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Construction of a new strain of mice that lack mast cells and set-up of a mouse asthma model

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Construction of a new strain of mice that lack mast cells and set-up of a mouse asthma model

Behdad Zarnegar

Asthma  is  a  chronic  inflammatory  disease  of  the  airways  which  causes  recurrent  episodes  of  coughing,  wheezing,   chest   tightness   and   shortness   of   breath   in   susceptible   individuals.   Today,   asthma   is   one   of   the   most   common   chronic   diseases   affecting   approximately   300   million   people   globally   and   about   5%   of   the   adult   Swedish   population.   Normally   when   foreign   substances   such   as   pathogens   enter   the   body,   the   host   immune   system   recognizes  them  and  starts  to  produce  specific  proteins  so-­‐called  immunoglobulins  (Ig)  or  antibodies  against  them.  

These   are   capable   of   neutralizing   foreign   substances.   However,   individuals   that   are   genetically   susceptible   to   allergy,   produce   immunoglobulins   of   IgE   type   against   one   or   more   harmless   non-­‐infectious   environmental   substances,   termed   allergens.   These   allergen-­‐specific   IgE   molecules   can   then   bind   strongly   to   their   receptors   (FcεRI)  that  are  present  on  the  surface  of  mast  cells.  This  process  is  called  sensitization.  In  sensitized  individuals,  re-­‐

exposure  to  the  same  allergen  leads  to  crosslinking  of  FcεRI-­‐bound  IgE  with  allergen.  This  activates  mast  cells  to   release  proinflammatory  substances.  

Even  though  mast  cells  are  well  known  for  their  important  role  in  allergic  diseases,  the  exact  role  of  mast  cells  in   pathogenesis  of  allergic  asthma  is  yet  to  be  understood.  Today,  the  best  approach  to  investigate  the  contribution   of  mast  cells  is  to  study  their  roles  in  a  mouse  model  of  allergic  asthma  using  mice  that  lack  mast  cells.  Currently,   the  most  widely  used  mast  cell-­‐deficient  mice  are  those  that  have  mutation  in  the  gene  encoding  c-­‐Kit.  This  cell   surface  receptor  is  required  for  survival  and  development  of  mast  cells.  However,  the  main  disadvantage  of  these   mice  with  regard  to  allergic  asthma  modeling  is  that  they  are  available  on  mouse  strains  that  do  not  have  a  genetic   tendency  to  react  with  allergy  toward  foreign  substances.  Therefore,  one  aim  of  this  study  was  to  create  mast  cell-­‐

deficient  mice  on  a  mouse  strain  that  have  a  genetic  predetermined  tendency  to  develop  allergic  reactions.  In  the   present  study  we  created  such  mast  cell-­‐deficient  mice  and  used  different  techniques  to  prove  that  they  lacked   mast  cells.    

Moreover,  since  mice  do  not  spontaneously  develop  asthma,  an  artificial  asthma-­‐like  reaction  needs  to  be  induced   in   the   airways.   This   can   be   achieved   by   exposing   mice   to   inhaled   allergen   which   consequently   leads   to   development  of  lung  inflammation  as  a  result  of  migration  of  immune  cells  into  the  lung.  Accordingly,  we  set-­‐up  a   model  of  allergic  asthma  using  a  common  human  allergen,  house  dust  mite,  which  was  exposed  to  the  airways.  

Using  this  model,  we  were  able  to  induce  allergic  airway  inflammation  in  normal  mice  characterized  by  a  massive   increase  of  inflammatory  cells  including  eosinophils,  lymphocytes  and  macrophages  in  the  lung.  This  experimental   model   if   combined   with   mast   cell-­‐deficient   mice   which   have   a   tendency   to   react   with   allergy   toward   foreign   substances  provides  an  excellent  tool  to  study  the  roles  of  mast  cells  in  pathogenesis  of  allergic  asthma.  Because   the  type  of  allergen,  the  route  of  exposure  and  the  genetic  predisposition  of  mouse  strain  resembles  the  onset  of   allergic  asthma  in  humans  as  closely  as  possible.    

 

Degree  project  in  biology,  Master  of  science  (2  years),  2012   Examensarbete  i  biologi  30  hp  till  masterexamen,  2012  

Biology  Education  Centre  and  Department  of  Medical  Biochemistry  and  Microbiology,  Uppsala  University,  Sweden   Supervisor:  Jenny  Hallgren  Martinsson

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