2015	  	  CFAI	  10th	  Special	  Lectures	“	  Heat	  shock	  proteins	  in	  the	  microbiota-­‐nutriEon-­‐immunoregulaEon	  interphase.	  ”	  	Dr.	  Willem	  van	  Eden	  	  Professor,	  Department	  of	  InfecDous	  Diseases	  	  and	  Immunology,	  Utrecht	  University	Date	  	   :	  Jan.	  13th	  (Wed.),	  2016	  Time	   :	  15:00	  −	  16:30	  Venue	  	   :	  Lecture	  room	  No.	  2	  	  	  (Graduate	  School	  of	  Agricultural	  Science)	  		  	   Heat	   shock	   proteins	   (HSP)	   are	   immuno-­‐dominant	   stress	   proteins,	   present	   in	   both	   prokaryotes	   and	  eukaryotes.	  By	  their	  evolu6onary	  conserva6on	  microbial	  HSP	  contain	  T	  cell	  epitopes	  that	  are	  shared	  between	  microbes	  and	  their	  mammalian	  hosts.	  These	  T	  cell	  epitopes	  are	  targets	  of	  immuno-­‐regulatory	  T	  cells	  (Treg)	  which	   have	   the	   capacity	   to	   suppress	   inﬂamma6on	   (van	   Eden	   et	   al.	   2005).	   Previously,	   we	   have	   shown	   the	  ability	   of	   mycobacterial	   HSP70-­‐derived	   pep6de	   B29	   to	   induce	   HSP-­‐speciﬁc	   regulatory	   T	   cells	   (Tregs)	   in	   Balb/c	  mice	   (van	   Herwijnen	   et	   al.	   2012).	   These	   pep6de-­‐speciﬁc	   Tregs	   were	   found	   to	   suppress	   experimental	   arthri6s	  by	   cross-­‐recogni6on	   of	   their	   mammalian	   HSP70	   homologs,	   mB29a	   and	   mB29b,	   both	   abundantly	   present	   in	  the	   MHC	   class	   II	   ligandome	   of	   stressed	   mouse	   and	   human	   an6gen	   presen6ng	   cells	   in	   inﬂamed	   6ssues.	   In	   the	  context	  of	  human	  MHC	  molecules	  we	  found	  a	  highly	  promiscuous	  HLA	  class	  II	  binding	  paVern	  of	  our	  mouse	  deﬁned	   pep6de.	   With	   the	   help	   of	   HLA-­‐DR4/B29	   tetramers	   more	   than	   threefold	   expansions	   of	   self-­‐cross-­‐
reac6ve	  Tregs	  were	  seen	  in	  the	  CD4+CD25+Foxp3+	  T	  cell	  popula6ons	  a]er	  in	  vitro	  s)mula)on	  with	  B29.	  On	  the	   basis	   of	   this,	   a	   tolerance	   inducing	   therapy	   for	   chronic	   inﬂammatory	   diseases	   is	   now	   being	   developed.	  
Furthermore,	   the	   current	   observa)ons	   may	   explain	   the	   supposed	   role	   of	   microbiota	   and	   possibly	   also	  infec)ous	   diseases	   in	   the	   crea)on	   of	   resistance	   against	   allergies	   and	   autoimmune	   diseases	   in	   humans	   (a	  possibility	   known	   as	   ‘hygiene	   hypothesis’).	   As	   an	   alterna)ve	   approach	   we	   have	   produced	   a	   screening	   method	  to	  select	  compounds	  that	  have	  the	  capacity	  to	  co-­‐induce	  HSP	  molecules	  in	  vivo	  €i0(Wieten	  et	  al.	  2010).	  The	  more	  abundant	  presence	  of	  HSP	  aPer	  co-­‐induc)on	  in	  vivo€i0,	  can	  lead	  to	  a	  beQer	  performance	  of	  Tregs.	  The	  discovery	  of	  such	  co-­‐inducing	  compounds	  in	  plants,	  indicates	  that	  it	  will	  be	  possible	  to	  develop	  a	  nutri)onal	  strategy	  for	  the	  preven)on	  or	  therapy	  of	  chronic	  inﬂammatory	  condi)ons.	  	  	  LiQerature:	  	  van	  Eden	  W,	  van	  der	  Zee	  R,	  Prakken	  B.	  Heat-­‐shock	  proteins	  induce	  T-­‐cell	  regula)on	  of	  chronic	  inﬂamma)on.	  Nat	   	  Rev	  Immunol.	  2005	  Apr;5(4):318-­‐30.	  Review	  	  Van	  Herwijnen,	  M.	  J.,	  Wieten,	  L.,	  van	  der	  Zee,	  R.,	  van	  Kooten,	  P.	  J.,	  Wagenaar-­‐Hilbers,	  J.	  P.,	  Hoek,	  A.,	  et	  al.	  (2012).	  	  Regulatory	  T	  cells	  that	  recognize	  a	  ubiquitous	  stress-­‐inducible	  self-­‐an)gen	  are	  long-­‐lived	  suppressors	  of	  	  autoimmune	  arthri)s.	  PNAS	  USA,	  109,	  14134-­‐14139	  	  Wieten	  L,	  van	  der	  Zee	  R,	  Spiering	  R,	  Wagenaar-­‐Hilbers	  J,	  van	  Kooten	  P,	  Broere	  F,	  van	  Eden	  W.	  A	  novel	  heat-­‐shock	  	  protein	  coinducer	  boosts	  stress	  protein	  Hsp70	  to	  ac)vate	  T	  cell	  regula)on	  of	  inﬂamma)on	  in	  autoimmune	  	  arthri)s.	  Arthri)s	  Rheum.	  2010	  Apr;62(4):1026-­‐35.	  	

(	  These	  lectures	  are	  included	  in	  Class	  2(2)	  of	  Interna6onal	  Food	  &	  Agricultural	  Immunology	  Lecture,	  2015	  and	  are	  also	  highly	  recommended	  for	  Master	  course	  students)	  	Graduate	  School	  of	  Agricultural	  Science,	  TOHOKU	  UNIVERSITY