CHAPTER

 16:  HYPERSENSITIVITY  II  AND  III   • Risk  of  kidney  damage  and  toxic  effects  of  heme  
GUILLERMO,  JANINA  SUZETTE      
  B. Drug-­‐Induced  Reaction  
INTRODUCTION   • Certain  drugs  act  as  haptens  and  combine  with  cells  
• Type  II  and  type  III  reactions  are  mediated  by   or  with  other  circulating  blood  constituents.  
antibodies  belonging  to  the  IgG,  IgM,  and,  in  some   • When  antibody  combines  with  cells  coated  with  the  
cases,  IgA  or  IgE  isotypes.   drug,  cytotoxic  damage  results.  
• Type  II  hypersensitivity  reactions  are  the  result  of   • Injury  depends  on  the  type  of  drugs  
the  binding  of  antibody  directly  to  an  antigen  on  the   o Chlorampenicol  –  binds  to  WBC    
surface  of  a  cell.   o Phenacetin,  Chlorpromazine  –  binds  to  RBC  
• Type  III  reactions  are  the  result  of  deposition  of    
antigen–antibody  immune  complexes.   C. Rhesus  Incompatibility  reaction  
• Antigens  involved  are  often  self  antigens   • Rh−  mothers  can  become  sensitized  to  Rh  antigens  
  during  their  first  pregnancy  with  a  child  whose  RBCs  
TYPE  II  HYPERSENSITIVITY    
• The  targeted  cell  is  either  damaged  or  destroyed   are  Rh+.  
through:   • If  the  mother  is  thereby  sufficiently  immunized  to  
a. Complement  mediated  reaction   produce  anti-­‐Rh  antibody  of  the  IgG  isotype,  
b. Antibody-­‐dependent  cell  mediated  toxicity   subsequent  Rh+  fetuses  will  be  at  risk.  
c. Antibody  mediated  cellular  dysfunction   • Result  is  progressive  destruction  of  the  fetal  or  
  newborn  RBCs,  with  the  pathologic  consequences  
COMPLEMENT  MEDIATED  REACTIONS   that  come  from  decreased  transport  of  oxygen  and  
• Antibodies  react  with  cell  membrane  self-­‐antigens   from  increased  bilirubin  from  the  products  of  the  
and  this  is  followed  by  complement  fixation  that   breakdown  of  hemoglobin,  a  condition  known  as  
leads  to  lysis  of  cells   Erythroblastosis  fetalis  
• Blood  cells  are  commonly  affected  by  this    
mechanism   D. Reactions  involving  the  cell  membrane  receptors  
• Myasthenia  gravis  
ANTIBODY  DEPENDENT  CELL  MEDIATED  CYTOTOXICITY   o Antibody-­‐mediated  cellular  dysfunction  due  to  
reactivity  with  a  cell  receptor  is  seen  in  the  
• Utilizes  Fc  receptors  expressed  on  many  cell  types   autoimmune  disease,  Myasthenia  gravis  
(NK  cells,  macrophage,  neutrophils,  eosinophil)  as  a   o Autoantibodies  react  with  acetylcholine  
means  of  bringing  these  cells  into  contact  with   receptors  in  motor  end  plates  impairing  
antibody-­‐coated  target  cells.   muscular  transmission  
• ADCC-­‐mediated  lysis  of  target  cells  is  analogous  to   • Grave’s  disease  
that  of  cytotoxic  T  cells  and  involves  the  release  of   o Autoantibodies  serves  as  agonist  causing  
cytoplasmic  granules  (modified  lysosomes)   stimulation  of  target  cells,  TSH  receptors  
containing  perforins  and  granzymes.     resulting  in  hyperthyroidism  
 
ANTIBODY  MEDATED  CELLULAR  DYSFUNCTION   E. Reactions  involving  other  Cell  membrane  
determinants  
• Some  antibodies  (autoantibodies)  bind  to  cell  
• Anti-­‐RBC  autoantibody  
surface  receptors  that  are  critical  for  the  functional  
o RBC  hemolysis  or  mediated  by  phagocytosis  
integrity  of  the  cell.  
following  the  binding  of  phagocytes  to  the  Fc  
• Binding  impairs  or  dysregulate  cell  function  without  
regions  of  autoantibodies  or  C3b  bound  to  
causing  cell  injury  or  inflammation.  
these  cells.  
o May  lead  to  progressive  anemia  
EXAMPLES  OF  TYPE  II  HYPERSENSITIVITY  
• Immune  thrombocytopenia  purpura  (ITP)  
A. Transfusion  reactions   o Antibodies  directed  to  platelets  result  in  
• Complement  mediated  cytotoxic  reactions   platelet  destruction  by  complement  or  
• Lysis  of  RBC  and  destructive  action  of  complement   phagocytic  cells  with  Fc  or  C3b  receptors.  
on  their  membranes   o Bleeding  
 
• Good  pasture  syndrome   • Platelets  form  microthrombi  and  contribute  to  
o Antibodies  may  form  against  other  tissue   cellular  proliferation  by  releasing  platelet-­‐derived  
components  such  as  a  type  of  basement   growth  factor  (PDGF).  
membrane  collagen  particularly  prevalent  in  the  
lung  and  kidneys   SYSTEMIC  IMMUNE  COMPLEX  DISEASE  
• Involves  3  phases:  
TYPE  III  HYPERSENSITIVITY   (1) Antigen-­‐antibody  complex  form  in  the  
• Circulating  immune  complexes  composed  of   circulation  
antibodies  bound  to  foreign  antigens  are  removed   (2) Deposition  of  immune  complex  to  various  
by:   tissues  
o Phagocytic  cells     (3) Inflammatory  reactions  occur  
o By  binding  of  C3b  and  transporting  them  to  the    
liver  removed  by  Kupffer  cell   • Several  factors  help  to  determine  whether  immune  
o Histidine  rich  glycoprotein  (HRG)     complex  formation  will  lead  to  tissue  deposition  
! Immune  complex  clearing  mechanism   and  disease:  
! Synthesized  in  the  liver   o Size  of  complex:  
! Readily  available   ! Very  large  complexes  formed  under  
! Also  clear  apoptotic  cells     conditions  of  antibody  excess  are  
• Immune  complex  deposition  in  the  kidneys,  skin,   rapidly  removed  from  the  circulation  by  
joints,  choroid  plexus,  and  ciliary  artery  of  the  eye.   phagocytic  cells  and  therefore  are  
• Generation  of  immune  complex:   harmless.  
o Exogenous:  bacteria  and  viruses  or,  as  in  the   ! Small  or  intermediate  complexes  
case  of  the  Arthus  reaction,  by  intradermal  or   circulate  for  longer  periods  of  time  and  
intrapulmonary  exposure  to  large  amounts  of   bind  less  avidly,  therefore,  small-­‐to-­‐
foreign  protein.   intermediate  sized  immune  complexes  
o Endogenous:  DNA  –  can  serve  as  target,  in  the   tend  to  be  more  pathogenic  
case  of  SLE.   o Integrity  of  the  mononuclear  phagocytic  
• The  mechanism  of  injury  seen  in  immune  complex-­‐   system.  
mediated  disease  is  the  same  regardless  of  which   ! An  intrinsic  dysfunction  of  this  system  
pattern  of  immune  complex  deposition  is  seen   increases  the  probability  of  persistence  
• Central  to  the  pathogenesis  of  tissue  injury  is  the:   of  immune  complexes  in  the  circulation.  
o Fixation  of  complement  by  the  immune    
complexes   • Serum  sickness  
o Activation  of  the  complement  cascade  -­‐  results   o Administration  of  large  quantities  of  
in  increased  vascular  permeability  and   heterologous  serum  from  another  species  
stimulates  the  recruitment  of   causes  the  recipient  to  synthesize  anti-­‐  bodies  
polymorphonuclear  phagocytes  that  release   to  the  foreign  immunoglobulin,  leading  to  the  
lysosomal  enzymes  that  can  damage  the   formation  of  antigen–antibody  complexes  that  
glomerular  basement  membrane.   result  in  the  clinical  symptoms  associated  with  
o Release  of  biologically  active  fragments   serum  sickness.  
• IgG  is  the  immunoglobulin  isotype  usually  involved   o The  classic  clinical  manifestations  consist  of  
in  type  III  hypersensitivity  reactions,  but  IgM  can   fever,  arthralgia,  lymphadenopathy,  and  skin  
also  be  involved.   eruption  
• IgG  Fc  receptors  (CD16)  expressed  on  leukocytes    
play  a  pivotal  role  in  initiating  type  III  reaction   • Rheumatic  fever  
cascades.   o Caused  by  group  A  streptococci  and  it  involves  
• C3a  and  C5a  generated  by  complement  activation   inflammation  and  damage  to  heart,  joints,  and  
induce  mast  cells  and  basophils  to  release   kidneys.  
arachidonic  acid  metabolites  and  chemokines  that   o A  variety  of  antigens  in  the  cell  walls  and  
attract  additional  basophils,  eosinophils,   membranes  of  streptococci  have  been  shown  to  
macrophages,  and  neutrophils  into  the  area.   be  cross-­‐reactive  with  antigens  present  in  
• Macrophages  are  stimulated  to  release  tumor   human  heart  muscle,  cartilage,  and  glomerular  
necrosis  factor-­‐α  (TNF-­‐α)  and  interleukin-­‐1  (IL-­‐1)   basement  membrane.  
 o Antibody  to  the  streptococcal  antigens  binds  to  
these  components  of  normal  tissue  and  induces  
inflammatory  reactions  via  a  pathway  similar  to  
that  described  above.  
 
• Rheumatoid  arthritis  
o Evidence  for  production  of  Rheumatoid  factor  
o An  IgM  autoantibody  that  binds  to  the  Fc  
portion  of  normal  IgG.  
o These  immune  complexes  participate  in  causing  
inflammation  of  joints  and  the  damage  
characteristic  of  this  disease.  

LOCALIZED  IMMUNE  COMPLEX  DISEASE  

• Arthus  reaction,  the  localized  immune  complex  
reaction  
• When  such  preformed  antibodies  come  in  contact  
with  antigen  at  the  appropriate  concentrations  
(antibody  excess),  in  or  near  vessel  walls  (venules),  
insoluble  immune  complexes  form  and  accumulate  
as  they  would  on  a  gel-­‐diffusion  plate.  
• The  end  result  is  rupture  of  the  vessel  wall  and  
hemorrhage,  accompanied  by  necrosis  of  local  
tissue  
• Clinical  example  of  Arthur  reaction,  type  III:  
Farmer’s  lung  
o Patient  with  extrinsic  allergic  alveolitis    
o In  sensitive  individuals,  exposure  to  moldy  hay  
leads  to  severe  respiratory  distress  or  
pneumonitis  within  6–8  hours.  
o Affected  individuals  have  made  large  amounts  of  
IgG  antibody  specific  for  the  spores  
o Inhalation  of  the  bacterial  spores  leads  to  a  
reaction  in  the  lungs  that  resembles  the  Arthus  
reaction  seen  in  skin,  namely,  the  formation  of  
antigen–antibody  aggregates  and  consequent  
inflammation.