INNATE IMMUNITY II

DegradationACTIVATION

Uptake

PHAGOCYTOSIS

Phagocyte

PRR

0.5 - 1 hours

The amount of internalized particles is limited Antigen + Antibody

ACQUIRED IMMUNITY

Bacterium

Intracellular killing

Antigen presentationT cell

ACQUIRED IMMUNITY

Reminder

Lysis of bacteria

COMPLEMENT ACTIVATION

InflammationChemotaxis

Complement-dependent phagocytosis

Bacterium

COMPLEMENT

Lectin pathwayAlternative

pathway

Antigen + Antibody

ACQUIRED IMMUNITY

Complement-proteins

Few minutes – 1 hour

Enzymes get fragmented, complement activity can be exhausted

Reminder

NK-cellIL-12

macrophageIFNcytokines

neutrophilTNF-

INFLAMMATION – ACUTE PHASE RESPONSE

hrs

Pla

sma

leve

l

1 2 3 4 5

LPS (endotoxin) (Gram(-) bacteria)

TNF-

IL-1IL-6

Kinetics of the release of pro-inflammatory cytokines in

bacterial infection

TNF-IL-1IL-6

Few hours

ACUTE PHASE RESPONSE

Bacterium

LPS

DANGER SIGNAL

ACTIVATION

PRR

Reminder

NK cells

Lysis of infected cell

ACTIVATION OF NATURAL KILLER CELLS

Kinetics of the activity of the complement system and NK

cells in virus infection

IFNIL-12

2 4 6 8 101 3 5 7 9 1211 13

Complement system

NK-cells

days

Rel

atív

szi

nt/a

ktiv

itás

NK-CELLS

Virus-infectedcell

PRR

RECOGNITIONACTIVATION

RECOGNITION OF ALTERED HOST CELLS

Adaptive components are also able to activate NK cells

ADCC-Antibody Dependent Cell Cytotoxicity

Activating NK cells through FcR on NK cells recognizing pathogen-bound Antibodies

INTERFERON RESPONSE

EFFECTS OF TYPE I INTERFERONS

Plasmacytoid dendritic cells produce 1000x more type I interferon than other cells

NATURAL INTERFERON PRODUCING CELLS – IPC

After viral infection they are accumulated at the T cell zone of the lymph nodes

vírus

paracrine

autocrine

Infected cell

subtypes

IFN-

IFN-

IFN response

IRF-3

IRF-7

Virus

IFN-

IFN-

NFBAP-1

Type I IFN receptor

IFN response

VIRUS INDUCED TYPE I INTERFERON PRODUCTION

IRF: interferon regulatory factor

IRF-3

Plasma membrane

Cytoplasm

Type I. IFN receptor Type II. IFN receptorType III. IFN receptor (IFNλ)

TYK2 JAK1TYK2 JAK1JAK2

JAK1JAK1

JAK2

STAT1STAT1

STAT2

Nucleus

STAT1 STAT2P

P

STAT1 STAT2P

P

STAT1STAT1 PP

STAT1STAT1 PP

IRF9

ISRE GAS – promoter elements

Antiviral immunity Antimycobacterial immunity

ISG15, Mx,OAS and

PKR

IL-10R2IFNLR1IFNAR1/2 IFNG1/2

Interferon-stimulated genes

Interferon-stimulated Regulatory elements

ISGF-3

GAS: Gamma Activating sequence

Signal Transducers and Activators of Transcription

INTERFERON EFFECTOR PATHWAYSinduction of the „antiviral state

• 1. Mx GTPase pathway– block viral transcription

• 2. 2',5'-oligoadenylate-synthetase (OAS)-directed Ribonuclease L pathway– degrade viral RNA

• 3. Protein kinase R (PKR) pathway (Ser/Thr kinase, dsRNA-dependent)– inhibit translation

• 4. ISG15 ubiquitin-like pathway– modify protein function

CONTROL ALL STEPS OF VIRAL REPLICATION

Oligomer accumulationin cytoplasmic

membranes(e.g. ER)

(Nucleus)

(Cytoplasm)

ISRE MxA

MxA monomer

MxA oligomer

Trapped viralcomponents

(Nucleus)

(Cytoplasm)

ISRE OAS1

Inactive OAS1 monomer

Induction byviral dsRNA

Active OAS1 tetramer

synthetized pppA(2’p5’A)ninactive

RNaseLmonomer

active RNaseLdimer

cleaved RNA

(Nucleus)

(Cytoplasm)

ISRE PKR

Inactive PKR monomer

Active PKR dimer

Induction byviral RNAs

EIF2a EIF2aP Inhibition of

translation

Mechanism of action of MxA, OAS1 and PKR

TRIF

TANK

IKKε TBK1

IRF-3

TRIF

TRAM

TLR3

TLR4

MyD88

IRF-5

TLR7TLR8TLR9

IFN-β, IFN-α1

RIG-1

Stimulation of Ig-productionin B-cells

Type I interferon receptor

IRF-7

Increased cytotoxicity and proliferation of NK-cells

Activation of - and γδ T-cells

Increased antigen presentationin myeloid dendritic cells

IRAK-1

TRAF-6

IRF-7

MULTIPLE EFFECTS OF TYPE I INTERFERONS

on immune cells