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The role of the basophil in allergic disease

Speaker: Bernhard F Gibbs

29 September 2012


The Role of the Basophil in Allergic Disease

Bernhard F. Gibbs


Disclosures Bernhard F. Gibbs, apl. Prof. Dr., University of Kent •

Lecture fees: ALK

Industry-sponsored grant (institution): N/A

Consultancy: N/A


Origins of some allergic effector cells Bone marrow

Other tissues Tissues

Blood

Fibroblast

IL-5

IL-3

SCF

CD34

Stem cells

Eosinophils

Mast cells

Basophils

MCTC

MCT

(tryptase only) “Mucosal mast cells”

(tryptase and chymase) “Connective tissue mast cells”


Mast cell/basophil depleted animal models Mast cell deficient mice

either:

k.o SCF production sl/sld

(can reconstitue mc’s by giving SCF)

or:

ckit ligand/ stem cell factor (SCF)

k.o cKit expression w/wv

BUT

cKit receptor

IL-3 k.o. mice still have basophils!!!! Redundancy of IL-3?


isolate and purify mouse basophils

inject into rat

inject into mice monoclonal antibodies deplete circulating basophils


Nature Immunology, July 2009

Allergen sensitization

Allergen

Internalized & processed

Antigen

Y

Antigen Presenting Cells ● Dendritic cells ● Macrophages ● B cells

APC

Major Histocompatibility Complex (MHC) Or Human Leukocyte Antigen (HLA)

MHC II

Migrates from the tissues to the lymph nodes

MHC II

Th2

Th CD4

Activation

Y

IL-4

B cell

IL-13

IL-4

IgE Antibodies

IL-1

Y

Sensitization Y

APC

Helper T cell (Th)

Y

TCR

Class-switching to IgE Antibody production

Y

1° exposure

YY

Mast cells Basophils


Mouse

IgG receptor: Stimulatory Histamine: ? FceRI: + IL-4: + CD49b: + CD203c: ? CCR3: ? CD123: ? MHCII/HLA-DR: High

?

Human

Inhibitory Yes + + ? + + + low


Allergen-mediated activation of basophils

B-cell IgE synthesis

Sensitization stage ď‚­ Fcď ĽRI expression

APC?

NH2

H

N

N

Histamine Itching

Th2 development

LTC4

Bronchoconstriction

IL-13 IL-4 VCAM-1 induction

Vascular permeability Leukocyte migration

VEGF

Angiogenesis


Crosslinking

BASO

BASO

BASO

BASO

BASO

Allergen

Lectin

Superantigens

Anti-IgE

Anti-FcRI

Specific IgE‘s

Non-IgE-Specific fMLP TLR2,-4,-9 BASO

INNATE IMMUNITY

IPSE

Non-crosslinking?!


Allergen

Basophils

Mast cells

Chemotaxis IL-3 IL-5 GM-CSF RANTES Eotaxin NGF

 Lung  Skin  Nose  Gut Histamine Eicosanoids

Allergic symptoms

Blood

Other tissues


Functional heterogeneity between human mast cells and basophils

Stimuli

Basophils Primer + IL-3 IL-5 NGF Eotaxin RANTES GM-CSF IL-33

YY

Substance P Allergen fMLP Ionophores c 48/80 C5a C3a Peptide 401 HRF

Mast cells YY

Mastoparan MCTC only

Mediators

Histamine IL-4 IL-13 TNFα? IL-3 (autocrine action)

Tryptase (Chymase)

VEGF LTC4

PGD2

TNF IL-8 IL-4 IL-13

+ Primer SCF


Th2-Type Cytokine generation in man: Mast cells or basophils? Cultured basophils but not cultured mast cells induce human IgE synthesis in B cells after immunologic stimulation (Yanagihara et al, Clin Exp Immunol 1998)

Mast cell

+ Ag

addition of rhIL-4 had no effect!

X Human cord blood

Y Y

IgE

B cell

Y

Y

CD40l

Basophil

IL-4 IL-13

-

IgE

Y

Y Y

Anti-IL-4 Anti-IL-13 Anti-CD40L

Y


Is basophil function different within inflamed tissues? Hours Basophils

[Low allergen] ď‚ŻpH Hypoxia

Blood

Other tissues


Involvement of HIF-1 in VEGF production and support of glycolysis HIF-1

Proteasomal degradation

Hypoxia HIF-1 HIF-1 HIF-1 HIF-1  Gene transcription

VEGF VEGFR EPO Transferrin

Angiogenesis

CD18β2

Adhesion

Nucleus

GAPDH Triose-phosphate isomerase Lactate dehydrogenase Glucose transporter

Glycolysis

•IgE-dependent crosslinking leads to:  ATP

Eur. J. Immunol (2009) 39, 3511-3519

HIF-1 stabilization •Stimulus concentration -dependent (not bell-shaped)


Involvement of HIF-1 in VEGF production and support of glycolysis HIF-1 expression by siRNA  VEGF not reversed by adding ATP  IL-4 reversed by ATP

VEGF synthesis is directly controlled by HIF-1, IL-4 only by  glycolysis


Rapid effects of allergen immunotherapy on basophil function

Adapted from: Akdis JACI 2007

Mechanism for early desensitization effect?


Histamine release (% )

SHIP phosphorylation is negatively associated with basophil reactivity Non-responders Moderate responders High responders

100 80 60 40 20

1

0.1

0.01

0.001

0.0001

Control

0

Moderate responders High responders 100 80 60 40 20

1

0.1

0.01

0.001

0.0001

0

Control

Histamine release (% of max.)

Anti-IgE (% )

Anti-IgE (% )

• Releasability is associated with increased Syk/p38MAPK but decreased SHIP activation. • However, SHIP also regulates basophil mediator release following supraoptimal stimulation

BF Gibbs et al, JACI (2006)


Summary Basophils: • May play a role in INNATE IMMUNITY by responding to non-

specific IgE-dependent and -independent triggers. However, their ability to act as APCs is not clear....

• They orchestrate chronic allergic inflammation and support Th2 immunity due to IL-4/IL-13 synthesis • HIF-1 contributes to basophil survival and ability to release cytokines over long periods

• SHIP plays an essential role in downregulating IgE- receptormediated signal transduction – rapid desensitization during SIT?


Acknowledgements Vadim Sumbayev (UoK, UK)

Francesca Levi-Schaffer (HUJ, IL)

Elena Borzova (NNUH, UK) Clive Grattan (NNUH, UK)

Gitte Lund (Alk, DK) Kaare Lund (Alk, DK) Lars Christensen (Alk, DK)

Franco Falcone (Nottingham, UK) Gideon Lack (KCL, UK) Alexandra Santos (KCL, UK)

Thank you!

Funding: University of Kent, Asthma UK, MRC, Alk, DFG SFB-TRR22, KCL, NNUH,

Bernhard F Gibbs  
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