  (IFN-­‐γ)  which  activates  macrophages   § Interleukins  that  activate  antibody  production  and  cytotoxic  T  lymphocytes   § Colony-­‐stimulating  factors  which  enhance  leukocyte  production   § Interleukins  that  support  actions  of  mast  cells  and  eosinophils   o Helper  T  cells  also  bind  to  B  cells  and  promote  differentiation  into  plasma  cells  and  memory  B  cells     Immune  response  pathways   -­‐ Innate  response  starts  first  and  is  reinforced  by  more  specific  acquired  response   -­‐ Two  pathways  are  interconnected  (cooperation  and   communication  is  important)     Bacterial  invasion  causes  inflammation   -­‐ Entry  of  bacterial  sets  of  several  interrelated  reactions   o Activity  of  complement  system     § Components  of  bacterial  cell  wall  activate  complement  system   § Some  complement  proteins  are  chemical   signals  (chemotaxins)  that  attract  leukocytes  from  circulation  to   help  fight  infection     § Others  act  as  opsonins  to  enhance  phagocytosis   § Complement  also  causes  degranulation  of  mast  cells  and  basophils   § Cytokines  secreted  by  mast  cells  act  as  additional  chemo taxins  attracting  more  immune  cells   § Vasoactive  chemicals  (IE  histamine)  dilate  blood  vessels  and  increase  capillary  permeability   § Enhanced  blood  supply  to  site  creates  redness  and  warmth  of  inflammation   § Plasma  proteins  that  escape  into  interstitial  space  pu ll  water  with  them  leading  to  tissue  edema   § Complement  cascade  ends  with  formation  of  membrane  attack  complex  molecules  that  insert  themselves   into  bacterial  wall  of  unencapsulated  bacteria   § Subsequent  entry  of  ions  and  water  lyses  bacteria  aided  by  enzyme  l ysozyme   § This  is  purely  chemical  process  that  does  not  involve  immune  cells   o Activity  of  phagocytes   § If  bacteria  not  encapsulated,  macrophages  can  begin  to  ingest  bacteria  immediately   § But  if  bacteria  encapsulated,  antibodies  must  coat  capsule  before  bacteria   can  be  ingested  by  phagocytes   § Opsonins  enhance  process  for  bacteria  that  are  not  encapsulated   § Molecules  that  act  as  opsonins  include  complement,  acute -­‐phase  proteins  and  antibodies   o Role  of  acquired  immune  system   § Some  elements  of  acquired  immune  response   are  called  in  bacterial  infections   § If  antibodies  against  bacteria  are  already  present,  they  enhance  innate  response  by  acting  as  opsonins   and  neutralizing  bacterial  toxins   § APCs  that  digest  bacteria  can  then  move  to  secondary  lymphoid  tissues  there  they  pre sent  antigen  to   memory  cells  to  initiate  more  antibody  production   § If  infection  is  novel  one,  some  bacteria  activate  naïve  B  cells  and  APCs  present  bacterial  fragments  to   helper  T  cells  to  activate  them   § This  triggers  cytokine  secretion  from  T Hcells,  B  cell  clonal  expansion,  antibody  production  by  plasma  cells   and  formation  of  memory  B  and  T cells   H   o Initiation  of  repair   § If  initial  wound  damaged  BVs,  platelets  and  proteins  of  coagulation  cascade  are  also  recruited  to  minimize   damage   § Once  bacteria  are  removed  b y  immune  response,  injured  site  is  repaired  under  control  of  growth  factor   and  other  cytokines         Viral  infections  require  intracellular  defense   -­‐ When  viruses  invade  body   o First  they  encounter  an  extracellular  phase  of  immune  response  similar  to  bacteria   o In  early  stages  of  viral  infection,  innate  immune  responses  and  antibodies  can  help  control  invasion  of  virus   o Once  viruses  enter  host’s  cells,  humoral  immunity  in  form  of  antibodies  is  no  longer  effective   o Cytotoxic  T  lymphocytes  (and  to  lesser  degree  NK  cell s)  are  main  defense  against  intracellular  viruses   o When  cells  recognize  infected  host  cells,  they  destroy  them   o Antibodies  can  play  important  defensive  role  in  early  extracellular  stages  of  viral  infection   § Antibodies  act  as  opsonins  coating  viral  particles  to  make  them  better  targets  for  macrophages.  Antibody -­‐ bound  viruses  are  prevented  from  entering  their  target  cells   –  however  once  virus  is  inside  host  cells,   antibodies  are  no  longer  effective   § Macrophages  that  ingest  viruses  insert  fragments  of  viral  antigen  into  MHC-­‐II  molecules  on  membrane.   Macrophages  also  secrete  a  variet y  of  cytokines.  Some  of  these  cytokines  initiate  inflammatory  response.   They  produce  interferon-­‐α,  which  causes  host  cells  to  make  antiviral  proteins  that  keep   viruses  from   replicating.  Other  macrophage  cytokines  stimulate  NK  cells  and  help  T  cells   § Helper  T  cells  bind  to  viral  antigen  on  macrophage  MHC -­‐II  molecules.  ActivaHed  T  cells  then  secrete   cytokines  to  stimulate  B  lymphocytes  and  cytotoxic  cells   § Previous  exposure  to  virus  creates  memory  B -­‐lymphocytes  with  viral  antibody  on  their  surface.  This   second  exposure  to  virus  activates  memory  cells  and  promotes  development  of  plasma  cells  resulting  in   additional  antibody  production   § Cytotoxic  T  cells  use  viral  antig en-­‐MHC-­‐I  complexes  to  recognize  infected  host  cells.  When  T  cells  bind  to   C infected  host  cell,  they  secrete  contents  of  their  granules  onto  cell  surface.  Perforin  molecules  insert   pores  into  host  cell  membrane  so  that  granzymes  can  enter  cell,  inducing  it   to  commit  suicide  and   undergo  apoptosis.  Destruction  of  infected  host  cells  is  key  step  in  halting  replication  of  invading  viruses     -­‐ NK  cells  recognize  virally  infected  cells  by  different  process   -­‐ Some  viruses  cause  host  cell  to  withdraw  MHC -­‐I  receptors  from  cell  surface  in  effort  to  hide  from  immune  system   -­‐ NK  cells  recognize  infected  host  cells  lacking  MHC -­‐I  complexes  and  kill  them  by  process  similar  to  one  described Cfor  T  cells     Antibodies  and  viruses   -­‐ Many  viruses  mutate  constantly  and  protein  coat  formin g  primary  antigen  may  change  significantly  over  time   -­‐ If  protein  coat  changes,  antibody  may  no  longer  recognize  it   -­‐ Rapid  mutation  of  viruses  also  reason  that  no  cure  for  HIV  yet   –  virus  that  causes  AIDS   -­‐ HIV  infects  cells  of  immune  system  particularly  T  lymp hocytes,  monocytes  and  macrophages   -­‐ When  HIV  wipes  out  helper  T  cells,  cell -­‐mediated  immunity  response  in  AIDS  leaves  pts  susceptible  to  variety  of  viral,   bacterial,  fungal  and  parasitic  infections     Specific  antigens  trigger  allergic  responses   -­‐ Allergy  –  inflammatory  immune  response  to  nonpathogenic  antigen   -­‐ Allergic  inflammatory  responses  can  range  from  milk  tissue  damage  to  fatal  reaction   -­‐ Immune  response  in  allergies  is  called  sensitivity  or  hypersensitivity  to  antigen   -­‐ Immediate  hypersensitivity  reactions  mediated  by  antibodies  and  occur  within  minutes  of  exposure  to  antigens  which  are   called  allergens   -­‐ Delayed  hypersensitivity  reaction  mediated  by  helper  T  cells  and  macrophages  and  may  take  several  days  to  develop   -­‐ Immediate  hypersensitivity  reaction  to  pollen   o Initial  step  –  first  exposure  or  sensitization  phase  is  equivalent  to  primary  immune  response:  allergen  is  ingested   and  processed  by  APC  (IE  macrophage  which  in  turn  activates  helper  T  cell)   o TH  cell  activates  B  lymphocytes  that  have  bound  all ergen   o Results  in  plasma  production  of  antibodies  (IgE  and  IgG)  to  allergen   o IgE  antibodies  are  immediately  bound  by  their  Fc  ends  to  surface  of  mast  cells  and  basophils   o Memory  T  and  memory  B  cells  store  record  of  initial  allergen  exposure   o Upon  re-­‐exposure,  equivalent  to  secondary  immune  response,  body  reacts  more  strongly  and  more  rapidly   o Allergen  binds  to  IgE  already  present  on  mast  cells  triggering  immediate  release  of  histamine,  cytokines  and  other   mediators   o Type  of  allergic  reaction  depends  on  antibody  o r  immune  cell  involved   o Allergen  binding  to  IgE  is  most  common  response  to  inhaled,  ingested  or  injected  allergens   o When  allergens  bind  to  IgE  antibodies  on  mast  cells,  cells  degranulate  releasing  histamine  and  other  cytokines   o Result  is  inflammatory  reaction   o Severity  of  reaction  varies  ranging  from  localized  reactions  near  site  of  allergen  entry  to  systemic  reactions  (total   body  rash)   o Most  sever  IgE-­‐mediated  allergic  reaction  is  called   anaphylaxis   o Massive  release  of  histamine  and  other  cytokines  causes  widesp read  vasodilation,  circulatory  collapse  and  severe   bronchoconstriction  –  can  cause  death           Lecture  5   Platelets  and  coagulation           -­‐ Stopping  blood  loss  involves  several  steps   o First,  pressure  in  vessel  must  be  decreased  long  enough  to  create  secure   mechanical  seal  in  form  of  blood  clot   o Once  clot  is  in  place,  blood  loss  has  been  stopped,  body’s  repair  mechanisms  can  take  over   o Then  as  wound  heals,  enzymes  gradually  dissolve  clot  while  scavenger  WBCs  ingest  and  destroy  debris   Platelets  are  small  fragments  of  cells   -­‐ Platelets  form  from  megakaryocytes   -­‐ Megakaryocytes  develop  in  size  by  mitosis  up  to  seven  times  without  undergoing  nuclear  or  cytoplasmic  division   -­‐ Result  is  polyploidy  cell  with  lobbed  nucleus   -­‐ Outer  edges  of  marrow  megakaryocytes  extend  through   endothelium  into  lumen  of  marrow  blood  sinuses  where   cytoplasmic  extensions  fragment  into  disk -­‐like  platelets   -­‐ Platelets  are  smaller  than  RBCs,  colorless  and  no  nucleus   -­‐ Their  cytoplasm  contains  mitochondria,  SER  and  many  granules  filled  with  clotting  protei ns  and  cytokines   -­‐ Typical  life  span  ~10  days   -­‐ Already  present  in  blood  but  not  active  unless  damage  occurs  to  walls  of  circulatory  system     Hemostasis  prevents  blood  loss  for  damaged  vessels   -­‐ Hemostasis  –  process  of  keeping  blood  within  damaged  BV   -­‐ Three  major  steps:  vasoconstriction,  temporary  blockage  of  break  by  platelet  plug  and  blood  coagulation  or  formation  of   clot  that  seals  hole  until  tissues  are  repaired   -­‐ First  step  is  immediate  constriction  of  damaged  vessels  caused  by  vasocontrictive  paracrines  release d  by  endothelium   -­‐ Vasoconstriction  temporarily  decreases  blood  flow  and  pressure  within  vessel   -­‐ Rapidly  followed  by  second  step,  mechanical  blockage  of  hole  by   platelet  plug   -­‐ Plug  forms  as  platelets  stick  to  exposed  collagen  ( platelet  adhesion)  and  become  activated,  releasing  cytokines  into  area   around  injury   -­‐ Platelet  factors  reinforce  local  vasoconstriction  and  activate  more  platelets  which  stick  to  one  another  ( platelet   aggregation)  to  form  loose  platelet  plug   -­‐ Simultaneously,  exposed  collagen  and   tissue  factor  initiate  third  step  –  a  series  of  reactions  known  as   coagulation  cascade   -­‐ Cascade  is  series
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