Gene-Environment Interaction in Chronic Inflammatory Disease

Gene-Environment Interaction in Chronic Inflammatory Disease

Gene-Environment Interaction
in Chronic Inflammatory Disease
Renz H, von Mutius E, et al. Nature Immunology 2011;12:273-7.
Renz H, Autenrieth IB, Brandtzeag P, Cookson WO, Holgate S, von Mutius E, et al.
JACI 2011;128(6):25-49.
Pre- and postnatal environment
opportunity for early
immuno-education
and –programming
Distribution of bacterial phyla
at different anatomical sites
Cho and Blaser Nat Rev Genetics 2012;13:260-70
Microbe – host interaction and immuno-programming
environmental
microbiota
barrier
microbiome
inhalation
oral
environmental
microbial
exposure
- diversity
- dose
- time
respiratory
colonisation
intestinal
microbiome
vaginal
microbiome
cutaneous
microbiome
Figure 3
Abrupt shifts in commensal microbiota
correspond with changes in diet and health
cefdinir
breast milk start
formula and
fever
cow milk and
amoxicillin
table foods
full adult diet
rice cereal
breast milk and
formula end
Koenig, Spor, Scalfone, Fricker, Stombaugh, Knight, Angenent, Ley.
Proc Natl Acad Sci USA 2011;108 Suppl 1:4578-58.
Impact of barrier microbes
on organ-based inflammation
•
•
•
•
allergic phenotype
(intestinal) colonization
mode of delivery
breast feeding
? allergic
• reduced diversity
• dysbiosis early in life
(0 ~ 6 mths)
birth
infancy
Sensitization (Th2)
Eczema
cause-effect Food allergy
relationship? Allergic rhinitis /
asthma
preceeds
(+)
(+)
(+/-)
(?)
diversity; # of OTUs
healthy
Maternal Factors
childhood
Garn H, Neves JF, Blumberg RS, Renz H.
JACI 2013;131(6):1465-78.
Altered microbiome preceeds development
of allergic phenotypes
Reduced diversity/
altered composition at
Phenotype
Assessed at
1 month
Eczema
2 years
Abrahamsson et al.
JACI 2012;129:43440.
day 7
Eczema
12 months
Ismail et al. PAI
2012; 23:674-81.
1 week
Eczema
18 months
Wang et al. JACI
2008; 121:129-34.
1 week / 12 months
IgE, eos., rhinitis;
not asthma,
eczema
up to 6 years
Bisgaard et al. JACI
2011; 128:646-52.
3 weeks
asthma
Vael et al. BMC
Microbiol 2011;
11:68.
Disturbed distribution of bacterial airway
colonization in children with difficult asthma
Asthma
- BAL fluids
- children with
difficult asthma
vs. controls
- no infections;
no antibiotics
Control
Hilti et al, Plos one, 2010
Mild asthma and microbiota
induced sputum
l6S rRNA
Marri et al, JACI 2013
Asthma associated microbiota in induced sputum
Marri et al, JACI 2013
Bacterial taxonomic classifications
in the AD skin microbiome.
Heidi H. Kong et al. Genome Res.
2012;22:850-859
© 2012, Published by Cold Spring Harbor Laboratory Press
Flare
Temporal shifts in skin microbiome associated with
disease activity
AD microbiome progression hypothesis.
Heidi H. Kong et al. Genome Res.
2012;22:850-859
© 2012, Published by Cold Spring Harbor Laboratory Press
Gut colonization with clostridium cluster I
at week 5 determines development of AD
non-colonized
colonized
Penders et al, JACI 2013
Microbial metabolites impact host response
• Short chain fatty acids
• Polysaccharide
• Peptidoglycane
• Trimethyl-amin-n-oxide
• 4-ethylphenol (sulfate)
Dorrestein, Mazmanian, Knight, Immunity 2014
Metabolites produced by commensal microbiota
promote T-reg generation
Clostridia
starch
fermentation
SCFA
(butyrate, propionate)
histone deacytylase
(HDAC)
H3 acetylation
Foxp3-Treg
(colon)
Arpaia et al, Nature 2013
Short chain fatty acids and gut homeostasis
Thorburn, Macia, Mackay, Immunity 2014
Tryptophan – Microbes – Immunity
Aryl hydrocarbon receptor
Thorburn, Macia, Mackay, Immunity, 2014
TLR-5 KO develop obesity
Vijay-Kumar et al., Science 2010;328:228-231.
Caesarean delivery: Allergy and asthma risk
Medline 1966-2007
26 studies
Bager et al, Clin Exp Allergy, 2009
Diversity of mother´s body habitats
Dominguez-Bello et al; PNAS 2010
Delivery – microbiota – asthma and atopy
at 1 month
n = 117.6
Clostridium
difficile
at 6/7 years
a
vaginal
Mode & Place
of delivery
home vs. hospital
mediation
analysis
c
b
n = 384
Allergic
manifestations
eczema, wheeze, asthma
n = 2733
KOALA study, van Nimwegen et al, JACI 2011
Placental microbial DNA
Aagaard et al, Am J Obstetrics and Gynaecology 2013
Biodiversity
Hannah Whitaker for The New York Times.
Prop stylist: Emily Mullin.
Traditional farming and early immuno-education
Courtesy: Erika von Mutius
ALEX-Study (1998 – 2002)
EU-6FWP PASTURE (2002 – 2007)
EU-7FWP PRO-IMMUNE (2008 – 2011)
Inverse relationship between microbial exposure
and probability of asthma
A - Bacteria
B - Fungi
Living on
a farm
Asthma
Ege et al., NEJM, 2011
Microbial diversity and asthma protection
one single
protective
pathway
convergence
into a
protective pathway
multiple synergistic
protective pathway
Environmental microbes with allergy protective
effects – identification of unique mechanisms
Staphylococcus sciuri
Hagner-Benes, 2013
TLR2; NOD2
DC-activation,
but no IL-12p35/70
anti-inflammatory
(TH1/TH2/TH17)
Environmental microbes with allergy protective
effects – identification of unique mechanisms
Staphylococcus sciuri
Hagner-Benes, 2013
TLR2; NOD2
DC-activation,
but no IL-12p35/70
anti-inflammatory
(TH1/TH2/TH17)
Acinetobacter lwoffii
Holst, JACI 2007
Conrad, JEM 2009
TLR4 (TLR7,9)
DC-activation,
IL-12, delta-4,
Jagged-1
anti-inflammatory
(TH2)
TH1/IFN-γ dependent
Environmental microbes with allergy protective
effects – identification of unique mechanisms
Staphylococcus sciuri
Hagner-Benes, 2013
TLR2; NOD2
DC-activation,
but no IL-12p35/70
anti-inflammatory
(TH1/TH2/TH17)
Acinetobacter lwoffii
Holst, JACI 2007
Conrad, JEM 2009
TLR4 (TLR7,9)
DC-activation,
IL-12, delta-4,
Jagged-1
anti-inflammatory
(TH2)
TLR2; NOD2
DCs/Monoc.  TNF-α
anti-inflammatory
(TH2)
some IFN-γ
Lactobacillus lactis
Holst, JACI 2007
Debarry, JACI 2007
TH1/IFN-γ dependent
Environmental microbes with allergy protective
effects – identification of unique mechanisms
Staphylococcus sciuri
Hagner-Benes, 2013
TLR2; NOD2
DC-activation,
but no IL-12p35/70
anti-inflammatory
(TH1/TH2/TH17)
Acinetobacter lwoffii
Holst, JACI 2007
Conrad, JEM 2009
TLR4 (TLR7,9)
DC-activation,
IL-12, delta-4,
Jagged-1
anti-inflammatory
(TH2)
TLR2; NOD2
DCs/Monoc.  TNF-α
anti-inflammatory
(TH2)
some IFN-γ
Lactobacillus lactis
Holst, JACI 2007
Debarry, JACI 2007
Bacillus licheniformis
Vogel, JACI 2008
TH1/IFN-γ dependent
anti-TH2, but
TH1 pathology
The Team
Cooperating Partners
Erika von Mutius, LMU München
Susan Prescott, Perth,
University of Western Australia
Otto Holst, Holger Heine,
Forschungs-Zentrum Borstel
Richard S. Blumberg, Harvard
Medical School, Boston, USA
Institute of
Laboratory Medicine
Holger Garn
Petra Pfefferle
Stefanie Hagner-Benes
Dörthe Kesper
Christoph Hudemann
Ayse Kilic
Ulrich Purath
Daniel Potaczek