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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Barrier dysfunction - Th2 Immunity - Microbial Dysbiosis:
Determinants of Atopic Dermatitis and Implications for New Treatments
Tilo Biedermann, MD
Professor & Chairman
Dept. of Dermatology and Allergy
Technical University Munich, Germany
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
• Introduction into atopy and AD
• Barrier dysfunction and Th2 immunity
• Consequences for AD treatment
• Microbial dysbiosis in AD pathogenesis
Barrier dysfunction - Th2 immunity - microbial dysbiosis in atopic dermatitis
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Genotypes (complex genetic trait) – Phenotypes (environmental triggers)
Atopic Dermatitis Allergic Asthma
Allergic Rhinoconjunctivitis
Gene 1:Mutation
Loss of protein
SNPs
Single Nucleotide Polymorphisms
Gain-of-function
SNPs
Single Nucleotide Polymorphisms
Loss-of-function
Gene 2:Mutation
Loss of protein
SNPs
Single Nucleotide Polymorphisms
Gain-of-function
SNPs
Single Nucleotide Polymorphisms
Loss-of-function
Gene 3:Mutation
Loss of protein
SNPs
Single Nucleotide Polymorphisms
Gain-of-function
SNPs
Single Nucleotide Polymorphisms
Loss-of-function
Gene 4:Mutation
Loss of protein
SNPs
Single Nucleotide Polymorphisms
Gain-of-function
SNPs
Single Nucleotide Polymorphisms
Loss-of-function
Gene 5:Mutation
Loss of protein
SNPs
Single Nucleotide Polymorphisms
Gain-of-function
SNPs
Single Nucleotide Polymorphisms
Loss-of-function
Gene 6:Mutation
Loss of protein
SNPs
Single Nucleotide Polymorphisms
Gain-of-function
SNPs
Single Nucleotide Polymorphisms
Loss-of-function
Food allergy
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
• Introduction into atopy and AD
• Barrier dysfunction and Th2 immunity
• Consequences for AD treatment
• Microbes in AD pathogenesis
Barrier dysfunction - Th2 immunity - microbial dysbiosis in atopic dermatitis
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
View
Dermatology
- Dry skin
- Reduced barrier
Atopic Dermatitis
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Hudson TJ. News&Views. Nat Genet. 2006;38:399-400
Palmer CN et al.. Nat Genet. 2006;38:441-6
Smith FJ et al.. Nat Genet. 2006;38:337-4
Mutation of the gene `Filaggrin´ associated with atopic dermatitis
Irvine AD. N Engl J Med. 2011; 365:1315-1327
- Impermeable proteolipids
- Low surface pH
- Antimicrobial activity
- `Natural moisturing factor´ (NMF)
Filaggrin:
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Atopic Dermatitis
Hudson TJ. News&Views. Nat Genet. 2006;38:399-400
Palmer CN et al.. Nat Genet. 2006;38:441-6
Smith FJ et al.. Nat Genet. 2006;38:337-4
Irvine AD. N Engl J Med. 2011; 365:1315-1327
Signals
for
Immune system
Anti-microbial peptides
Barrier
Eyerich K, Eyerich S, Biedermann T. Trends Immunol 2015
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Epid
erm
is
antimicrobial peptides
barrier
Adaptive immunity and atopic dermatitis
IL-4
Howell et al.. Immunity. 2006;24:341-8.
Ong et al. N. Engl. J. Med. 2002; 347:1151-1160
Howell et al. J All Clin Immunol 2009; 124, R7-R12
Guenova E et al.. Proc Natl Acad Sci U S A 2015:112: 2163-8
DZTh17
Th1
Interferon-g
Interleukin-17Interleukin-23
Th2
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
View
Dermatology
View
Immunology/Allergology
- Dry skin
- Reduced barrier
- “Allergy“
- Th2-disease
Atopic Dermatitis
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Microbiome and atopic dermatitis
Kong-HH et al. Genome Res 2012
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Kong-HH et al. Genome Res 2012
Microbiome and atopic dermatitis
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
View
Dermatology
View
Immunology/Allergology
- Dry skin
- Reduced barrier
- “Allergy“
- Th2-disease
Atopic Dermatitis
- “Infections“
- Cutaneous microbiome
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
• Introduction into atopy and AD
• Barrier dysfunction and Th2 immunity
• Consequences for AD treatment
• Microbial dysbiosis in AD pathogenesis
Barrier dysfunction - Th2 immunity - microbial dysbiosis in atopic dermatitis
Page 14
Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
T
TDC
T
T
T
T
TT
DCDC
`Immunity´
Consequences of innate immune signaling
Innate immunity Adaptive immunity
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Triggers of chronic atopic dermatitis
Toll-like receptor 2 ligands
Staphylococcus aureus Malassezia species Herpes simplex
Hypothesis: TLR2 ligands trigger atopic dermatitis
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Pathogenesis of chronic atopic dermatitis
Th2
IL-4
Th2
Staphylococcus aureus
Th2 inflammation
innate immune sensing
of S. aureus
?
Interplay
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Th2 + OVA
Th2+ OVA + Pam2Cys
OVA
Pam2
Th2
0
5
10
15
20
0 2 4 6 8 10 12 14 16
ear
sw
ellin
g (
x 0
.01m
m)
One single exposure to one TLR2 ligand
Days following actvation
Kaesler et al. J Allerg Clin Immunol 2014
• Dependent on IL-4
Pathogenesis of chronic atopic dermatitis
Skabytska et al.. Immunity 2014
Th2
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
• Introduction into atopy and AD
• Barrier dysfunction and Th2 immunity
• Consequences for AD treatment
• Microbial dysbiosis in AD pathogenesis
Barrier dysfunction - Th2 immunity - microbial dysbiosis in atopic dermatitis
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
• Rapid first response
• Immediate `relief´
• Complete response at about day 30
• Side effects: Conjunctivits
Blauvelt et al. The Lancet 2017;389:2288
New therapeutic strategies for atopic dermatitis
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Inflammation Tolerance
Inflammation
Tolerance
`Good´ microbes as therapeutic strategy?
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Vitreoscilla filiformis
Double-blind, prospective, randomized trial
75 patients with mild atopic dermatitis
Rando-
misation Day 0 (Visit 1) Day 15 (Visit 2) Day 29 (Visit 3)
Evaluation, SCORAD, TEWL on days 0 / 15 / 29
randomized in 2
groups (1:1)
Glycerylmono/-distearate, Polyethylenglycol-
stearat, 5% Isoparaffin, 15% Cyclopentadi-
methylsiloxan, 3% Glycerin and 2% Vaseline
(Vehicle)
Vehicle plus
5% Vitreoscilla
filiformis lysate
`Good´ microbes as therapeutic strategy?
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Gueniche et al. Br J Dermatol. 2008; Volz et al. J Invest Dermatol 2014
* p=0.004
10
15
20
25
30
35
Day 0
SC
OR
AD
Day 15 Day 29
* p < 0.0001
* p < 0.0001
n.s.
n.s.
Placebo
Verum
V. filiformis
Creme
`Good´ microbes as therapeutic strategy?
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
DZ
Volz et al. J Invest Dermatol 2014
TLR2 ligands
IL-10 IL-12
DC Treg
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Barrier dysfunction - Th2 Immunity - Microbial Dysbiosis in AD
Conclusion
• Th2 bias prerequsite for AD development Antimicrobial peptides down
Barrier function down
Antimicrobial immunity down
Th2
• S. aureus: Transition from acute to chronic AD
• Targeting the Th2 pathway – revolution for AD
TR1
• Cutaneous S. aureus overgrowth
• Further patient stratification (responder – non-responder analyses)
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
• Ecosystem `cutaneous microbiota´
Barrier dysfunction - Th2 Immunity - Microbial Dysbiosis in AD
Conclusion
• `Hen and egg´ problem Barrier down first?
Dysbiosis first?
Th2 first?
• Immune regulation
by non-pathogenic bacteria TR1
• Perspective for the `microbiome´
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Klinik und Poliklinik für Dermatologie und Allergologie
EADV/AAD Joint Symposium New York, 27.07.2017
Thank you for your attention!!
Barrier dysfunction - Th2 Immunity - Microbial Dysbiosis: Determinants of Atopic Dermatitis and Implications for New Treatments
• Susanne Kaesler
• Yuliya Skabytska
• Thomas Volz
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(665)
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