what’s wrong in atopy & allergy? schweizerisches institut für allergie- und asthmaforschung,...
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What’s Wrong in What’s Wrong in Atopy & Allergy?Atopy & Allergy?
Schweizerisches Institut für Allergie- und Asthmaforschung, Davos
PD Dr Liam O‘MahonyPD Dr Liam O‘MahonySwiss Insititute of Allergy and Asthma ResearchSwiss Insititute of Allergy and Asthma Research
University of Zürich, Davos, SwitzerlandUniversity of Zürich, Davos, Switzerland44thth December 2015 December 2015
Atopy and AllergySchweizerisches Institut für Allergie- und Asthmaforschung, Davos
“Atopy” is characterized by a tendency to be hyperallergic, also refers to a genetically mediated predisposition to an excessive IgE reaction
“Allergy” - a damaging immune response by the body to a substance, especially a particular food, pollen, fur, or dust, to which it has become hypersensitive
“Hypersensitivity” – lack of immunological regulation
Allergic reactions are designed to eliminate a “threat”
Akdis & Akdis, Science Translational Medicine, 2015
Regulatory LymphocytesSchweizerisches Institut für Allergie- und Asthmaforschung, Davos
Human Regulatory B Cell PhenotypeSchweizerisches Institut für Allergie- und Asthmaforschung, Davos
van de Veen et al., JACI 2013
PLA-Specific IL-10+ B CellsSchweizerisches Institut für Allergie- und Asthmaforschung, Davos
van de Veen et al., JACI 2013
Akdis & Akdis, Nature Reviews Drug Discovery 2009
Regulatory T CellsSchweizerisches Institut für Allergie- und Asthmaforschung, Davos
Mills, Nature Reviews Immunology 2004
Regulatory T Cell SubsetsSchweizerisches Institut für Allergie- und Asthmaforschung, Davos
TLR-4
DC-SIGNNOD-2
TLR-2
TLR-5
Dectin-1
DC Activation:Microbial Ligands
Micro-environment (e.g. cytokines)Transcription Factors (e.g. NF-B)
miRNA
Secreted Immunomodulatory Factors:
Cytokines (e.g. TNF-, IL-10)Lipid Mediators (e.g. RA)
Tryptophan Metabolism (IDO)
Cell-Cell Interactions:Antigen Presentation
Co-Stimulatory Molecules (e.g. CD80)Inhibitory Receptors (e.g. PD-L1) TH1 (T-bet)
TH2 (Gata-3)
TH17 (Ror-t)
T reg (Foxp3)
TH9
TH22
GRP41
Innate Pattern Recognition Shapes the Adaptive Immune Response
Schweizerisches Institut für Allergie- und Asthmaforschung, Davos
Bacterial Stimulation of Regulatory CellsSchweizerisches Institut für Allergie- und Asthmaforschung, Davos
Ngoi et al., Discov Med 2011
• Alternative defense strategy that minimizes the impact of an invader on host fitness• Allows for the establishment of a robust microbiome, which can provide nutrients and added protection to the host
Yatsunenko et al, Nature 2012
Abrahamsson et al., Clin Exp Allergy, 2013
Early Life Microbiome DiversitySchweizerisches Institut für Allergie- und Asthmaforschung, Davos
Ege et al. NEJM 2011
Microbiome Diversity and Asthma RiskSchweizerisches Institut für Allergie- und Asthmaforschung, Davos
Early Life Microbial Dysbiosis Early Life Microbial Dysbiosis Asociated with Atopy & Asthma RiskAsociated with Atopy & Asthma Risk
Schweizerisches Institut für Allergie- und Asthmaforschung, Davos
Arrieta et al., Sci Transl Med 2015
• Immature digestive tract• Abnormal gut transit• Poor stress response• Immune deficient
Mucosal lymphoid structures poorly developedLamina propria cellularity significantly reducedInnate immune system under-developed (e.g. phagocytic activity)B cell antibody response (particularly IgA & IgE) is significantly differentTh2 dominant responses, diminished Treg and Th17 responsesHowever, overall numbers of T cell & NK lymphoid populations are comparable to conventionally colonised animals
Schweizerisches Institut für Allergie- und Asthmaforschung, Davos
Germ Free Animals
Olszak et al., Science 2012
Schweizerisches Institut für Allergie- und Asthmaforschung, Davos
Colonisation Timing is Important
Lyons et al., CEA 2010
Bifidobacteria Bifidobacteria
*
*p<0.05
Schweizerisches Institut für Allergie- und Asthmaforschung, Davos
Induction of Tregs in Germ Free Animals
0
100
200
300
OVA
-Spe
cific
IgE
ng/m
l
Negative Control
Placebo Bifidobacterium AH1205
Bifidobacterium AH1206
Lactobacillus AH102
OVA + Cholera Toxin
Lyons et al., CEA 2010
*
*p<0.05
Schweizerisches Institut für Allergie- und Asthmaforschung, Davos
IgE Response Inhibited by Treg Promoting Bacteria
Noval Rivas et al., J Allergy Clin Immunol 2013
Schweizerisches Institut für Allergie- und Asthmaforschung, Davos
Pro- Allergic Microbiome is Transferable
IL-12TNF-
IL-10TGFIDORALDH2
Regulatory T Cells
IL-10IDOP
MTLR-2/6
CLR/DC-SIGN
TLR-9
Bifidobacterium
Intestinal Epithelial Cells
Schweizerisches Institut für Allergie- und Asthmaforschung, Davos
Bacterial-Dendritic Cell-Lymphocyte Regulation
O‘Hara et al., Immunology 2006O‘Mahony et al., AJPGLP 2006Sibartie et al., BMC Immunol 2009Konieczna et al., Gut 2012Konieczna et al., Gut Microbes 2012Symonds et al., Clin Transl Gastro 2012Scully et al., Cell Immunol. 2013Konieczna et al., PLoS One 2013