Atopic dermatitis cytokines and inflammation. Prof. Dr. Ortega Martell
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Atopic dermatitis is a complex inflammatory skin disease with different phenotypes and underlying molecular mechanisms (endotypes). It involves complex cytokine and immunological networks of Th2, Th1, Th17 and Th22 cells. The disease presentation and molecular profiles differ based on factors like age, chronicity, ethnicity, filaggrin mutations and immune status. Understanding the distinct endotypes can help develop personalized treatment approaches targeting specific cytokines and pathways. Further research is still needed to better characterize endotypes in relation to aspects like microbiome, specific allergens and autoantigens involved.
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Atopic dermatitis cytokines and inflammation. Prof. Dr. Ortega Martell
- 1. Atopic Dermatitis: cytokines and inflammation Dr. José Antonio Ortega Martell. Pachuca, Hidalgo, México
- 4. 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
- 5. 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
- 7. Tolerance: • Dendritic cells (immature) • T reg lymphocytes LC cDCTreg
- 8. Effector cell network: • Keratinocytes • Th lymphocytes • Tc lymphocytes • Macrophages • Granulocytes • B lymphocytes • Mast cells • ILC (1,2,3) • NKT cells
- 9. Maintenanceoftoleranceinresting-stateskin J Allergy Clin Immunol 2019;144:362-74
- 10. Resting state: tolerance J Allergy Clin Immunol 2019;144:362-74 Contact with Ag without damage
- 11. JAllergyClinImmunol2019;144:362-74 Resting state: tolerance J Allergy Clin Immunol 2019;144:362-74
- 12. J Allergy Clin Immunol 2019;144:362-74
- 13. Contact with Ag: inflammatory response J Allergy Clin Immunol 2019;144:362-74
- 14. Inflammatory state J Allergy Clin Immunol 2019;144:362-74
- 15. • Dendritic cells : • Mature (hMHC-II, hB7) • (+) Lymphocytes • Migrate to epidermis • Migrate to lymph node J Allergy Clin Immunol 2019;144:362-74
- 16. •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
- 17. • Macrophages: • Inflammatory (M1) • Granulocytes: • Neutrophils • Eosinophils J Allergy Clin Immunol 2019;144:362-74
- 19. • 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
- 21. J Allergy Clin Immunol 2019;143:1-11
- 22. 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
- 23. 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
- 24. 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
- 25. 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
- 26. 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
- 27. 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)
- 28. Latin America •Amerindians, Asians, Africans,
- 29. 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
- 30. • 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
- 31. 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
- 32. 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
- 33. 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
- 34. 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
- 41. 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
- 42. Atopic dermatitis: questions • Endotypes related to microbiome? • Endotypes related to specific allergens? • Endotypes related to autoantigens? • Different cytokine networks in AD types?