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