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Intrinsic molecular properties are not enough
for a protein to become an allergen
Esther C. de Jong
Dept. Cell Biology & Histology
In relation to this presentation, I declare that there are no conflicts of interest.
Type I allergic response
Sensitization
Inflammation
iDC
SM
IL-13
IL-13
Lymph node
Th2
IL-5
mDC
EO
IL-4/IL-5/IL-13
Thn
Th2
IgE
M
B
B
P
IgE
Mediatoren
Induction of specific T cell responses
requires multiple signals
NK
Signal 1
Inflammatory cytokines
chemokines
Signal 2
Tcyt
Th1
Bf
iDC
PMN
PMN
iDC
Tn
Th2
Th17
DC maturation
Th22
Signal 3
Signal 4
Allergenicity of proteins
•
Protease activity
•
Ligation of PRRs (TLRs)
•
Ligation of CLRs
•
Protein structure (folding, dimers)
Effect of allergen protease activity
Shakib et al, Trends Immunol (2008)
Allergens may ligate various receptors
expressed by denritic cells
Scheurer et al, Clin.Exp.allergy (2015)
C type lectins
Figdor et al, NRI (2002)
Ligation of CLRs inhibits TLR-mediated
signaling
Geijtenbeek & Gringhuis, NRI (2009)
CLRs as antigen
uptake receptors
Figdor et al, NRI (2002)
Allergen uptake via C-type lectins increases
T cell responsiveness
MF/
αDEC205
MF
3.6
7.8
5.8
7.7
4.8
IL-4
5.1
MF/
αDEC205-Bet v 1d
13.5
12.4
IFN-γ
11.9
JACI, 2015
Machado et al, JACI (2015)
Pathogen class-specific immunity mediated by T cells
NK
Tcyt
Th1
Viruses
Cancer cells
Tcyt
IFN-g
Mf
Endosomal
pathogens
Tcn
iDC
mDC
Thn
Th2
IL-4/5
EO
IL-9/13
Multicellular
parasites
Bf
Th17
IL-17
Th22 IL-22
Treg
TGF-b
IL-10
PMN
PMN
Bacteria/
Fungi
Tcyt Th1 Th2 Th17Th22
Tolerance
Pathogen class-specific immunity mediated by T cells
NK
iDC
mDC
Tcn
Tcyt
mDC
Thn
Th1
mDC
Thn
Th2
Viruses
Cancer cells
Tcyt
IFN-g
Mf
IL-4/5
EO
IL-9/13
Endosomal
pathogens
Multicellular
parasites
Bf
mDC
mDC
Thn
Thn
Th17
IL-17
Th22 IL-22
Treg
TGF-b
IL-10
PMN
PMN
Bacteria/
Fungi
Tcyt Th1 Th2 Th17Th22
Tolerance
Pathogen class-specific immunity mediated by T cells
NK
iDC
mDC
IL-12
Tcn
IL-27
Tcyt
mDC
IL-12
Thn
Delta-4
Th1
mDC
OX40L
Thn
Jagged1
Th2
Viruses
Cancer cells
Tcyt
IFN-g
Mf
IL-4/5
EO
IL-9/13
Endosomal
pathogens
Multicellular
parasites
Bf
mDC
IL-1/6
Thn
IL-23
mDC
TGF-b
Thn
RA
Th17
IL-17
Th22 IL-22
Treg
TGF-b
IL-10
PMN
PMN
Bacteria/
Fungi
Tcyt Th1 Th2 Th17Th22
Tolerance
Allergic disorders are characterized by a disturbed balance
between effector and regulatory T cells
Th1
Treg
Akdis et al. JEM (2004) 199:1567
SIT restores the balance
Allergic individuals
Healthy individuals
Th2
Th1
Th1
Tr
Th2
SIT
Tr
Vaccine delivery routes
Subcutaneous
(SC)
Intramuscular
(IM)
Intradermal
(ID)
Chester, 1998
Different types of dendritic cells in human skin
Epidermis
Dermis
CD1a (Langerhans cells)
FXIIIa (dermal dendritic cells)
Dendritic cells are functionally heterogenous
Different types of dendritic cells in normal human skin
Langerhans cells
TGF-b
CD1a++/CD14Langerin (CD207)
Birbeck granules
E-cadherin
In vitro/vivo: monocytes -> LCs
CD1a
Dermal dendritic cells
CD1a± / CD14DC-SIGN(CD209)-
CD1a- / CD14+
DC-SIGN(CD209)+
M.B.M.Teunissen
Selective loss of cell surface TLR on Langerhans cells
TGF-b
Extracellular pathogens
LPS (Gram -)
Flagellin
Proteoglycans/Lipoproteins
peptides/zymosan
MD
2
TLR4/TLR4
TLR5/TLR5
TLR2/TLR2 TLR2/TLR1 TLR2/TLR6
bglucans
Dectins
Cytosolic pathogens
dsRNA
dsRNA
dsRNA
MDA5
DAI
RIG-I recognition
….which abolishes bacterial
Endosomal pathogens
ssRNA
ssRNA
dsDNA
dsRNA
TLR7/TLR7 TLR8/TLR8 TLR9/TLR9 TLR3/TLR3
Van der Aar et al, JI (2007), JID (2013)
Dendritic cells are functionally heterogenous
Different types of dendritic cells in normal human skin
Langerhans cells
TGF-b
CD1a++/CD14Langerin (CD207)
Birbeck granules
E-cadherin
In vitro/vivo: monocytes -> LCs
CD1a
Dermal dendritic cells
CD1a± / CD14DC-SIGN(CD209)-
Epidermal LCs favor tolerance to the
bacterial skin flora through ignorance
CD1a- / CD14+
DC-SIGN(CD209)+
M.B.M.Teunissen
The skin is a bacterial zoo
Constante activatie van het afweersysteem
geeft schade aan het weefsel en is gevaarlijk
SIT restores the balance
Allergic individuals
Healthy individuals
Th2
Th1
Th1
Tr
Th2
SIT
Tr
Regulatory T cells associated with various
compounds
Viruses
Cytomegalovirus
Herpes simplex
HIV
Bacteria
Bordetella pertussis
FHA
Helicobacter hepaticus
Lactobaccilli ssp.
LTA
Mycobacterium spp.
SRP299
ManLam
Salmonellae
Yeast
Candida albicans
Zymosan
Protozoa
Leishmania spp.
Listeria major
Toxoplasma gondii
Helminths
A. viteae
ES62
Schistosoma mansoni lysoPS
Etc, etc.
Cytokines
IL-10
TGF-B
Microbial components
CpG-DNA
via PDC!
Drugs
Rapamycin
Cortosteroids
Vitamin D3 analogues
PGD2 analogues
24
Effects of 1,25(OH)2VitD3 on
antigen presenting cells
Hart et al. Nature Review Immunol. 2011
VitD3-primed DDCs and LCs have a reduced
T cell stimulatory capacity
VitD3-primed DDCs and LCs induce
suppressive activity in CD4+ naïve T cells
MF
DDC
*
MF/Vit D3
LC
MF
*
MF/Vit D3
0
25
50
75
Proliferation (%)
100
Only VitD3-primed DDCs induce IL-10
production in naïve CD4+ T cells
MF
MF/VitD3
4.5
15
4.8
6.8
DDC
IL-10
LC
CD4
Only VitD3-primed LCs induce Foxp3
expression in naïve CD4+ T cells
MF
MF/VitD3
41
1.5
36
1
49
8
56
7
40
3
23
4
50
7
46
27
DDC
CD127
LC
FOXP3
VitD3 primed DDCs & LCs induce distinct
types of Tregs
IL-10
mDC
iDC
Maturation/
VitD3
iLC
Tr
TGF-β
mLC
Tr
IL-10+
CTLA-4+
Foxp3_
IL-10CD25+
CD127low
Foxp3+
Van der Aar et al. JACI (2011)
Skin explant protocol
Skin injection of VitD3 induces emigration of
CD14+ dermal DCs
Bakdash et al. Hum Vaccine Immunother.. 2013
Skin injection of VitD3 induces a tolerogenic
phenotype in DCs
Bakdash et al. Hum Vaccine Immunother.. 2013
Vitamin D inhibits antigen-specific proliferation
and cytokine production
10000
+VitD
8000
CPM
6000
4000
2000
D
1d
v
Is
oBe
t
EC
-B
e
tv
1d
-
0
Vitamin D diminishes antigen-specific
proliferation and cytokine production
10000
+VitD
8000
IFNg
IL-13
0.4
0.2
0.4
0.6
0.3
0.4
4000
0.2
0.0
2000
0 0.3
2
0.1
3
0
Bet v 1 d (g/ml)
VitD
1d
v
none
0
0.3
1
2
Bet v 1 d (g/ml)
Is
oBe
t
Bet v 1 d (g/ml)
0.2
0.0
1
1d
3
tv
2
-B
e
1
EC
0.3
D
0
-
0.0
0.8
6000
IL-10 (ng/ml)
CPM
IL-13 (ng/ml)
IFN-g (ng/ml)
0.6
IL-10
3
Vitamin D metabolism
7-dehydroxycholesterol
Cholecalciferol
Calcidiol
Calcitriol
Calcidiol but not cholecaciferol reduces T cell
stimulatory capacity of DCs
Bakdash G. et al. Vaccine 2014
Calcitriol metabolites prime DCs for the
induction of Treg cells
Bakdash G. et al. Vaccine 2014
Calcitriol metabolites prime DCs for the
induction of IFN-g-producing T cells
Bakdash G. et al. Vaccine 2014
SIT restores the balance
Allergic individuals
Healthy individuals
Th2
Th1
Tr
Th1
Th2
Tr
VitD
Pathogen class-specific immunity mediated by T cells
NK
iDC
mDC
IL-12
Tcn
IL-27
Tcyt
mDC
IL-12
Thn
Delta-4
Th1
mDC
OX40L
Thn
Jagged1
Th2
Viruses
Cancer cells
Tcyt
IFN-g
Mf
IL-4/5
EO
IL-9/13
Endosomal
pathogens
Multicellular
parasites
Bf
mDC
IL-1/6
Thn
IL-23
mDC
TGF-b
Thn
RA
Th17
IL-17
Th22 IL-22
Treg
TGF-b
IL-10
PMN
PMN
Bacteria/
Fungi
Tcyt Th1 Th2 Th17Th22
Tolerance
Dendritic cells in tolerance and immunity
Dept. Cell Biology & Histology, AMC, Amsterdam
Esther de Jong
Martien Kapsenberg
Dept. of Dermatology
Marcel Teunissen
Dept. of Experimental
Immunology
Serge Versteeg
Ronald van Ree
Yuri Souwer
Angelic van der Aar
Ghaith Bakdash
Fong Lin
Toni van Capel
Esther Taanman
Femke Muller
Rosa de Groot
Jeroen den Dunnen
Laura Schneider
Lisa Vogelpoel
Ivo Hansen
Kai Jun Liu
Bianca Blom42
Problems in SIT
1. Risk of serious side effects
Using modified allergens
T cell epitope
B cell epitope
Natural defence against pathogens
Start of specific immunity through activation of dendritic cells
Epithelium
Defensines
Chemokines
Cytokines
Endocytosis
Macrophage
Gr
Neutrophil
Platelets
Complement
activation
Coagulation
Cytotoxicity
Fibroblast
NK cell
Endothelium
Induction of specific T cell responses
requires multiple signals
NK
Signal 1
Inflammatory cytokines
chemokines
Signal 2
Tcyt
Th1
Bf
iDC
PMN
PMN
iDC
Tn
Th17
DC maturation
Th22
Signal 3
PathogenAssociated
Molecular
Patterns
Pattern
Recognition
Receptors
DangerAssociated
Molecular
Patterns
Endangered
Tissue
Receptors
Th2
Signal 4
Vitamin D precursors differentially affect
cytokine production by DCs
Bakdash G. et al. Vaccine 2014
Allergen uptake via C-type lectins increases
T cell responsiveness
Allergen uptake via C-type lectins increases
T cell responsiveness
MF/
αDEC205
MF
3.6
7.8
5.8
IL-4
5.1
13.5
12.4
IFN-γ