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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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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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9/38Grice E et al. Science. 2009
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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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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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)
Kong et al. Genome Res 2012.
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Drop in microbial diversity during ADflare specific to sites of predilection
Popliteal
fossa
Antecubital
fossa
Volar
forearm
Nares
(N=11)
Kong et al. Genome Res 2012.
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Staphylococcus spp increaseduring AD flares
Kong et al. Genome Res 2012.
?
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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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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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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