RECOGNITION BY SOLUBLE RECOGNITION BY SOLUBLE MOLECULESMOLECULES

MANNOSE BINDING LECTINMANNOSE BINDING LECTIN

PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENSPHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS

CR3

Toll receptor

Toll receptor

OTHER PATTERN RECOGNITION MOLECULES

MANNOSE RECEPTOR

MANNOSE BINDING LECTIN

EEukariotic cellsukariotic cells

GluGluccooseseaminamin

MannMannoseose

GalaGalactosectose

NeuraminNeuraminidaseidase

GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES

MannoseMannose

ProkarProkariotic cellsiotic cells

MaMaccrorophage/dendritic cellsphage/dendritic cells

MannMannose ose ReRecceptoreptor

BaBaccttereriumiumMannMannoseose

MANNOSE RECEPTORS ON PHAGOCYTES

PATTERN RECOGNITION BY MANNAN BINDING LECTINPATTERN RECOGNITION BY MANNAN BINDING LECTIN

Strong binding No binding

BaBacteriumcterium

lysis

Complementactivation

MacrophagePhagocytosis

CR3

LECTIN PATHWAY

WHAT IS RECOGNIZED BY INNWHAT IS RECOGNIZED BY INNAATE AND ACQUIRED TE AND ACQUIRED IMMUNITY?IMMUNITY?

HOHOW DO THEY RECOGNIZE PATHOGENS?W DO THEY RECOGNIZE PATHOGENS?

Common pattern of groups of pathogensCommon pattern of groups of pathogensPathogen Associated Molecular PatternPathogen Associated Molecular Pattern

PAMPPAMPRecognition by receptorsRecognition by receptors

Pattern Recognition ReceptorPattern Recognition ReceptorPRRPRR

9-19-133 various various Toll-Toll-rreecceptoreptorssTLR familyTLR family

RECEPTORS

InInnate immunitynate immunity

AncientAncient

RECOGNITION

INNATE IMMUNITY

CYTOPLASMIC SENSORSCYTOPLASMIC SENSORS

TLR

CYTOPLASMCYTOPLASM

CARD-CARD-helicase

RLH

CONSERVED RECEPTORS SENSING DANGER SIGNALSCONSERVED RECEPTORS SENSING DANGER SIGNALSNLR

Leucin rich repeatsLeucin rich repeatsNucleotide binding domain

NLRP1 – ASCNLRP1 – ASCNLRP3 – ASC – CARDINALNLRP3 – ASC – CARDINAL

NBDNBDNN CC

PYRPYR

CARDCARD

NOD1/2, IPAF/NLRC4NOD1/2, IPAF/NLRC4

MEMBRANMEMBRAN

TLR3TLR3

BIRBIRIPAFIPAF

FibroblastFibroblastEpithelial cellEpithelial cellDCDC

NBDNBD

NBDNBD

SIGNALING

INNATE IMMUNITY

paracrine

autocrine

Infected cell

subtypes

IFN-

IFN-

IFN response

IRF-3

IRF-7

Virus

IFN-

IFN-

NFBAP-1

Type I IFN receptor

IFN response

VÍRUS INDUCED TYPE I INTERFERON PRODUCTION

Plasma membrane

Cytoplasm

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

TYK2 JAK1TYK2 JAK1

JAK2

JAK1JAK1

JAK2

STAT1STAT1

STAT2

Nucleus

STAT1 STAT2P

P

STAT1 STAT2P

P

STAT1STAT1 PP

STAT1STAT1 PP

IRF9

ISREISRE GAS – promoter elementsGAS – promoter elements

Antiviral immunity Antimycobacterial immunity

ISG15, Mx,OAS and

PKR

IL-10R2IFNLR1IFNAR1/2 IFNAG1/2

Interferon-stimulated genes

INTERFERON EFFECTOR PATHWAYS

• 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– 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

EIF2 EIF2P Inhibition of

translation

Mechanism of action of Mechanism of action of MxA, OAS1 and PKRMxA, OAS1 and PKR

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

NF-κB IRF3

ACTIVATION OF TRANSCRIPTION FACTORS UPON INNATE ACTIVATION OF TRANSCRIPTION FACTORS UPON INNATE IMMUNE RESPONSEIMMUNE RESPONSE

Primary responsePrimary response

INNATE/NATURAL IMMUNITY

MECHANISMS

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 citotoxicity of NK-cells

Activation of - and γδ T-cells

Increased cross-presentationin myeloid dendritic cells

IRAK-1

TRAF-6

IRF-7

MULTIPLE EFFECTS OF TYPE I INTERFERONS

Bacterium

Complement proteins Lysis of bacteria

Inflammation

Complement-dependent phagocytosis

COMPLEMENT

PhagocytosisIntracellular killing

PHAGOCYTOSIS Phagocyte

Bacterium

CELLULAR AND HUMORAL MECHANISMS OF INNATE IMMUNITY

INFLAMMATION

BacteriumLPS

Cytokines Neutrophil

NK-cell

Macrophage

TNF

IL-12

IFN

NK-CELLSVirus-infected

cell

NK-cell Lysis of infected cell

DegradationACTIVATION

Uptake

PHAGOCYTOSIS

MECHANISMS OF INNATE IMMUNITY

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

Cytokines/chemokines produced by activated Cytokines/chemokines produced by activated macrophages - macrophages -

local and systemic effects local and systemic effects

Szisztémás hatás

Failure of phagocytes to produce reactive oxigen speciesin chronic granulomatous didease

PROTECTIONPROTECTION

against against bacteriabacteria and and fungifungi is down is down

regulatedregulated

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

MECHANISMS OF INNATE IMMUNITY

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 citokines in bacterial

infection

TNF-IL-1IL-6

Few hours

ACUTE PHASE RESPONSE

Bacterium

LPS

DANGER SIGNAL

ACTIVATION

PRR

MECHANISMS OF INNATE IMMUNITY

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

MECHANISMS OF INNATE IMMUNITY

CELLS

HUMORAL

FACTORS

Phagocytes (monocyte/macrophage, neutrophil, dendritic cell)

Killer cells (NK cell, δ T cell)

B1 lymphocytes (CD5+)

Enzymes (lysozyme,transferrin, lactoferrin, spermin, trypsin)

Antibacterial peptides

Complement system

Cytokines, chemokines

TWO LINES OF IMMUNE DEFENSE

TWO TYPES OF IMMUNE RESPONSES

INNATE/NATURAL IMMUNITY

B1 cells:Fast response within 48 hrsT cell independentSurface IgMLong life spanPeritoneal cavity

γδ T-cells:skin, gutslimited diversityBinds pathogen derived organic phosphatesexpress NKG2DNKT-cells:fast responselipid antigensswift cytokine release

NATURAL/INNATE• Rapid, prompt response

(hours)• No variable receptors• Limited number of

specificities• No improvement during

the response• No memory• Not transferable• Can be exhausted,

saturated

CHARACTERISTICS OF INNATE IMMUNITY

COMMON EFFECTOR MECHANISMS FOR THE ELIMINATION OF PATHOGENS

TOW LEVELS OF DEFENSE

TWO TYPES OF THE IMMUNE RESPONSE

INNTE/NATURAL IMMUNITY

Protects without prior activation or multiplication against pathogens

AQUIRED/ADAPTIVE IMMUNITY

Protects after activation and clonal expansion against pathogens

First line of defense

Inrerited

Persistant presence

Rapid response

Short term protection