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Eczema, immunity &

the skin microbiome

Heidi H. KongDermatology Branch, CCR, NCI

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Eczema, immunity &the skin microbiome

Do skin microbes influence host skinimmunity?

Healthy human skin microbiomesurveys

The microbiome in eczematous skin Atopic dermatitis Primary immunodeficiency syndromes

Gaps, needs & challenges

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Skin commensals restore immunity toLeishmania major in germ-free mice

0

250

500

750

P a r a s

i t e s p e r

1 0 3

c e

l l s

SPF GF S.epi

I F N -

CD4

20 9 50

L. major

SPF GF GF+S. epidermidis

Parasite Burden

Naik S et al . Science 2012

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The host immunity-microbialinteractions in skin are distinct.

In mice, skin microbes can Tune the level of activation & function of

skin-resident T cells, Promote immunity to pathogens, & Drive responses locally that are distinct

and independent from the gut flora.

What about human skin immunity-

microbial interactions?

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Relative abundance of predominantbacteria dependent on microenvironment

D r y

M o

i s t

S e

b a c e o u s

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Life stages

Infant Child Adult Elderly

Carefullydefined cohorts

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Life Stages

Infant Child Adult ElderlyTannerstages

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Shifts in healthy skin and nare microbiomesTanner stages 1-3 vs. 4-5

Oh et al. Genome Med 2012

Lipophilic bacteria

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What about non-bacterial membersof the skin microbiome?

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http://www.biomedcentral.com/1471-2415/8/7/figure/F1?highres=y

Sequencing fungal organisms

Optimizing sample collection Optimizing DNA extraction (bead-beating) Selecting primers (Internal Transcribed Spacer, ITS) Selecting a robust database

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Survey of fungal diversity in human skin

Findley K, Oh J et al . Nature. 2013.

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Peripheral skin sites harbor a greaternumber of different species

F U N G I

BACTERIA Findley K, Oh J et al . Nature. 2013.

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Skin microbiome in healthyindividuals

Skin bacterial microbiome is highlydependent on sampled skin site. Neonatal skin bacterial microbiome varies

based on mode of delivery. Dramatically shifts between Tanner stages 1-3

and 4-5. Fungal communities over skin surface vary

differentially from bacterial microbiome.

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Atopic Dermatitis (AD)

Chronic itchy inflammatoryskin condition

15% US children Direct costs = $2 billion/yr Disease flares associated

with colonization andinfections withStaphylococcus aureus

Common treatments include combinations oftopical and systemic antimicrobials and steroids

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Atopic Dermatitis (AD)

Atopic march:40-70% severe AD asthma/hay fever Incidence has doubled in last

three decades in industrializedcountries

Possible external factor Mice: skin exposure to antigens

mucosal sensitization Understanding triggers of AD may allow us to

modify the development of AD/atopic diseasesand develop therapeutic targets

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Skin Barrier(Filaggrin)

ImmuneSystem

(IgE, AMP)

Microbes(S. aureus, viral

infections)

AD is a complex disease

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Baseline

Flare

Post-flare

26.2

47.353.6

11.136.7

28.2

Atopic dermatitis skin microbiome

Objective SCORAD range: 0-83

Pediatric patientswith moderate tosevere disease(N=12)

Healthy age-matched controls(N=11)

Sampledcharacteristicallyaffected areas

Kong et al. Genome Res 2012.

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Skin bacterial diversity correlates withAD disease severity

Increasingbacterial

communitydiversity

Increasing disease severity

N=12

(0-83)


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Drop in microbial diversity during ADflare specific to sites of predilection

Popliteal

fossa

Antecubital

fossa

Volar

forearm

Nares

(N=11)


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Staphylococcus spp increaseduring AD flares


?

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In contrast, fungal communities can bestable despite disease flares

unpublished

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What can we learn from patients withprimary immunodeficencies with

eczematous skin disease? Monogenic disorders AD-like dermatitis Antibiotic-responsive

Do common and raredisorders with similarphenotype share skinmicrobiome features?

How does innate andadaptive immunity shapeskin microbiome?

Eczema

Immunity Microbes

Skin Barrier

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What can we learn from patients withprimary immunodeficencies with

eczematous skin disease? Hyper IgE syndrome(STAT3 mutations)

Staphylococcal skin &

lung infections Candidal infections Secondary Aspergillus

lung infections STAT1 mutations

Chronicmucocutaneous

candidal infections

Eczema

Immunity Microbes

Skin Barrier

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Exposure to certain skin microbes may alterPBMC cytokine response to pathogens

Smeekens et al. J Innate Immun . 2013.

#1 Corynebacterium OR Acinetobacter OR Staphylococcus

+

PBMCs

#2 C. albicans OR

S. aureus Acinetobacter baumaniiTNF - , IFN- & IL-22 inhealthy volunteerPBMCs

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Primary immunodeficiency patients arecolonized with atypical skin microbiota

Serratia,Gammaproteobacteria

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

BaselineAD patients

Hyper IgE SyndromePatients ( STAT3

mutations)

See POSTER #31, Julia Ohunpublished

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Skin microbiome in eczematous skin AD flares are associated with shifts in the

skin bacteria. S. aureus and S. epidermidis

These specific primary immunodeficiencypatients harbor bacterial skin microbiomedistinct from healthy & AD skin. Altering the skin microbiome may alter PBMC

response to specific microbes. More studies needed to understand

microbial role & potential for therapeutic

targets.

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Gaps, needs, challenges Evolution of skin microbiome over life stages Physiological factors contributing to skin

microbiome differences (skin barrier, hormones,etc.)

Skin microbiomeimmunity interactions (human &animal models)

Correlation to causation Magnitude of interaction between fungi & bacteria

and role in health & disease Skin metagenomics

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Deborah SchoenfeldAmynah PradhanSheila Phang

Martin GlatzEffie NomicosMelony BeatsonMaria L TurnerMark C UdeyEric PolleySeth Steinberg

Alexandra FreemanSteve HollandHirsh Komarow

Yasmine BelkaidShruti Naik

Karen FrankAdrian ZelaznyPatrick R Murray

Julie A SegreSean ConlanClay Deming

Elizabeth A GriceJulia OhCynthia NgJennifer ThompsonKeisha FindleyFabio CandottiRobert Sokolic

Elizabeth Garabedian

Jim MullikinGerard BouffardBob BlakesleyAlice YoungTyra Wolfsberg

Morgan ParkEric Green

Our patients & volunteers

AD, Tanner, Fungal sequencingfunded byNIH UH2AR057504 & UH3AR057504

Acknowledgements

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