PPT Casali "Storia naturale della TB"


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PPT Casali "Storia naturale della TB"

  1. 1. Università  degli  Studi  di  Perugia   Facoltà  di  Medicina  e  Chirurgia   Lucio  Casali   Mariano  E.  Crapa   Ca<edra  di  Mala=e  dell’Apparato   Respiratorio   Storia  naturale  della   Tubercolosi   Milano,  21  marzo  2014  
  2. 2. Genetic epidemiology of TB The analysis of the epidemic wave of tuberculosis observed in Europe in the XVIII and XIX centuries, have shown mortality frequencies that reach the 2% per year. In particular, in absence of chemotherapy, a spike can be observed in the first 50-100 years, followed by a slow decline in the next 200-250 years. These data support the hypothesis, developped by E.R.N. Grigg, that in the first phase of the epidemic wave the most susceptible portion of population has been eliminated (rappresenting up to 20% of the whole population). Grigg ERN. Am Rev Tuberc 1958; 78: 426-53
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  4. 4. The   life   cycle   of   M.   tuberculosis.   The   infecLon   is   iniLated  when  Mtb  bacilli,  present  in  exhaled   droplets   or   nuclei,   are   inhaled   and   phagocytosed   by   resident  alveolar  macrophages.  The  resulLng   proinflammatory  response  triggers  the  infected  cells  to   invade  the  subtending  epithelium.  This  response   also   leads   to   the   recruitment   of   monocytes   from   the   circulaLon,  as  well  as  extensive  neovascularizaLon  of   the  infecLon  site.  The  macrophages  in  the  granulomas   differenLate  to  form  epithelioid  cells,  mulLnucleate   giant  cells,  and  foam  cells  filled  with  lipid  droplets.  The   granuloma  can  become  further  straLfied  by  the   formaLon   of   a   fibrous   cuff   of   extracellular   matrix   material   that   is   laid   down   outside   the   macrophage   layer.   Lymphocytes   appear   to   be   restricted   primarily   to   this   peripheral  area.  Many  of  the  granulomas  persist  in   this   balanced   state,   but   progression   toward   disease   is   characterized  by  the  loss  of  vascularizaLon,   increased  necrosis,  and  the  accumulaLon  of  caseum  in   the  granuloma  center.  UlLmately,  infecLous  bacilli   are   released   into   the   airways   when   the   granuloma   cavitates  and  collapses  into  the  lungs.  
  5. 5. Fact  and  ficLon  in  tuberculosis  vaccine  research:  10  years  later  
  6. 6. Percentage  of  CD4CD25high  T  cells  from  PBMC  of  21  healthy  control  subjects  and   24  paLents  with  acLve  TB.    
  7. 7. Fact  and  ficLon  in  tuberculosis  vaccine  research:  10  years  later   Targets  and  effectors  of  protecLve  immunity  in   tuberculosis   T   cells   parLcipate   in   protecLon.   Cytokines   acLvate   macrophages,   killer   molecules  lyse  target  cells  and  Mycobacterium   tuberculosis.   The   role   of   B   cells   is   unknown.   Th=T   helper,   CTL=cytolyLc   T   lymphocytes,   TNF=tumour  necrosis  factor.  
  8. 8. Mycobacterium  tuberculosis  evades  host  immunity   by  recruiLng  mesenchymal  stem  cells   S.  Raghuvanshi  et  Al.www.pnas.org/cgi/doi/10.1073/pnas.1007967107   Infusion   of   MSCs   converts   a   mouse   strain   resistant   to   M.   tb   infecCon   to   disease   suscepCbility.   TGF-­‐βRIIDN   transgenic   mice   were   infused   with   5   ×   106   MSCs   derived   from  C57BL/6  mice  infected  for  30  d  with  M.   tb,  followed  by  M.  tb  challenge  (∼110  bacilli)   by   the   aerosol   route.   (A)   Bacterial   loads   in   lungs  and  spleens  of  mice  at  different  days   aUer   infecCon.   (B)   Histological   secCons   of   spleens.   (C)   Numbers   of   granuloma-­‐like   structures   per   cross-­‐secCon   evaluated   by   examining   30   slides   of   each   sample.   (D)   Bacterial  loads  in  MSC-­‐treated  C57BL/6  mice   at  different  Cme  points  aUer  M.  tb  infecCon.   (E)   Sorted   CD4+Thy1.2+FoxP3−   cells   from   FoxP3   knock-­‐in   mice   were   adopCvely   transferred   to   Thy1.1+   mice   along   with   MSCs,   followed   by   infecCon   with   H37Rv.   Conversion   to   cells   with   a   Treg   phenotype   was   followed   in   the   spleens   by   analyzing   Thy1.2+CD4+FoxP3+   cells.   Results   presented   here   are   representaCve   of   three   independent  experiments.  
  9. 9. Hypoxia:  a  window  into  Mycobacterium   tuberculosis  latency   Tige  R.  et  Al.  Cellular  Microbiology  (2009)  11(8),  1151–1159     Hypoxic  gene  expression  is   rapidly  dominated  by  the   Enduring  Hypoxic  Response   (EHR).   Each  bar  represents  the  total   number  of  genes  induced  at   that  hypoxic  Cme  point.     The  bars  aredivided  into  the   genes  of  the  DosR  response   (blue),  the  EHR  (red),   and  other  induced  genes   (green)  
  10. 10. The  Mycobacterium  tuberculosis  DosR  Regulon  Assists   in  Metabolic  Homeostasis  and  Enables  Rapid  Recovery   from  Nonrespiring  Dormancy   Rachel  L.  et  Al.  J.  Bacteriol.  2010,  192(6):1662.   Growth  and  survival  during  anaerobic  dormancy  determined  by  recovery  on  solid   and  liquid  media.  Wild-­‐type,  DorKO  mutant,  and  complemented  bacteria  were   grown  in  glass  tubes  with  sCr  bars  and  a  culture-­‐to-­‐headspace  raCo  of  0.65.   Cultures  were  sCrred  with  magneCc  sCrrers.  (A)  CFU  were  counted  at  various  Cmes   by  plaCng  samples  from  tubes  harvested  sacrificially.  Squares,  H37Rv;   triangles,  DorKO;  circles,  DorCO.  
  11. 11. The  Mycobacterium  tuberculosis  DosR  Regulon  Assists   in  Metabolic  Homeostasis  and  Enables  Rapid  Recovery   from  Nonrespiring  Dormancy   Rachel  L.  et  Al.  J.  Bacteriol.  2010,  192(6):1662.   ATP  measurement  during   early  dormancy.  Samples   from  RAD  model  cultures   were  harvested  at  various   Cme  points  in  an  anaerobic   chamber.  ATP  was  extracted   using  a  chloroform  heat-­‐ based  method  and  frozen   unCl  measurements  could  be   obtained  using  the   Promega  Enliten  ATP  assay   system.  The  values  are  the   averages  of  three   experiments.  Open  bars,   H37Rv;  black  bars,  DorKO;   gray  bars,  DorCO.  RLUs,   relaCve  light  units.  
  12. 12. No Anti TNF Pz  italiano  di  56  aa,  in  tra<amento  con  infliximab   da  2  se=mane,  esordio  con  stato  confusionale,   crisi  epile=che,  tanto  da  portare  a  ricovero  in   neurologia  per  sospe<a  encefalite.     Successivamente    febbre  e  grave  dispnea.     Deceduto  in  rianimazione  dopo  3  se=mane  per   shock  se=co.  
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  17. 17. U.  Mack  et  Al.  Eur  Respir  J  2009;  33:  956–973   Summary  of  the  dynamic   sequence  of  events  governing   the  generaCon,  persistence   and  reacCvaCon  of   granulomatous  lesions  in  the   course  of   Mycobacterium  tuberculosis   infecCon.  For  details  of  T-­‐ helper  cell  priming,  triggering   and  effector  molecules,  and   sequenCal  progress  of  lesions   to  latency  and  reacCvaCon,   please  refer  to  secCon  1  of   the  present  arCcle.  IFN:   interferon;  IL:  interleukin;   TNF:  tumour  necrosis  factor;   ESAT:  early  secreted  anCgenic   target;  CFP:  culture  filtrate   protein;   ROI:  reacCve  oxygen   intermediates.