Barrier dysfunction - Th2 Immunity - Microbial Dysbiosis S002... · Klinik und Poliklinik für Dermatologie und Allergologie EADV/AAD Joint Symposium New York, 27.07.2017 Barrier

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



• 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



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


Loss-of-function

Gene 2:Mutation

Loss of protein

SNPs


Gain-of-function

SNPs


Loss-of-function

Gene 3:Mutation

Loss of protein

SNPs


Gain-of-function

SNPs


Loss-of-function

Gene 4:Mutation

Loss of protein

SNPs


Gain-of-function

SNPs


Loss-of-function

Gene 5:Mutation

Loss of protein

SNPs


Gain-of-function

SNPs


Loss-of-function

Gene 6:Mutation

Loss of protein

SNPs


Gain-of-function

SNPs


Loss-of-function

Food allergy






• Microbes in AD pathogenesis




View

Dermatology

- Dry skin

- Reduced barrier

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

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:



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



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



View

Dermatology

View

Immunology/Allergology

- Dry skin

- Reduced barrier

- “Allergy“

- Th2-disease

Atopic Dermatitis



Microbiome and atopic dermatitis

Kong-HH et al. Genome Res 2012



Kong-HH et al. Genome Res 2012

Microbiome and atopic dermatitis



View

Dermatology

View

Immunology/Allergology

- Dry skin

- Reduced barrier

- “Allergy“

- Th2-disease

Atopic Dermatitis

- “Infections“

- Cutaneous microbiome










T

TDC

T

T

T

T

TT

DCDC

`Immunity´

Consequences of innate immune signaling

Innate immunity Adaptive immunity



Triggers of chronic atopic dermatitis

Toll-like receptor 2 ligands

Staphylococcus aureus Malassezia species Herpes simplex

Hypothesis: TLR2 ligands trigger atopic dermatitis



Pathogenesis of chronic atopic dermatitis

Th2

IL-4

Th2

Staphylococcus aureus

Th2 inflammation

innate immune sensing

of S. aureus

?

Interplay



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










• 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



Inflammation Tolerance

Inflammation

Tolerance

`Good´ microbes as therapeutic strategy?



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




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




DZ

Volz et al. J Invest Dermatol 2014

TLR2 ligands

IL-10 IL-12

DC Treg



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)



• 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´



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

(1394)

(665)

(1500)

Documents

Barrier dysfunction - Th2 Immunity - Microbial Dysbiosis S002... · Klinik und Poliklinik für Dermatologie und Allergologie EADV/AAD Joint Symposium New York, 27.07.2017 Barrier