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Intrinsic molecular properties are not enough for a protein to become an allergen Esther C. de Jong Dept. Cell Biology & Histology In relation to this presentation, I declare that there are no conflicts of interest. Type I allergic response Sensitization Inflammation iDC SM IL-13 IL-13 Lymph node Th2 IL-5 mDC EO IL-4/IL-5/IL-13 Thn Th2 IgE M B B P IgE Mediatoren Induction of specific T cell responses requires multiple signals NK Signal 1 Inflammatory cytokines chemokines Signal 2 Tcyt Th1 Bf iDC PMN PMN iDC Tn Th2 Th17 DC maturation Th22 Signal 3 Signal 4 Allergenicity of proteins • Protease activity • Ligation of PRRs (TLRs) • Ligation of CLRs • Protein structure (folding, dimers) Effect of allergen protease activity Shakib et al, Trends Immunol (2008) Allergens may ligate various receptors expressed by denritic cells Scheurer et al, Clin.Exp.allergy (2015) C type lectins Figdor et al, NRI (2002) Ligation of CLRs inhibits TLR-mediated signaling Geijtenbeek & Gringhuis, NRI (2009) CLRs as antigen uptake receptors Figdor et al, NRI (2002) Allergen uptake via C-type lectins increases T cell responsiveness MF/ αDEC205 MF 3.6 7.8 5.8 7.7 4.8 IL-4 5.1 MF/ αDEC205-Bet v 1d 13.5 12.4 IFN-γ 11.9 JACI, 2015 Machado et al, JACI (2015) Pathogen class-specific immunity mediated by T cells NK Tcyt Th1 Viruses Cancer cells Tcyt IFN-g Mf Endosomal pathogens Tcn iDC mDC Thn Th2 IL-4/5 EO IL-9/13 Multicellular parasites Bf Th17 IL-17 Th22 IL-22 Treg TGF-b IL-10 PMN PMN Bacteria/ Fungi Tcyt Th1 Th2 Th17Th22 Tolerance Pathogen class-specific immunity mediated by T cells NK iDC mDC Tcn Tcyt mDC Thn Th1 mDC Thn Th2 Viruses Cancer cells Tcyt IFN-g Mf IL-4/5 EO IL-9/13 Endosomal pathogens Multicellular parasites Bf mDC mDC Thn Thn Th17 IL-17 Th22 IL-22 Treg TGF-b IL-10 PMN PMN Bacteria/ Fungi Tcyt Th1 Th2 Th17Th22 Tolerance Pathogen class-specific immunity mediated by T cells NK iDC mDC IL-12 Tcn IL-27 Tcyt mDC IL-12 Thn Delta-4 Th1 mDC OX40L Thn Jagged1 Th2 Viruses Cancer cells Tcyt IFN-g Mf IL-4/5 EO IL-9/13 Endosomal pathogens Multicellular parasites Bf mDC IL-1/6 Thn IL-23 mDC TGF-b Thn RA Th17 IL-17 Th22 IL-22 Treg TGF-b IL-10 PMN PMN Bacteria/ Fungi Tcyt Th1 Th2 Th17Th22 Tolerance Allergic disorders are characterized by a disturbed balance between effector and regulatory T cells Th1 Treg Akdis et al. JEM (2004) 199:1567 SIT restores the balance Allergic individuals Healthy individuals Th2 Th1 Th1 Tr Th2 SIT Tr Vaccine delivery routes Subcutaneous (SC) Intramuscular (IM) Intradermal (ID) Chester, 1998 Different types of dendritic cells in human skin Epidermis Dermis CD1a (Langerhans cells) FXIIIa (dermal dendritic cells) Dendritic cells are functionally heterogenous Different types of dendritic cells in normal human skin Langerhans cells TGF-b CD1a++/CD14Langerin (CD207) Birbeck granules E-cadherin In vitro/vivo: monocytes -> LCs CD1a Dermal dendritic cells CD1a± / CD14DC-SIGN(CD209)- CD1a- / CD14+ DC-SIGN(CD209)+ M.B.M.Teunissen Selective loss of cell surface TLR on Langerhans cells TGF-b Extracellular pathogens LPS (Gram -) Flagellin Proteoglycans/Lipoproteins peptides/zymosan MD 2 TLR4/TLR4 TLR5/TLR5 TLR2/TLR2 TLR2/TLR1 TLR2/TLR6 bglucans Dectins Cytosolic pathogens dsRNA dsRNA dsRNA MDA5 DAI RIG-I recognition ….which abolishes bacterial Endosomal pathogens ssRNA ssRNA dsDNA dsRNA TLR7/TLR7 TLR8/TLR8 TLR9/TLR9 TLR3/TLR3 Van der Aar et al, JI (2007), JID (2013) Dendritic cells are functionally heterogenous Different types of dendritic cells in normal human skin Langerhans cells TGF-b CD1a++/CD14Langerin (CD207) Birbeck granules E-cadherin In vitro/vivo: monocytes -> LCs CD1a Dermal dendritic cells CD1a± / CD14DC-SIGN(CD209)- Epidermal LCs favor tolerance to the bacterial skin flora through ignorance CD1a- / CD14+ DC-SIGN(CD209)+ M.B.M.Teunissen The skin is a bacterial zoo Constante activatie van het afweersysteem geeft schade aan het weefsel en is gevaarlijk SIT restores the balance Allergic individuals Healthy individuals Th2 Th1 Th1 Tr Th2 SIT Tr Regulatory T cells associated with various compounds Viruses Cytomegalovirus Herpes simplex HIV Bacteria Bordetella pertussis FHA Helicobacter hepaticus Lactobaccilli ssp. LTA Mycobacterium spp. SRP299 ManLam Salmonellae Yeast Candida albicans Zymosan Protozoa Leishmania spp. Listeria major Toxoplasma gondii Helminths A. viteae ES62 Schistosoma mansoni lysoPS Etc, etc. Cytokines IL-10 TGF-B Microbial components CpG-DNA via PDC! Drugs Rapamycin Cortosteroids Vitamin D3 analogues PGD2 analogues 24 Effects of 1,25(OH)2VitD3 on antigen presenting cells Hart et al. Nature Review Immunol. 2011 VitD3-primed DDCs and LCs have a reduced T cell stimulatory capacity VitD3-primed DDCs and LCs induce suppressive activity in CD4+ naïve T cells MF DDC * MF/Vit D3 LC MF * MF/Vit D3 0 25 50 75 Proliferation (%) 100 Only VitD3-primed DDCs induce IL-10 production in naïve CD4+ T cells MF MF/VitD3 4.5 15 4.8 6.8 DDC IL-10 LC CD4 Only VitD3-primed LCs induce Foxp3 expression in naïve CD4+ T cells MF MF/VitD3 41 1.5 36 1 49 8 56 7 40 3 23 4 50 7 46 27 DDC CD127 LC FOXP3 VitD3 primed DDCs & LCs induce distinct types of Tregs IL-10 mDC iDC Maturation/ VitD3 iLC Tr TGF-β mLC Tr IL-10+ CTLA-4+ Foxp3_ IL-10CD25+ CD127low Foxp3+ Van der Aar et al. JACI (2011) Skin explant protocol Skin injection of VitD3 induces emigration of CD14+ dermal DCs Bakdash et al. Hum Vaccine Immunother.. 2013 Skin injection of VitD3 induces a tolerogenic phenotype in DCs Bakdash et al. Hum Vaccine Immunother.. 2013 Vitamin D inhibits antigen-specific proliferation and cytokine production 10000 +VitD 8000 CPM 6000 4000 2000 D 1d v Is oBe t EC -B e tv 1d - 0 Vitamin D diminishes antigen-specific proliferation and cytokine production 10000 +VitD 8000 IFNg IL-13 0.4 0.2 0.4 0.6 0.3 0.4 4000 0.2 0.0 2000 0 0.3 2 0.1 3 0 Bet v 1 d (g/ml) VitD 1d v none 0 0.3 1 2 Bet v 1 d (g/ml) Is oBe t Bet v 1 d (g/ml) 0.2 0.0 1 1d 3 tv 2 -B e 1 EC 0.3 D 0 - 0.0 0.8 6000 IL-10 (ng/ml) CPM IL-13 (ng/ml) IFN-g (ng/ml) 0.6 IL-10 3 Vitamin D metabolism 7-dehydroxycholesterol Cholecalciferol Calcidiol Calcitriol Calcidiol but not cholecaciferol reduces T cell stimulatory capacity of DCs Bakdash G. et al. Vaccine 2014 Calcitriol metabolites prime DCs for the induction of Treg cells Bakdash G. et al. Vaccine 2014 Calcitriol metabolites prime DCs for the induction of IFN-g-producing T cells Bakdash G. et al. Vaccine 2014 SIT restores the balance Allergic individuals Healthy individuals Th2 Th1 Tr Th1 Th2 Tr VitD Pathogen class-specific immunity mediated by T cells NK iDC mDC IL-12 Tcn IL-27 Tcyt mDC IL-12 Thn Delta-4 Th1 mDC OX40L Thn Jagged1 Th2 Viruses Cancer cells Tcyt IFN-g Mf IL-4/5 EO IL-9/13 Endosomal pathogens Multicellular parasites Bf mDC IL-1/6 Thn IL-23 mDC TGF-b Thn RA Th17 IL-17 Th22 IL-22 Treg TGF-b IL-10 PMN PMN Bacteria/ Fungi Tcyt Th1 Th2 Th17Th22 Tolerance Dendritic cells in tolerance and immunity Dept. Cell Biology & Histology, AMC, Amsterdam Esther de Jong Martien Kapsenberg Dept. of Dermatology Marcel Teunissen Dept. of Experimental Immunology Serge Versteeg Ronald van Ree Yuri Souwer Angelic van der Aar Ghaith Bakdash Fong Lin Toni van Capel Esther Taanman Femke Muller Rosa de Groot Jeroen den Dunnen Laura Schneider Lisa Vogelpoel Ivo Hansen Kai Jun Liu Bianca Blom42 Problems in SIT 1. Risk of serious side effects Using modified allergens T cell epitope B cell epitope Natural defence against pathogens Start of specific immunity through activation of dendritic cells Epithelium Defensines Chemokines Cytokines Endocytosis Macrophage Gr Neutrophil Platelets Complement activation Coagulation Cytotoxicity Fibroblast NK cell Endothelium Induction of specific T cell responses requires multiple signals NK Signal 1 Inflammatory cytokines chemokines Signal 2 Tcyt Th1 Bf iDC PMN PMN iDC Tn Th17 DC maturation Th22 Signal 3 PathogenAssociated Molecular Patterns Pattern Recognition Receptors DangerAssociated Molecular Patterns Endangered Tissue Receptors Th2 Signal 4 Vitamin D precursors differentially affect cytokine production by DCs Bakdash G. et al. Vaccine 2014 Allergen uptake via C-type lectins increases T cell responsiveness Allergen uptake via C-type lectins increases T cell responsiveness MF/ αDEC205 MF 3.6 7.8 5.8 IL-4 5.1 13.5 12.4 IFN-γ