AUTOTOLERANCIJA I AUTOIMUNOST
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AUTOTOLERANCIJA I AUTOIMUNOST
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Mehanizmi uspostavljanja autotolerancije
centralna
negativna selekcija
periferna
“intrinsic” faktori
“extrinsic” faktori
Mehanizmi nastanka autoimunski bolesti
genetska predispozicija
faktori spoljašnje sredine
Podela autoimunskih bolesti
Principi terapije autoimunskih bolesti
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AUTOIMUNOST
FIZIOLOŠKA PATOLOŠKA
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AUTOIMUNOST
FIZIOLOŠKA PATOLOŠKA
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AUTOIMUNSKE BOLESTI KOD LJUDI
Učestalost 5% populacije
Najčešće Reumatoidni artritis bolesti Autoimunske bolesti štitaste
žlezde Insulin zavisni diabetes melitus
Perniciozna anemija Sistemski lupus eritematozus Multipla skleroza
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AUTOTOLERANCIJA
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Sir Peter Medawar Sir Frank Macfarlane Burnet
1960 Nobel Prize in Physiology or Medicine
"for discovery of acquired immunological tolerance"
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T limfociti
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CENTRALNA TOLERANCIJA
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PERIFERNA TOLERANCIJA
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DENDRITSKE ĆELIJE
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REGULATORNE ĆELIJE
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Howard D. Johnson
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REGULATORNE ĆELIJE
Prirodne
CD4+CD25+, CTLA-4+, GITR+,....., Foxp3
IndukovaneTh3Tr1NK TCD8+......
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Treg
Naivna CD4+TNaivni CD4+T
Th1
Th2
Th17
TGF-
TGF-+IL-6
IL-4
IL-12+IL-18
IFN-
IL-23…
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Treg
Naivna CD4+TNaivni CD4+T
Th1
Th2
Th17
TGF-
TGF-+IL-6
IL-4
IL-12+IL-18
IFN-
IL-23…
Odbrana- intracelularni patogeni
Odbrana - helminti
Odbrana-bakterije, gljive
Autotolerancija
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Treg
Naivna CD4+TNaivni CD4+T
Th1
Th2
Th17
TGF-
TGF-+IL-6
IL-4
IL-12+IL-18
IFN-
IL-23…
Organ-specifične autoimunske bolesti
Alergija
Autoimunost i hronična inflamacija
Inhibicija odgovora na tumore i infektivne agense
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B limfociti
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Mehanizmi nastanka autoimunski bolesti
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GENETSKA OSNOVA
- MHC geni
- non MHC geni
FAKTORISPOLJAŠNJE SREDINE
- infekcija
- lekovi
AUTOIMUNOST
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MHC genie.g.
HLA-DRB1*1501HLA- DQB1*0602HLA –DQA1*0102.....
Non-MHC geni
IL2RA/CD25
IL7R
CD58
CLEC16A
....
GENETSKA OSNOVA
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MONOGENSKE AUTOIMUNSKE BOLESTI
ALPS- autoimmunski limfoproliferativivni sindrom, uslovljen mutacijom gena za Fas ili FasL
IPEX -imunski poremećaj, poliendokrinopatija, enteropatija, povezani sa X hromozomom, koji nastaje usled mutacije gena za Foxp3
APECED – poliendokrinopatija, kandidijaza, ektodermalna distrofija, kao rezultat mutacije gena koji kodira AIRE
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FAKTORISPOLJAŠNJE SREDINE
Infekcija
Lekovi
Pušenje
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PODELA AUTOIMUNSKIH BOLESTI
Prema ciljnom tkivu
organ-specificne
sistemske
Prema mehanizmu
II tip preosetljivosti
III tip preosetljivosti
IV tip preosetljivosti
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Spektar autoimunskih bolesti
Hashimoto thyroiditis Pernicious anaemia Insulin dependent diabetes
Myasthenia gravis Multiple sclerosis
Ulcerative colitisRheumatoid arthritis
Systemic lupus erythematous
SistemskeOrgan specifične
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EKSPERIMENTALNI MODELI AUTOIMUNSKIH BOLESTI
Spontane
Indukovane
Autoimunske bolesti kod transgenih iknock-out zivotinja