????G?????S? ??? ??????S???S? ???????????O? ???? ?? F??G????

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??? ???S???G?? 3/4-2-2014 ?.
Ga?ta????

• ????G?????S? ??? ??????S???S? ???????????O? ????
  ?? F??G????

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??????S???S? ???????????O???? F??G???O??S
???????S?

• ????? ?????????S ???S?????S?S
• ??????????S
• ???GG??OS? ?O? ???????????O?-??? ???????G??
  ????O? S????O?
• ??????????F???O? ?O? ???F???????O?
• ?F?GG??OS? ?O? ???F???????O?
• ????? ??S???????S F??G????S
• ? F??G???O??S ???????S?
• ????F??G???O???S ????G????S

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??S?GOG? ?a ?eµf???tta?a ?????f????? s??e??? st?
a?µa ?a? t? ??µf?, ?a??? ep?s?? ?a? st??? ?st???,
se ??se?? µ????s?? ? t?a?µat?sµ??. ? ?????f???a
a?t? ??? ap?? a????e? t?? p??a??t?ta epaf?? t???
µe t? ?at?????? a?t?????, a??? ap?te?e? s?µa?t???
pa?????ta ??a t?? a??pt??? t?? f?e?µ???d???
ap????s??. ? f?e?µ??? e??a? µ?a p???p????
d?ad??as?a, p????? stad???, se ??se??
t?a?µat?sµ??. S a?t? s?µµet????? ??tta?a t??
?.S., ?a??? ep?s?? ?a? p???????µa µ???a.
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????? ?????????S ???S?????S?S

• ?a ??tta?a t?? ?S d?a??t??? t? µ??ad??? ??a??t?ta
  ?a µeta??????ta? ap? t? ??a s?µe?? t?? s?µat??
  st? ????, µe t? ß???e?a t?? µ????? ??tta?????
  p??s?????s?? (CAMs).
• ???GG??OS? ??SO ?O? ????T?????O? ??????O? ?O?
  ????????O? ??SO ?O? CAMs.
• CAMs f????? ta ?eµf???tta?a, µ?????tta?a ?a?
  ????????tta?a t?? ?????f???a?.
• ?a CAMspa????? ep?s?? ???? st?? e??s??s? t??
  a????ep?d??se?? t?? ?? µe ta APCs, t?? TH µe ta ?
  ?a? t?? CTLs µe ta ??tta?a-st?????.

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????? ???S?????S?S

• ????G????? S???????O?
• G????p??te??e? µe µ?a ep????te?a ?e?t????
• ?????ep?d?as? µe ?data???a????? ?µ?de? µ???????
• L (?e?????tta?a), ? ?a? ? (e?d?????a?? ??tta?a)
• ????G????? ??????O?
• ???te??e? se?????-??e??????, ??t??a
  ?????s????µ??e?
• CD34, GlyCAM-1
• ??f?????ta? sta e?d?????a?? ??tta?a ?a? ta
  ?e?????tta?a

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????? ???S?????S?S

• ????G????? ????G????O?
• ?te??d?µe?? a/ß
• ??f?????ta? sta ?e?????tta?a
• ??ep???e?a p??s?????s?? ?e?????tt???? (LAD)
  (a?t?s?µ??? ?p??e?p?µe?? ??s?µa)
• ????G????? ???S?SF?????O?
• ICAM-1, ICAM-2, ICAM-3, VCAM
• ??f?????ta? sta e?d?????a?? ??tta?a

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????? ???S?????S?S
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(No Transcript)
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??????????S

• ????????G????? ????O? ???????????O? (90-130
  ????????? ?????????)
• ???????? e??e?t??? t?? p??s?????s?, t?
  ??µe??ta??a ?a? t?? e?e???p???s? p?????
  ?e?????tta????? p????sµ??.
• F?e?µ???de?? (µeta??ste?s? ??tt???? se ??se??
  f?e?µ????, epa??µe?? ??f?as?)
• ?? f?e?µ???de?? (?µ???stas?/a??pt???)

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????G????? ?????????O?

• 43 ????
• ??????????F?? (???F????? S????F?
  RNA,????-????F??S???? ?????????S?, ?S????F?S)
• ???-????? C-C ????????? ??S?????S G????????
• ???-????? C-X-C ?- ??????????? ???? ???????

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????????S ?????????O?

• CCRs
• CXCRs
• ????? S?GG?????
• ????? ??????????
• S? ??T? ???????? ??S???????? ????SS?????S
  ??????????S

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????GOG? S?????S ??SO ??????????S
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?etaß???? st? ??tta?? ???? t?? s?µat?d?t?s??
??sa se de?te???epta s?µßa????? d?aµat????
a??a??? st? s??µa t?? ??tt???? ?????eta? ?
p??s?????t??? t?? ??a??t?ta p??? t?
e?d?????? ?a?????ta? µ????ß???t??e? e?e??e?e?
???e? ???????? ap? ta µa???f??a ?pe?e??e?????ta?
p??te?se? ap? ta ?????a t?? ??dete??f???? ?a?
µa???f????, ?staµ??? ap? ta ßase?f??a ?a?
??tta??t?????? p??te??e? ap? ta e?s???f??a
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????? ???????O? ?????????O? S? ??????T?S???S
???????????O?
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???GG??OS? ? ?????S ?O? ????????F??O?

• ???????????? 4 S?????
• 1) ????s? p?? µes??aße?ta? ap? se?e?t??e?
• 2) ??e???p???s?
• 3) ?a????s?/???s?????s?
• 4) ??a-e?d?????a?? ???d??

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??????S??S ?????? ????????F??O?
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??????S??S ?????? ????????F??O?
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????? ??? S??????????

• ?-S???????? ???????
• Il-8 (??µe??????) ?p?d???a? t?? st?
  ??dete??f???, µ?s? p??te???? G
• S?µa µetaß???e? t? d?aµ??f?s? ??te???????
  ?µetaß??? t?? s?????e?a? ??a Ig-CAM
• ???d?? ??tt????

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????G?????S? ?????????????

• ??µe??ta?t???? pa?????te?
• ??µe?????e? (IL-8 ?a? f?e?µ???d?? p??te??? t??
  µa???f????, ???-1)
• ?? ??µe?????e? pa?????ta? e?e???p???s?? t??
  a?µ?peta????, s?stat??? t?? s?µp????µat?? C5a,
  C3a ?a? C5b67 ?a? d??f??a ?-f??µ???pept?d?a p??
  p????pt??? ap? t? d??spas? ßa?t???a??? p??te????)

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?????????????? ????G????S

• Il-8
• MIP-1B (F?e?µ???d?? p??te??? t?? µa???f????)
• PAF (?a?????ta? e?e???p???s?? t?? a?µ?peta????)
• ??????ta d??spas?? t?? s?µp????µat?? ?p?? C5a,
  C3a C5b67)
• ???f??a f??µ???pept?d?a p?? pa?????ta? ?at? t?
  d??spas? t?? ßa?t???a??? p??te???? ?at? t?
  d????e?a t?? ???µ????)

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???GG??OS? ??????????O?
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?????F???? ???F???????O?
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?????S ???F???????O?

• ?e????? pe?????? t?? a??e?a??? e?d??????? sta
  µetat????e?d??? f?eß?d?a ap?te????ta? ap? e?d???
  ??ß?e?d? ??tta?a (High Endothelial Venules, HEVs)
• ?a HEVs e?f?????? µe???? p??????a CAMs p??
  ?????ta? a??e?a??? p??s?????t??e?
• ?? p??s?????t??e? ?a??d????? t?? ???d?
  d?af??et???? ?p?p????sµ?? ?eµf???tt???? se
  d?af??et??? de?te???e?? ?eµf??? ???a?a
• ? d?ad??as?a a?t? e??a? ???st? ?? ep????sµ??
  (trafficking ? homing) ?a? ep?t?????eta? µe
  e?d????? ?p?d??e?? ep????sµ??

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???? ??? HEV
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???F???????? ??T??O???? S? HEV
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???F???????? ??T??O???? S? HEV
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?????S ???T??O? ???F???????O?
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????????S ??????S??? ???F???????O?
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????????? ??? ????G?????????? S? ????? F??G????
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??S???????S ??S F??G????S ??µe?????e? ?µ?da
µ????? p???pept?d??? p?? ??µe??ta?t???
p??se?????? d?af??et????? t?p??? ?e?????tt????
?a? ???µ????? t?? ??f?as? ?a? d?aµ??f?s?
??te??????? st? µeµß???? t?? ?e?????tt????. ? p??
?a?? ?a?a?t???sµ??? ??µe?????? e??a? ? ?L-8.
?a???eta? ap? p??????a ??tt???? (p.?. µ???p????a,
µa???f??a, ??dete??f??a, ?a? e?d?????a??
??tta?a). ?a?aµ??e? st? e?d?????? t?? pe??????
t?? f?e?µ???? ?a? ?s?? s??d?eta? µe µ???a
p??te????????? st? e?d?????? ? st?? e??a??e?a??
????. ? s??des? t?? se ?at???????? ?p?d??e??
e?e???p??e? µ???a ??te??????? st? µeµß???? t??
??dete??f???? ?a? ep?t??pe? ?s???? p??s?????s?
t?? ??dete??f???? st? e?d?????? t?? pe??????
f?e?µ????
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?? s?st?µa t?? ??????? ap?te?e? µ?a d?ad?????
a???????a e???µ???? a?t?d??se?? p?? ?e???? ap?
??a? pa?????ta p???? (t?? pa?????ta Hageman) ?
?p???? e?e???p??e?ta? µet? ap? t?a?µat?sµ? ?st??.
?p? t?? a???????a t?? a?t?d??se?? pa???eta?
ß?ad??????? (?s???? a??e?e?e??? pept?d??), ?
?p??a d?a a??e??d?asta?t???, a????e? t?
d?ape?at?t?ta t?? a??e???, p???a?e? p??? ?a?
s?spas? t?? ?e??? µ???.
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    ?? s?st?µa p???? e??a? µ?a ???? a???????a
e???µ???? a?t?d??se?? p?? p???a?e?ta? ap?
t?a?µat?sµ? a??e??? ?a? ?d??e? st? µa????
pa?a???? ???µß????. ? ???µß??? µetat??pe? t?
d?a??t? ???d????? t?? ?st?? ? t?? p??sµat?? se
ad????t? ????? ? pept?d?a ??????. ?ts?,
s??µat??eta? ? ???µß?? p?? eµp?d??e? t??
a?µ???a??a ?a? t?? e??p??s? t?? µ????s??. ?a
pept?d?a t?? ?????? d???? ?? µes??aß?t??
f?e?µ????, ep????ta? a???s? t?? d?ape?at?t?ta?
t?? a??e??? ?a? ??µe??ta??a t??
??dete??f????.     ?? ???d???t??? s?st?µa ?
afa??es? t?? ???µß?? ap? t?? pe????? t?a?µat?sµ??
ep?t?????eta? µe t? d??s? t?? s?st?µat?? a?t??.
?? te???? p????? a?t?? t?? a???????a?, ?
p?asµ???, e??a? ?s???? p??te???t??? ????µ?, p??
d?asp? t?? ????? se d??f??a p?????ta p?? d????,
?? µes??aß?t?? f?e?µ????, ??µe??ta?t??? ??a ta
??dete??f??a. ?p?s?? e?e???p????? t? s?st?µa t??
s?µp????µat??.
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    S?st?µa t?? s?µp????µat?? ????? s?stat???
t?? s?st?µat?? d???? ?? a?af??at????e? (C3a, C4a
?a? C5a) se ?at???????? ?p?d??e?? µast???tt????
p???a???ta? ap???????s? t???, ape?e?????s?
?staµ???? ?a? ????? µes??aß?t??. ?? µes??aß?t??
a?t?? p???a???? a??e??d?ast???, a???s? t??
d?ape?at?t?ta? t?? a??e??? ?a? s?spas? t?? ?e???
µ???.
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??S???????S F??G????S
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???S? IL-1 TNF-a IL-6
???et?????
S???es? p??te???? ??e?a? f?s?? ap? t? ?pa?
???e??d?ast???
????s? CAMs st? e?d?????? -
???/µ?? ???ß?ast?? -
?a?a???? a?µ?peta???? -
?pa???? ??µe??????? -
?pa???? IL-6 -
??e???p???s? ? /? ??tt????
????s? s???es?? Igs - -
??????S??S ??? ????????????S ???S??S
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?????????S???? F??G????S
??????s?
?????µa
?p??e?a ?e?t?????a?
Te?µ?t?ta
?????
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?????? F??G???O??S ??????S?
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?????? F??G???O??S ??????S?

• ???a??? st? d?ape?at?t?ta t?? t?p???? a??e???
• ??dete??f??a fa????tta?????? ta pa?????a ?a?
  ape?e??e?????? d??f????? µes??aß?t?? f?e?µ????
• ??e???p???s? µa???f???? µ?s? t?? MIP-1a, MIP-1b
  (macrophage inflammatory proteins), p?? µe t?
  se??? t??? e???????? ?????? µes??aß?t?? (IL-1,
  IL-6, TNF-a), µe p?e??t??p??? d??s?
• ?pa???? ??f?as?? d?af???? CA?s sta ??tta?a t??
  a?µat??, ???d?? t??? ap? ta a??e?a

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S?S???????? F??G????
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S?S???????? F??G????

• ????? F?S?
• ??????S? ??????????O? S??? ???T????? (IL-1, IL-6,
  TNF-a)
• ??F???S? ???????, ???????? S??T?S? ?????O? ???
  ??? ???F?S? (p? ACTH) ? ?????S? ?????????S ??? ??
  ?????F?????
• ????GOG? ???????T?O? ??O????O? ?????S F??G????S
  C-a?t?d??sa p??te???, ?µ???e?d?? ? ????,
  ???d?????, S?stat??? s?µp????µat??, p??te??? p??
  deµe?e? µa????? (MBP)

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????S ??S IFN-? ??? ??? TNF-a S?? ?????? F??G????

• IFN-a ap? ?e?????tta?a µ???sµ??a µe ??
• IFN-ß ap? ???ß??ste? µ???sµ????? µe ??
• IFN-? ap? ?? ?a? ?? ??tta?a µe d??f??e?
  p?e??t??p???? d??se?? p?? t? d?a??????? ap? t??
  a ?a? -ß
• TNF-a ap? e?e???p???µ??a µa???f??a

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????????????S ???S??S IFN-?
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?????? F??G????IFN-? ?a? TNF-a

• ? e?e???p???s? t?? µa???f???? ap? t?? IFN-?
  p???a?e? a???s? t?? µeta??af?? ?a? sta?e??p???s?
  t?? mRNA t?? TNF-a.
• ?? d?? a?t?? ??tta?????e? d???? s??e???st??? ??a
  t?? ??a??? t?? ?????a? f?e?µ????. ? ????s? t??
  ??f?as?? CAMs ?a? MHCII? St?at?????s? µe?????
  a???µ?? ??tt????

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??s?? ???a?? st???? HEV CAMs t?p?? µ??????? st? e?d??????
??s?? t?? Crohn ??te??
Sa??a??d?? d?aß?t?? ?????ea?
??s?? t?? Graves T??e?e?d?? ad??a?
T??e?e?d?t?da t?? Hashimoto T??e?e?d?? ad??a?
?e?µat?e?d?? a????t?da ???????? ?µ??a?
????d?? ????t?da ??te??
?????a F?e?µ???d? ??s?µata p?? s?et????ta? µe ta
a??e?a t?p?? HEV
Se a?t? s?µpe???aµß????ta? ta GlyCAM-1,
MAdCAM-1 ?a? CD34
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????F??G???O??

• ???????S????????
• ?e?????? t? a???µ? t?? ?eµf???tt???? t??
  ?????f???a?
• ?a a????µa ?eµf???tta?a pe?a????? µe ap?pt?s?
• O? ??p?f??a µ???a, desµe???ta? se ?at????????
  ?p?d??e?? st? ??tta??p?asµa, af?? d?ape??s??? t??
  ??tta???? µeµß????.
• ?a s?µp???a µetaf????ta? st?? p????a ?a?
  desµe???ta? se ???µ?st???? a???????e? t?? DNA,
  e?e???p????ta? ? a?ast?????ta? t? µeta??af?.
• ?p????? t? µeta??af? t?? a?ast???a t?? NF-??.
• ?e?????? t? d??s? µa???f???? ?a? ??dete??f????,
  t? ??µe??ta??a t?? ??, t?? ??f?as? µ????? MHCII
  ?a? t?? pa?a???? IL-1 ap? ta µa???f??a
• Sta?e??p????? t?? ??s?s?µ???? µeµß???e?,
  µe?????ta? t?? ape?e?????s? e???µ?? st?? ??se??
  f?e?µ????

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????F??G???O??

• ?? ???????S???????? (NSAID)
• ?p? t?? ep??? t?? ?pp????t? ???s?µ?p????? f????
  ?t??? ??a t?? ?atap???µ?s? t?? p????.
• ??ast?????? t?? ?d? t?? ?????????e??s?? µe
  ap?t??esµa t? µe??s? t?? s???es??
  p??sta??a?d????. ?ts?, pe??????eta? ? a???s? t??
  d?ape?at?t?ta? t?? a??e??? ?a? ? ???d??
  ??dete??f????.

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NSAID a?ast??? t?? ?d?? t?? ?????????e??s??
48
?????????e??s? (COX)
ARACHIDONIC ACID
COX-2
5-lipoxygenase
COX-1
LEUKOTRIENES
PROSTAGLANDINS
LTB4
F??G????
IL-1ß
TNF-a
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(No Transcript)
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?????????? ??S ???S?????S?S ???????????O? (LAD)

• ?fe??eta? st?? a?ep???e?a t?? ?p?µ???da? CD18 t??
  ??te??????? p?? e?f?????ta? sta ?e?????tta?a
• S???de?eta? ap? ad??aµ?a p??s?????s?? t??
  ?e?????tt???? st?? ??se?? f?e?µ????
• ?pa?a?aµßa??µe?e? ßa?t???a??? ???µ??e??, p??
  ?p?t??p??????
• ??t?µet?p??eta? µe µetaµ?s?e?s? µ?e??? t?? ?st??
• ?p???e? a?t?st???? ??s?µa ?a? sta ß??e?d? (BLAD)

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??????G??F??

• Cyster JG (2005). Ann Rev Immunol 23 127
• Imhof BA Aurrad-Lions M (2005). Nature Rev
  Immunol 4 432
• Kim CH (2005) Curr Opin Hematol 12 298
• Rosen SD (2004) Ann Rev Immunol 22 129
• Stein JV Nombela-Arrieta C (2005) Immunol 116 1