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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen

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(1)

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(2)

FCΕ RECEPTOR SIGNALING

Tímea Berki and Ferenc Boldizsár Signal transduction

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(3)

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 TLRs

Granule constituents: histamine,

proteases, proteoglycans

Allergens FceRI

Synthesis of eicosanoids from

arachidonic acid

(4)

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-γ, TNF-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

(5)

Other mast cell activators

• MIP-1a: macrophage inflammatory chemokine

• C3a, C5a anaphylatoxins: complement

• Neuropeptides : P-substance, somatostatin, VIP

• FcgR - IgG

(6)

IgE bound FceR I

b

N

C P

g N N

C C

ITAMs P P

P P

a

IgE

FceR I Bound IgE

a N

C

b

N

C P

g N N

C C ITAMs

P P

P P

FceR I

LYN SYK

(7)

FceR II

N N N

C-terminal tail

Head domain

Coiled-coil stalk

N-linked glycolisation

IgE

FceR II

IgE bound FceR II

(8)

IL-4 and IL-13 signal induce IgE switch

P P JAK3

JAK1 P

P P

STAT6 Tyk1 IL-4

IL-4Ra gC

Tyk2 JAK1

P

P P

STAT6 IL-13

IL-4Ra IL-13Ra1/2

STAT6 dimer translocates to nucleus

(9)

The IgE promoter region

BSAP – B cell specific activator protein C/EBP CCAAT/enhancer binding protein PU.1 – Spi1 equivalent in humans

Ie

Ce1 Ce2 Ce3 Ce4 Se

Ie

NFB Stat6

C/EBP PU.1 BSAP

AP-1

Activation/cytokine responsive promoter

IL-4,13 CD40L

(10)

Signal transduction pathways

IP3

Plasma membrane

GRB2 SOS

SYK

PLCg

Ca2+

LAT GADs

DAG

PKC SPL-76

LYN

P P a

g b

FceR I a

b g

FceR I

BTK

VAV Nck

Antigen IgE

Cytoplasm

(11)

FceRI mediated signaling

PIP3

BTK Sphingosine

SK

PLD

IP3 PIP2

RAS RAS

MAPKKK

or RAF MAPKK MAPKs

Cytokines Degranulation

Transcription factors

Plasma membrane Lipid raft

GRB2 SOS

NTAL

?

P Y P P Y

P Y

GAB2 GRB2 a

g b

FceR I

LYN

SYK SYK PI3K

PLCg

VAV

Ca2+

GTP GDP

S1P

FYN

(12)

Similarities in TcR and FceR signaling

Lyn Lck

g g 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

CD3

a b z z g

d e e

CD3

ITAM

Syk ZAP-70 ZAP-70

(13)

Biological effects of FcεR signaling

P

P P

P P

P

P P

P P

Signaling pathways

Enzymatic modification of arachidonic acid Transcriptional activation

of cytokine genes

Granule with preformed mediators

Granule exocytosis

Lipid mediators

Secretion Secretion

Cytokines

Leukotrienes Prostaglandins Vasoactive amines Cytokines, e. g., TNF

Vascular dilatation, smooth muscle contraction

Tissue damage Smooth muscle Vascular dilatation

contraction Inflammation

(leukocyte recruitment)

Allergen

Proteases

(14)

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

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