Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

FCΕ RECEPTOR SIGNALING

Tímea Berki and Ferenc BoldizsárSignal transduction

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

TÁMOP-4.1.2-08/1/A-2009-0011

Mast cell activation mechanisms

• They express several hundred thousand high affinity receptors for IgE (FceR1) and thus respond to IgE-directed antigens

• Express the pathogen-recognizing Toll-like receptors (TLRs) which probably account for the ability of mast cells to mount an effective innate immune response

Stem cell factor cKit Production of cytokines

Pathogens TLRsGranule constituents: histamine, proteases, proteoglycans

Allergens FceRI Synthesis of eicosanoids from arachidonic acid

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Selected mediators produced by mast cells

Mediators Potential role in atherosclerosis

Pro-inflammatory cytokines:IL-4, IL-5, IL-6, IL-13, IL-18, IFN- , γTNF-α

•chemotaxis •endothelial cell activation •monocyte recruitement •induction of protease expression

Chemokines:MCP-1, IL-8, RANTES, eotaxin, leukotriene

•monocyte recuitement •foam cell formation

Proteases:Tryptase, chymase, angiotensin converting enzyme (ACE), carboxypeptidase, cathepsin G, cysteinyl cathepsins

•endothelial cell activation •fibrinogen cleavage •angiotensis II generation •lipoprotein degradation •tissue/vascular remodelling •protease activation

Hematopoeitic factors:IL-3, GM-CSF

•hematopoiesis •foam cell formation

Growth factors:bFGF, VEGF, TGF-b, PDGF

•angiogensis •cellular proliferation

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Other mast cell activators• MIP-1a: macrophage inflammatory chemokine• C3a, C5a anaphylatoxins: complement• Neuropeptides : P-substance, somatostatin, VIP• FcgR - IgG

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IgE bound FceR I

a1a2

Ce2

C e4

C H3Ce2

C e3

C e4

V L

C L

VH VH

Cε1

Ce1

VL

CL

b

N

C

P

g

N N

C C

ITAMsPP

P P

a

IgE

FceR I

Bound IgE

a

N

C

b

N

C

P

g

N N

C C

ITAMs

PP

P P

FceR I

LYN SYK

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FceR II

N N N

C-terminal tail

Head domain

Coiled-coil stalk

N-linked glycolisation

Ce2

C e4

C H3Ce2

C e3

C e4

V L

C L

VHV

H

C1ε

Ce1

VL

CL

IgE

FceR II

IgE bound FceR II

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IL-4 and IL-13 signal induceIgE switch

P

P

JAK3JAK1P

P

P

STAT6

Tyk1

IL-4

IL-4Ra gC

Tyk2

JAK1P

P

P

STAT6

IL-13

IL-4Ra IL-13Ra1/2

STAT6 dimertranslocates to nucleus

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The IgE promoter region

BSAP – B cell specific activator proteinC/EBP CCAAT/enhancer binding proteinPU.1 – Spi1 equivalent in humans

Ie

Ce1 Ce2 Ce3 Ce4SeIe

NFBStat6C/EBP PU.1 BSAPAP-1

Activation/cytokineresponsive promoter

IL-4,13 CD40L

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Signal transduction pathways

IP3

Plasma membrane

GRB2

SOS

SYK

PLCg

Ca2+

LATGADs

DAG

PKC

SPL-76

LYNP

P

a

bg

FceR I a

bg

FceR I

BTK

VAV

Nck

Antigen

IgE

Cytoplasm

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FceRI mediated signaling

PIP3

BTK Sphingosine

SK

PLD

IP3

PIP2

RAS

RAS

MAPKKKor RAF MAPKK MAPKs

Cytokines Degranulation

Transcription factors

Plasma membraneLipid raft

GRB2

SOS

NTAL

?

P PY

P Y

PY

GAB2

GRB2

a

bg

FceR I

LYNSYK SYK PI3K

PLCg

VAV

Ca2+

GTP

GDP

S1P

FYN

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Similarities in TcR and FceR signaling

LynLck

gg b

a

IgE

ITAM

FceRI

Antigen-specific receptor

Src-family kinase

Syk-family kinase

ZAP-70 expression is restricted to T cells, NK cells and a subpopulation of CLL

Syk is present in most hematopoetic cell types

TCR

CD3a b

zzgd e e

CD3

ITAM

SykZAP-70 ZAP-70

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Biological effects of FcεR signaling

PP P

PPP

PP

P PSignaling pathways

Enzymatic modificationof arachidonic acid

Transcriptional activationof cytokine genes

Granule withpreformed mediators

Granule exocytosis

Lipid mediators

Secretion Secretion

Cytokines

Leukotrienes ProstaglandinsVasoactive amines Cytokines, e. g., TNF

Vascular dilatation,smooth muscle contraction

Tissue damage Vascular dilatationSmooth musclecontraction

Inflammation(leukocyte recruitment)

Allergen

Proteases

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Mast cell mediators• Biogen amines: histamin, serotonin (H1,2,3,4R) →

vasodilatation, plasma leak, smooth muscle consriction

• Serin proteases: tryptase, chymase, carboxypeptodase A, cathepsin G

• Proteoglycans: heparin, chondroitin sulphate• Lipid mediators: rapid de novo synthesis

ProstaglandineD2, Leukotrien C4, D4, E4, PAF → vasodilatation, bronchus constriction

• Cytokines: TNF, IL-1, IL-4, IL-5, IL-6, IL-13, MIP-1a, IL-3, GM-CSF