Advances and highlights in mechanisms of allergic disease in 2015 Paulina Wawrzyniak, MSc, Cezmi A. Akdis, MD, Fred D. Finkelman, MD, Marc E. Rothenberg, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 137, Issue 6, Pages 1681-1696 (June 2016) DOI: 10.1016/j.jaci.2016.02.010 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Role of cells and cytokines in allergic airway diseases. Epithelial cells are activated by external factors, such as allergens and viruses. IL-33 secreted from epithelial cells acts on mast cells and ILC2s, which results in a predominantly IL-13–regulated gene expression (Nagarkar et al108). During the development of fibrosis, bleomycin induces IL-33 release by epithelial cells and stimulates a neutrophil-dependent processing of IL-33. IL-33 stimulates the production of IL-13 by ILC2s and macrophages and the production of TGF-β by macrophages. This currently acts as a major mechanism in the development of lung fibrosis (Li et al110). IL-9 secreted by TH9 cells is apparently important for the accumulation and activation of mast cells in the lungs (Sehra et al109). Journal of Allergy and Clinical Immunology 2016 137, 1681-1696DOI: (10.1016/j.jaci.2016.02.010) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Mechanisms of allergen-specific immunotherapy. Allergen-specific immunotherapy induces Treg and regulatory B (Breg) cells. As a consequence, peripheral tolerance is induced, which in term regulates the effector cells of allergy, in various ways. Treg cells suppress TH2 cells and their cytokine production, which are indispensable for the differentiation, survival, and activity of mast cells, basophils, eosinophils, and mucus-producing cells and for tissue homing of TH2 cells. IL-10 and TGF-β suppress IgE production, while inducing IgG4, a noninflammatory immunoglobulin isotype. Allergen-specific Breg cells are characterized by high IL-10, CD25, programmed cell death 1 ligand 1 (PD-L1), GARP, IL-1 receptor antagonist (IL-1ra), and vascular endothelial growth factor (VEGF) expression. DC, Dendritic cell; SOC3, suppressor of cytokine signaling 3. Journal of Allergy and Clinical Immunology 2016 137, 1681-1696DOI: (10.1016/j.jaci.2016.02.010) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions