What’s Wrong in Atopy & Allergy? Schweizerisches Institut für Allergie- und Asthmaforschung, Davos PD Dr Liam O‘Mahony Swiss Insititute of Allergy and Asthma Research University of Zürich, Davos, Switzerland 4 th December 2015

Atopy and Allergy Schweizerisches 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 Lymphocytes Schweizerisches Institut für Allergie- und Asthmaforschung, Davos

Human Regulatory B Cell Phenotype Schweizerisches Institut für Allergie- und Asthmaforschung, Davos van de Veen et al., JACI 2013

PLA-Specific IL-10+ B Cells Schweizerisches Institut für Allergie- und Asthmaforschung, Davos van de Veen et al., JACI 2013

Akdis & Akdis, Nature Reviews Drug Discovery 2009 Regulatory T Cells Schweizerisches Institut für Allergie- und Asthmaforschung, Davos

Mills, Nature Reviews Immunology 2004 Regulatory T Cell Subsets Schweizerisches Institut für Allergie- und Asthmaforschung, Davos

TLR-4 DC-SIGN NOD-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) T H 1 (T-bet) T H 2 (Gata-3) T H 17 (Ror-  t) T reg (Foxp3) TH9TH9 T H 22 GRP41 Innate Pattern Recognition Shapes the Adaptive Immune Response Schweizerisches Institut für Allergie- und Asthmaforschung, Davos

Bacterial Stimulation of Regulatory Cells Schweizerisches 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 Diversity Schweizerisches Institut für Allergie- und Asthmaforschung, Davos

Ege et al. NEJM 2011 Microbiome Diversity and Asthma Risk Schweizerisches Institut für Allergie- und Asthmaforschung, Davos

Early Life Microbial Dysbiosis Asociated 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 developed Lamina propria cellularity significantly reduced Innate immune system under-developed (e.g. phagocytic activity) B cell antibody response (particularly IgA & IgE) is significantly different Th2 dominant responses, diminished Treg and Th17 responses However, 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 * * p<0.05 Schweizerisches Institut für Allergie- und Asthmaforschung, Davos Induction of Tregs in Germ Free Animals

OVA-Specific IgE ng/ml Negative Control PlaceboBifidobacterium 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-12 TNF-  IL-10 TGF  IDO RALDH2 Regulatory T Cells IL-10 IDO P M TLR-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 2006 O‘Mahony et al., AJPGLP 2006 Sibartie et al., BMC Immunol 2009 Konieczna et al., Gut 2012 Konieczna et al., Gut Microbes 2012 Symonds et al., Clin Transl Gastro 2012 Scully et al., Cell Immunol Konieczna et al., PLoS One 2013