Toleranta Imunologica II

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

Toleranta centrala: Ag self

OLP

L imature

Innascuta

Toleranta periferica:

Ag self/non-self

OLS

L mature naïve/autoreactive

innascuta/dobandita

TIMUS

Scapa Deletiei Clonale

Cel T Autoreactive (Naïve)

Ag Sechestrate

Ignoranta Clonala/ Imunologica

MHC/Ag + Costim.

MHC/Ag No Costim.

Autoimunitate Anergie Clonala

Toleranta Periferica a Celulelor T

Supresia prin Celule T reg

PERIPHERY

APC TCR

T cell CD28

Activated T cells

APC TCR

Functional unresponsiveness

Normal T cell response

Anergy

Apoptosis (activation-induced cell death) APC

Deletion

APC

Block in activation

Suppression

Regulatory T cell

Off signals

Activated T cell

1st signal

2nd signal

Toleranta Periferica LT

I N N A T E

A C Q U I R E D

I N N A T E

Mecanisme de Mentinere a Tolerantei LT

Deletia clonala

Supresia

Toleranta centrala

Toleranta periferica

T regulatory CD4⁺ CD28⁺ FoxP3⁺

T suppressor

CD8⁺ CD28⁻ FoxP3⁺

Celulele T reg

• Generalitati

• Caracteristici

• Fenotipuri

• Mecanism de actiune

• Functii

Markeri Fenotipici ai Tregs

Regulatory T cells Effector/Memory T cell

Surface markers CD25/IL-2Rα chain (high) CD127 (IL-7Rα chain) (low) CTLA4

CD25/IL-2Rα chain (high→medium) CD127 (IL-7Rα chain) (low: effector cells high: memory cells)

CK produced on activation (main)

TGF-β IL-10

TH1: IFNγ TH2: IL-4 & IL-5 TH17: IL-17

CCR CCR6 CXCR3

GF requirement IL-2 Effector: IL-2, IL-4 Memory: IL-7

Major transcript fact expressed

FoxP3, STAT-5 ≠ Effector subsets: GATA-3, STATs Memory: BLIMP-1

Dupa A Abas et al. Cellular & Molecular Immunology. 2012 (7th ed)

Clasificare T regs

• Clasificare subseturi • Functii • Fenotip • Foxp3

Dezvoltarea celulelor

T reg

A Abas et al. Cellular & Molecular Immunology. 2012 (7th ed)

Tregs Timice

• Caracteristici

• Origine:

• Trigger:

• Localizare:

• Rol:

Tregs Periferice

A Abas et al. Cellular & Molecular Immunology. 2012 (7th ed)

Supresia raspunsurilor LT da catre Tregs

A Abas et al. Cellular & Molecular Immunology. 2012 (7th ed)

Treg Periferice (Adaptative, Induse)

Ch Janeway et al. Immunobiology. .

Toleranta Celulelor B

• Ag self T-independente

(PZ self, lipide, acizi nucleici) → nu sunt recunoscute de LT→ necesar inducerea tolerantei LB

• Ag self T-dependente

(Proteinele) self → necesar inducerea tolerantei LTh & LB pentru a preveni producerea de AAc (auto-anticorpi).

• Dovezi experim arata ca P self induc toleranta si in LB.

• Boli asociate cu productia de Aac (LES) sunt rezultatul tolerantei defectuoase in LT si LB.

Toleranta Celulelor B: Centrala & Periferica

Mecanismele de inducere a tolerantei centrale pentru LB

Deletia clonala a LB Resintetizarea secventei receptorului in LB imature

A Abas et al. Cellular & Molecular Immunology. 2012 (7th ed)

Toleranta periferica dobandita a LB

Ag T-dependente: Ag T-independente:

Ch Janeway et al. Immunobiology

Conditii de obtinere a tolerantei LB in periferie

Termeni Opusi Importanti

• Toleranta Centrala (self-toleranta) vs toleranta periferica • Toleranta Activa vs. toleranta pasiva

(ignoranta) • Toleranta LT vs. Toleranta LB

• Toleranta naturala vs. artificiala

Bibliografie selectiva:

• Ch Janeway et al. Immunobiology. 2005, 2007. Garland Science .

• A Abas et al. Cellular & Molecular Immunology. 2012 (7th ed)

• C Bara. Esential de imunologie. 2002. Ed Bic ALL.