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Atopic dermatitis cytokines and inflammation. Prof. Dr. Ortega Martell

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Atopic dermatitis
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Atopic dermatitis cytokines and inflammation. Prof. Dr. Ortega Martell

  1. 1. Atopic Dermatitis: cytokines and inflammation Dr. José Antonio Ortega Martell. Pachuca, Hidalgo, México
  2. 2. Th2 Th1 Th17Th22 TSLP IL-4 IL-13 IL-31 Inflammatory disease with complex cytokine and immunological networks
  3. 3. Atopic Dermatitis Inflammatory cutaneous disease Atopic diathesis Multifactorial onset and aggravation Skin barrier dysfunction Allergology International 66 (2017) 230-247 and/or predisposition to overproduce immunoglobulin E (IgE) antibodies Personal or family history of asthma, allergic rhinitis and conjunctivitis, and/or atopic dermatitis Environmental factors, sweating, physical irritation (including scratching), microbes/fungi, stress, and allergens (dust mites, foods) Decreased expression of ceramide and filaggrin (primary or secondary), increased transepidermal water loss, lowered treshold of itch Th2 Th1 Th17
  4. 4. J Allergy Clin Immunol 2019;144:362-74 • Skin = active immune organ • Contact with Ag: • Tolerance vs Immunity • Immunological cells: • Dendritic cells • T reg lymphocytes Toleroge n Immunoge n
  5. 5. Tolerogen Immunogen
  6. 6. Tolerance: • Dendritic cells (immature) • T reg lymphocytes LC cDCTreg
  7. 7. Effector cell network: • Keratinocytes • Th lymphocytes • Tc lymphocytes • Macrophages • Granulocytes • B lymphocytes • Mast cells • ILC (1,2,3) • NKT cells
  8. 8. Maintenanceoftoleranceinresting-stateskin J Allergy Clin Immunol 2019;144:362-74
  9. 9. Resting state: tolerance J Allergy Clin Immunol 2019;144:362-74 Contact with Ag without damage
  10. 10. JAllergyClinImmunol2019;144:362-74 Resting state: tolerance J Allergy Clin Immunol 2019;144:362-74
  11. 11. J Allergy Clin Immunol 2019;144:362-74
  12. 12. Contact with Ag: inflammatory response J Allergy Clin Immunol 2019;144:362-74
  13. 13. Inflammatory state J Allergy Clin Immunol 2019;144:362-74
  14. 14. • Dendritic cells : • Mature (hMHC-II, hB7) • (+) Lymphocytes • Migrate to epidermis • Migrate to lymph node J Allergy Clin Immunol 2019;144:362-74
  15. 15. •Effector T cells: • Th1 g IFN-g • Th2 g IL-4, 5, 13 • Th17 g IL-17, 26, 29 • Th22 g IL-22 J Allergy Clin Immunol 2019;144:362-74
  16. 16. • Macrophages: • Inflammatory (M1) • Granulocytes: • Neutrophils • Eosinophils J Allergy Clin Immunol 2019;144:362-74
  17. 17. https://doi.org/10.1016/j.alit.2019.08.013
  18. 18. • Tolerogenic Dendritic cells, Treg lymphocytes Non AD • Langerhan Cells, IDEC, Th2 lymphocytes Non lesional • LC, Monocyte derived LC, ILC2, IDEC, Th2 Acute lesion • LC, MDLC, IDEC, ILC2, Th2, Th1, Th17, Th22 Chronic lesion Atopic dermatitis: cells & biomolecules IL-10, TGF-b, IL-35, CTLA-4, PD-1 TARC: CCL17, CCL22, Eotaxins, S100A7, 8, 9 TSLP, IL-25, IL-33, IL-4, IL-13, IgE, IL-5, IL-31 IFN-g, FAS-L, TNF-a, IL-17, IL-22 https://doi.org/10.1016/j.alit.2019.08.013
  19. 19. https://doi.org/10.1016/j.alit.2019.08.013
  20. 20. J Allergy Clin Immunol 2019;143:1-11
  21. 21. Atopic dermatitis: endotypes Phenotype Endotype J Allergy Clin Immunol 2019;143:1-11 e.g. : Allergic e.g. : IgE disease’s visible features molecular mechanisms
  22. 22. Acute • New onset • < 72 hours • Erythematous • Wet • Highly inflammatory Chronic • Relapsing • > 72 hours • Lichenified • Dry, thick • Hyperpigmented J Allergy Clin Immunol 2019;143:1-11 Different clinical presentation Atopic dermatitis: classification
  23. 23. Atopic dermatitis: classification Nonlesional Acute Chronic Antimicrobial peptides (S100A7, S100A8, S100A9) -- hhh h Proliferation, hyperplasia (Keratin 16 mRNA, Ki67) -- h hhh Th2 markers h hhh hhhhh Th22 markers -- hhh hhhhh Th17 markers -- h hhh Th1 markers -- h hhhh J Allergy Clin Immunol 2019;143:1-11 Different skin profile
  24. 24. Extrinsic • Frequency: 80% • High total IgE • (+) Specific IgE • Eosinophilia • Atopic background • > rate filaggrin mutation Intrinsic • Frequency: 20% • Normal IgE • Delayed onseat • Female predominance • Increased metal contact sensitization J Allergy Clin Immunol 2019;143:1-11 Similar clinical presentation Atopic dermatitis: classification
  25. 25. Extrinsic • Th2 markers correlate positively with disease severity and negatively with barrier products (loricrin, periplakin, and filaggrin) Intrinsic • Th1/interferon-related gene expression and levels of the Th17 chemokine CCL20 correlate with disease severity J Allergy Clin Immunol 2019;143:1-11 Similar clinical presentation Atopic dermatitis: classification
  26. 26. J Allergy Clin Immunol 2019;143:1-11 Atopic dermatitis: endotypes Greater expression of: • Th2 hhh • Th22 hhh • Th1 hh Decreased expression of: • FLG iii • LOR iii • PPL ii Greater expression of: • Th22 hhhh • Th17 hhh • Th2 hh • hh epidermal hyperplasia and hh parakeratosis • Relatively preserved barrier proteins LOR/FLG Greater expression of: • Th22 hhhh • Th2 hhh • Th1/Th17 = absent • Lichenified phenotype • FLG mutations = rare • h IL-22 g proliferation (barrier abnormalities)
  27. 27. Latin America •Amerindians, Asians, Africans,
  28. 28. Atopic dermatitis: children g adult • face, trunk, and extensor limb inflammatory involvement • lichenified, chronic, dry, and flexural distribution J Allergy Clin Immunol 2019;143:1-11
  29. 29. • hhh Th2 / Th22 • h barrier defect • h sensitization • hhh Th1 / Th17 • i barrier defect J Allergy Clin Immunol 2019;143:1-11 • i sensitization Atopic dermatitis: children g adult
  30. 30. J Allergy Clin Immunol 2019;143:1-11 Atopic dermatitis: endotypes • Pediatric atopic dermatitis: • 85% AD cases begin before age of 5 years • Increased Th2 IL-9, IL-13, OX40L, IgE, FceRI • Increased Th17/22 IL-17A, IL-12/23p40, CCL20, IL- 19, IL-22, LL37, S100A7 • Resemblance to psoriasis
  31. 31. J Allergy Clin Immunol 2019;143:1-11 Atopic dermatitis: endotypes • Psoriasis: • Increased expression: • Th17/22, IL-23, Th1 • Epidermal hyperplasia • Parakeratosis • strong genetic predisposition • autoimmune pathogenic trait
  32. 32. Atopic dermatitis: summary TSLP, IL-25, IL-33 Alarmins g Th2 polarization IL-4, IL-5, IL-13 Th2 g h IgE, i FLG, h Eos IL-9 MC, Bas g h FceR, h Histam CRTH2 PGD2 g h Th2, ILC2, Eos, Ba Histam, IL-31, NK Sensory neuron g h Pruritus OX40, JAK, PDE4 Activation g Th2 polarization IL-12, IL-23 Th17 polarization IL-17, IL-22 Epidermal hyperplasia IFNg, TNFa Eczema, spongiosis
  33. 33. Atopic dermatitis: bio- targets IL-4 IL-13 IL-5 CRTH2 TSLP OX40 IgEJAK PDE4 IL- 12/23 IL-31 IL-22 IL-17 Dupilumab Pitakinra Lebrikizuma b Tralokinuma b Mepolizuma b Reslizuma bBenralizuma b Fevipiprant OC000459 Tezepeluma b MK-8226 GBR830 KHK4083 Omalizumab QGE031TofacitinibBaricitini b ASN002 CrisaboroleRoflumilast Apremilast Ustekinumab Nemolizuma b BMS-981164 Fezakinumab Secukinumab MOR106 J Allergy Clin Immunol 2019;143:1-11
  34. 34. Atopic dermatitis: bio- targets JAllergyClinImmunol2019;143:1-11
  35. 35. Atopic dermatitis: bio- targets JAllergyClinImmunol2019;143:1-11
  36. 36. Atopic dermatitis: bio- targets JAllergyClinImmunol2019;143:1-11
  37. 37. Atopic dermatitis: bio- targets JAllergyClinImmunol2019;143:1-11
  38. 38. Atopic dermatitis: bio- targets JAllergyClinImmunol2019;143:1-11
  39. 39. Atopic dermatitis: bio- targets JAllergyClinImmunol2019;143:1-11
  40. 40. Atopic dermatitis: conclusions• Heterogenous inflammatory skin disease • Different phenotypes based on: • age, chronicity, ethnicity, FLG and immune status • Underlying molecular mechanisms (endotypes) g personalized medicine
  41. 41. Atopic dermatitis: questions • Endotypes related to microbiome? • Endotypes related to specific allergens? • Endotypes related to autoantigens? • Different cytokine networks in AD types?
  42. 42. https://www.worldallergy.org
  43. 43. drortegamartell@prodigy.net.mx Thank you Merci Gracias

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