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Intrinsic molecular properties are not enough for a protein to become an allergen

This presentation explores the factors that contribute to protein allergenicity, including protease activity, ligation of PRRs and CLRs, and protein structure. It also discusses the role of dendritic cells in allergic responses and the potential for regulatory T cell-based therapies.

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Intrinsic molecular properties are not enough for a protein to become an allergen

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  1. 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.

  2. Thn Th2 Th2 Type I allergic response Sensitization Inflammation iDC SM IL-13 IL-13 Lymph node IL-5 P B EO mDC IL-4/IL-5/IL-13 IgE M B IgE Mediatoren

  3. Tn Th1 Tcyt Th17 Th22 Th2 Bf PMN PMN Induction of specific T cell responses requires multiple signals Signal 1 Inflammatory cytokines chemokines Signal 2 NK iDC iDC DC maturation Signal 3 Signal 4

  4. Allergenicity of proteins • Protease activity • Ligation of PRRs (TLRs) • Ligationof CLRs • Proteinstructure (folding, dimers)

  5. Effect of allergen protease activity Shakib et al, Trends Immunol(2008)

  6. Allergensmayligatevariousreceptorsexpressedbydenriticcells Scheurer et al, Clin.Exp.allergy(2015)

  7. C type lectins Figdor et al, NRI(2002)

  8. Ligation of CLRsinhibits TLR-mediatedsignaling Geijtenbeek & Gringhuis, NRI (2009)

  9. CLRs as antigen uptakereceptors Figdor et al, NRI(2002)

  10. Allergenuptake via C-type lectinsincreases T cellresponsiveness MF/ αDEC205 MF/ αDEC205-Bet v 1d MF 7.7 4.8 7.8 5.8 5.1 3.6 IL-4 11.9 13.5 12.4 IFN-γ

  11. JACI, 2015 Machado et al, JACI(2015)

  12. Tcn Thn Tcyt Tcyt Tcyt Mf EO iDC Th2 Th2 Bf PMN PMN Th22 Th17 Th1 Pathogen class-specific immunity mediated by T cells NK Viruses Cancer cells IFN-g Endosomal pathogens Th1 IL-4/5 IL-9/13 Multicellular parasites mDC IL-17 IL-22 Bacteria/ Fungi Th17 Th22 TGF-b IL-10 Treg Tolerance

  13. Thn Tcn Thn Thn Thn Tcyt Tcyt Tcyt Mf EO iDC Th2 Th2 Bf PMN PMN Th22 Th17 Th1 Pathogen class-specific immunity mediated by T cells NK Viruses Cancer cells mDC IFN-g Endosomal pathogens Th1 mDC IL-4/5 IL-9/13 Multicellular parasites mDC IL-17 IL-22 Bacteria/ Fungi Th17 mDC Th22 TGF-b IL-10 Treg mDC Tolerance

  14. Thn Thn Tcn Thn Thn Tcyt Tcyt Tcyt Mf EO iDC Th2 Th2 Bf PMN PMN Th22 Th17 Th1 Pathogen class-specific immunity mediated by T cells NK Viruses Cancer cells IL-12 IL-27 mDC IFN-g IL-12 Delta-4 Endosomal pathogens Th1 mDC IL-4/5 IL-9/13 Multicellular parasites OX40L Jagged1 mDC IL-17 IL-22 Bacteria/ Fungi Th17 IL-1/6 IL-23 mDC Th22 TGF-b IL-10 TGF-b RA Treg mDC Tolerance

  15. Allergicdisorders are characterized by a disturbed balance between effector and regulatory T cells Treg Th1 Akdis et al. JEM (2004) 199:1567

  16. Th2 SIT restores the balance Allergic individuals Healthy individuals Th1 Tr Th1 Tr Th2 SIT

  17. Vaccine delivery routes Subcutaneous (SC) Intramuscular (IM) Intradermal (ID) Chester, 1998

  18. Different types of dendritic cells in human skin Epidermis Dermis CD1a (Langerhans cells) FXIIIa (dermal dendritic cells)

  19. Dendritic cells are functionally heterogenous Different types of dendritic cells in normal human skin Langerhans cells TGF-b CD1a++/CD14- Langerin (CD207) Birbeck granules E-cadherin In vitro/vivo: monocytes -> LCs CD1a Dermal dendritic cells CD1a± / CD14- DC-SIGN(CD209)- CD1a- / CD14+ DC-SIGN(CD209)+ M.B.M.Teunissen

  20. MD2 Selective loss of cell surface TLR on Langerhans cells TGF-b Extracellular pathogens b-glucans Proteoglycans/Lipoproteins peptides/zymosan Flagellin LPS (Gram -) Dectins TLR2/TLR2 TLR2/TLR1 TLR2/TLR6 TLR4/TLR4 TLR5/TLR5 Cytosolic pathogens dsRNA dsRNA dsRNA ….which abolishes bacterial recognition MDA5 DAI RIG-I Endosomal pathogens ssRNA ssRNA dsDNA dsRNA TLR3/TLR3 TLR7/TLR7 TLR8/TLR8 TLR9/TLR9 Van der Aar et al, JI(2007), JID (2013)

  21. Dendritic cells are functionally heterogenous Different types of dendritic cells in normal human skin Langerhans cells TGF-b CD1a++/CD14- Langerin (CD207) Birbeck granules E-cadherin In vitro/vivo: monocytes -> LCs CD1a Dermal dendritic cells CD1a± / CD14- DC-SIGN(CD209)- Epidermal LCs favor tolerance to the bacterial skin flora through ignorance CD1a- / CD14+ DC-SIGN(CD209)+ M.B.M.Teunissen

  22. The skin is a bacterial zoo Constante activatie van het afweersysteem geeft schade aan het weefsel en is gevaarlijk

  23. Th2 SIT restores the balance Allergic individuals Healthy individuals Th1 Tr Th1 Tr Th2 SIT

  24. RegulatoryTcellsassociatedwithvariouscompounds 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

  25. Effects of 1,25(OH)2VitD3 on antigen presenting cells Hart et al. Nature Review Immunol. 2011

  26. VitD3-primed DDCs and LCs have a reduced T cell stimulatory capacity

  27. VitD3-primed DDCs and LCs induce suppressive activity in CD4+ naïve T cells MF DDC * MF/Vit D3 MF LC * MF/Vit D3 0 25 50 75 100 Proliferation (%)

  28. Only VitD3-primed DDCs induce IL-10 production in naïve CD4+ T cells MF MF/VitD3 4.5 15 DDC 6.8 4.8 LC IL-10 CD4

  29. Only VitD3-primed LCs induce Foxp3 expression in naïve CD4+ T cells MF MF/VitD3 36 1 41 1.5 DDC 8 56 49 7 23 4 3 40 LC 7 50 CD127 27 46 FOXP3

  30. VitD3 primed DDCs & LCs induce distinct types of Tregs IL-10+ CTLA-4+ Foxp3_ IL-10-CD25+CD127lowFoxp3+ IL-10 mDC iDC Tr Maturation/ VitD3 TGF-β mLC iLC Tr Van der Aar et al. JACI (2011)

  31. Skin explant protocol

  32. Skin injection of VitD3 induces emigration of CD14+ dermal DCs Bakdash et al. Hum Vaccine Immunother.. 2013

  33. Skin injection of VitD3 induces a tolerogenic phenotype in DCs Bakdash et al. Hum Vaccine Immunother.. 2013

  34. Vitamin D inhibits antigen-specific proliferation and cytokine production

  35. Vitamin D diminishes antigen-specific proliferation and cytokine production IFNg IL-13 IL-10 none VitD

  36. Vitamin D metabolism 7-dehydroxycholesterol Cholecalciferol Calcidiol Calcitriol

  37. Calcidiol but not cholecaciferol reduces T cell stimulatory capacity of DCs Bakdash G. et al. Vaccine 2014

  38. Calcitriol metabolites prime DCs for the induction of Treg cells Bakdash G. et al. Vaccine 2014

  39. Calcitriol metabolites prime DCs for the induction of IFN-g-producing T cells Bakdash G. et al. Vaccine 2014

  40. Th2 SIT restores the balance Allergic individuals Healthy individuals Th1 Tr Th1 Tr Th2 VitD

  41. Thn Thn Tcn Thn Thn Tcyt Tcyt Tcyt Mf EO iDC Th2 Th2 Bf PMN PMN Th22 Th17 Th1 Pathogen class-specific immunity mediated by T cells NK Viruses Cancer cells IL-12 IL-27 mDC IFN-g IL-12 Delta-4 Endosomal pathogens Th1 mDC IL-4/5 IL-9/13 Multicellular parasites OX40L Jagged1 mDC IL-17 IL-22 Bacteria/ Fungi Th17 IL-1/6 IL-23 mDC Th22 TGF-b IL-10 TGF-b RA Treg mDC Tolerance

  42. Dendritic cells in tolerance and immunity Dept. Cell Biology & Histology, AMC, Amsterdam Esther de Jong Martien Kapsenberg Dept. of Dermatology Marcel Teunissen Yuri Souwer Angelic van der Aar GhaithBakdash FongLin Toni van Capel Esther Taanman Femke Muller Rosa de Groot Jeroen den Dunnen Laura Schneider Lisa Vogelpoel Ivo Hansen Kai Jun Liu Bianca Blom Dept. of ExperimentalImmunology Serge Versteeg Ronald van Ree

  43. Problems in SIT 1. Risk of serious side effects Using modified allergens T cell epitope B cell epitope

  44. Natural defence against pathogens Start of specific immunity through activation of dendritic cells Epithelium Defensines Chemokines Cytokines Endocytosis Macrophage Complement activation Fibroblast Neutrophil Gr Coagulation NK cell Cytotoxicity Platelets Endothelium

  45. Tn Th1 Tcyt Th17 Th22 Th2 Bf PMN PMN Induction of specific T cell responses requires multiple signals Signal 1 Inflammatory cytokines chemokines Signal 2 NK iDC iDC DC maturation Signal 3 Pathogen- Associated Molecular Patterns Danger- Associated Molecular Patterns Pattern Recognition Receptors Endangered Tissue Receptors Signal 4

  46. Vitamin D precursors differentially affect cytokine production by DCs Bakdash G. et al. Vaccine 2014

  47. Allergenuptake via C-type lectinsincreases T cellresponsiveness

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