Toleranta Imunologica (I)
Obiective• Definitie si clasificare
– conditii de obtinere a tolerantei imunologice• Mecanismele inductiei tolerantei
imunologice a limfocitelor T– Toleranta innascuta centrala– Toleranta innascuta periferica– Toleranta dobandita
• Mecanismele inductiei tolerantei imunologice a limfocitelor B
Caracteristica fiziologica SI
Recunoastere : self / non-selfReactie limitata doar → non-self
=> Mecanisme de control SI
Toleranta Imunologica• Definitie:
→ Inhibitie activa & specifica a RIA → Ag complet* (exo/endo)
• Semnificatie: a. Natural:b. Artificial:
Statusul Ag in declansarea RI
Tolerogen
Imunogen
Favorizeaza Toleranta
F influenteaza RIA
Favorizeaza RIA
ExcesiveDoza optimaDoza de Ag exogen*
Forma fizica a Ag(exogen)
Molecule mari, agregate, complexe
Molecule solubile, neagregate, simple
Procesarea Ag (exogen)
Corespunzatoare Necorespunzatoare
Ruta de administrareAg exogen Sc / im Oral (+/- iv)
Factori care influenteaza statusul Ag* (dependenti de Ag)
*Originea Ag Endogen (self)Exogen (non-self):
- [Ag]↓: - [Ag] medii: - [Ag]↑:
Factori care influenteaza statusul Ag* Doza de antigen
Factorii care influenteaza statusul Ag: dependenti de organism
Argumente experimentale:
Favor immune response
Factors which affect response
Gradul de maturitate al SI (~varsta org. respondent)
matur (Adult) Imatur (Nou-nascut)
Std diferentiere al cel imunocompetente
LB, LT diferentiate, LB/T memorie
L B/L T* nediferentiate
Factorii care influenteaza statusul Ag: dependenti de organism
Factori care afecteaza raspunsul
Favorizeaza RIFactori care influenteaza RI
Favorizeaza RI Favorizeaza toleranta
Soarta limfocitelor dupa intalnirea cu Ag
Imunitatea
Normal:
Patologic:
Toleranta
Normal: Patologic:
Raspuns Imun
Caracteristicile tolerantei imunologice
• imunologic specifica
• Toleranta Ag self: • Toleranta Ag non-self
Mecanisme generale ale Inductiei Tolerantei Imunologice
Mecanismele Principale ale Tolerantei Centrale
Maturizarea limfocitelor T
MOH & ficat: CSU→pre- timocite +CC (timoxina & β2 microglobulina) =>Timus
• Timocite • Cel epiteliale
corticale • CD
TIMUS
• Macrofage • Cel epiteliale
medulare
I. Stadiile Maturizare a L T
Pre-limfocit T
Limfocit Timatur
CD4+CD8+TCR+
CD44
Timus soareceConstant1-2 x 108
Rata de supravietuire a LT in timus
LT Daunator
Y Y
T T
APC
LT Folositor
Toleranta Imunologica Centrala Procese TIMICE
YT YTY YY YT T
Y YT T
Y Y YT T T Y YYYT
YT T T
Repertoriu TCR randomizat => diversitate
YT YTYT
LT Nefolositor
Y
T
?
Y
T
Cortex
Medulara
Selectia pozitiva & negativa – localizare TIMUS
SP
CD3+ TcR+CD8+ or CD4+
Cel epiteliale corticale
DNProliferareCD3-
DPSelectie pozitiva
CD3+ TcR+
DPSelectie negativa
CD3+ TcR+
Toleranta Imunologica Centrala
Toleranta Imunologica Centrala -Etape:
Toleranta Centrala LT:Deletia Clonala & Diferentierea
MHCI
MHCII
TCR↓ [GC] ↑: + apoptoza
TCR=0 [GC] ↑: +apoptoza
TCR >[GC] : -apoptoza
II
IIII
Consecintele recunoasterii intra-timice a Ag self
CD4+
Apoptosis
CD4+
Consecintele recunoasterii intra-timice a Ag self (II)
TIMUS
Scapa Deletiei Clonale
Cel T Autoreactive (Naïve)
Antigene Sechestrate
Ignoranta Clonala/Imunologica
MHC/Ag + Costim.
MHC/Ag No Costim.
Autoimunitate Anergie Clonala
Soarta Celulelor T autoreactive
Supresia prin Celule T reg
PPEERRIIFFEERRIIEE
Situsurile Privilegiate Imunologic
AutoAg cerebral→MBP
Ignoranta Imunologica
Iv: MBP + adj.
Activ LT autoreactive
Encefalita & Deces
Migrare→tesuturi→ BHE: SNC
Soarece → LT specifice anti-MBP
No BAI, Normal
Ignoranta Imunologica :Model experimental-EAE
Toleranta Periferica
INNATE
ACQUIRED
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