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