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Immunopathology of asthma

Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale. Marina Saetta Dept. of Cardiac, Thoracic and Vascular Sciences

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Immunopathology of asthma

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  1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra.Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

  2. Marina Saetta Dept. of Cardiac, Thoracic and Vascular Sciences University of Padua International Guidelines on Rhinitis, Asthma and COPDGlobal Initiatives ARIA, GINA and GOLDModena, 1-3 March 2011 Immunopathology of asthma

  3. Immune response in asthma Innate and adaptive immune responses are relevant and cross-talk to each other in asthma Strict categorization of immune responses (Th1/Th2) may not help to understand what is happening in this disease

  4. Thisissueismuchdebated In COPD: from a viewcentred on the innate immune responseto a pictureinvolving the adaptiveimmunity In asthma: traditionalviewcentred on the adaptive immune response innate immunity

  5. The traditional view of asthma Central role of adaptive immunity Allergic asthma IgE synthesis Persistence of this Th2 driven eosinophilic inflammation responsible for structural changes typical of asthma Airway remodeling chronic inflammation Eosinophilia

  6. Airwayremodeling in asthma • Picture in adults • In children? Based on the traditionalhypothesis Inflammationstructuralchanges

  7. AJRCCM, 2003; 167: 78 AJRCCM, 2003; 168: 798 AJRCCM 2006;174:975 Young children Epithelial loss BM thickening Angiogenesis Eosinophils Asthmatic child Control child Remodeling begins early in the course of the disease and occurs in parallel with inflammation

  8. Studies in youngchildren The immune response is already characterized by an increased expression of IL-4 and IL-5 Whether atopy and eosinophilia are required for the development of the structural changes typical of asthma or whether these can occur even in their absence AJRCCM 2008;178:476

  9. Even non-atopic asthmatic children have evidence of airway remodeling similar to that of atopic asthma AJRCCM 2008;178(5):476-82

  10. Epithelialshedding, BM thickening and eosinophilia Non atopicasthma Atopicasthma Controlchild AJRCCM 2008;178(5):476-82

  11. Up-regulation of IL-4 Controls Asthmatic children without atopy Asthmatic children with atopy AJRCCM 2008;178(5):476-82

  12. Role of eosinophilic inflammation and its relation with airway remodeling in asthmatic children Asthmatics have eosinophils levels higher than controls, yet a significant proportion shows no evidence of eosinophilia symptoms functional alterations

  13. Non-eosinophilic asthma in children: relation with airway remodeling Baraldo S, Turato G, Bazzan E, Ballarin A, Damin M, Balestro E, Lokar-Oliani K, Calabrese F, Maestrelli P, Snijders D, Barbato A and Saetta M Whether airway remodeling would develop in children with non-eosinophilic asthma as it does in children with the eosinophilic form of the disease ERJ 2011, in press

  14. Same structural changes in the two groups of children Baraldoet al, ERJ 2011, in press

  15. Baraldoet al, ERJ 2011, in press

  16. Non-eosinophilic asthma eosinophilic asthma Baraldoet al, ERJ 2011, in press

  17. Up-regulationof IL-5 Even in the presenceof a pro-eosinophilic milieu some children do notexhibiteosinophilia Baraldoet al, ERJ 2011, in press

  18. The structural changes characteristic of asthma are present also in children with the non-eosinophilic form of the disease Do not question the importance of eosinophils Rather suggest that other pathways may be involved

  19. Complexity of the disease Limit of attributing the whole mechanism to a single factor

  20. Th-2 driven eosinophilic inflammation is not the only player in the pathogenesis of asthma - Cells of the innate immunity Epithelialcellsare importantmodulatorsof immune responses Nat Immunol 2010; 11:577

  21. Epithelialcellsfromadultswithasthmahaveanimpaired innate responsewhenstimulatedwithrhinovirusdeficientIFNl • Such a deficientresponse • leadstoanincreasedviralreplication • isassociatedtoworseningofsymptoms and lungfunction

  22. Itisunknownwhetherthisimmunologicdefectrepresentsanintrinsiccharacteristicofasthmaticpatients (presentearly in life) • or whetheritdevelopslater on, as a consequenceof a long term immune deregulation • To investigate ex-vivo innate immune responsestorhinovirus in bronchialepithelialcellsfrom: • asthmaticchildren (eitheratopic or non-atopic) • controlchildrenwithoutasthma

  23. p=0.01 p=0.001 6 5 INF-l mRNA expression (log10 copies/mg RNA) 4 3 Control Children Asthmatic Children without Atopy Asthmatic Children with Atopy 2 Epithelialcellsfromasthmaticchildren: deficient production ofIFNl Unpublished data

  24. SamedeficientresponseforIFNb p=0.04 p=0.007 6 5 INF-b mRNA expression (log10 copies/mg RNA) 4 3 2 Control Children Asthmatic Children without Atopy Asthmatic Children with Atopy Unpublished data

  25. Impaired immune response mirroredbyanincreasedviralreplication p=0.008 7 p=0.008 6 5 RV16vRNA production (log10 copies/mg RNA) 4 3 Control Children Asthmatic Children without Atopy Asthmatic Children with Atopy Unpublished data

  26. Impaired immune response similar in atopic and non- atopic asthmatic children • Pathogenetic similarities ? • Immunopathological profile in airway biopsies from the same children from whom we obtained the epithelial cells for the ex-vivo study

  27. Impaired immune response associatedtoincreasedexpressionof IL-4 p=0.03 p=0.006 700 600 500 400 IL-4+ cells/mm2 300 200 100 0 Control Children Asthmatic Children without Atopy Asthmatic Children with Atopy Unpublished data

  28. Impaired immune response associatedtoepithelialdamage p=0.04 p=0.02 100 90 80 70 60 Epithelial loss (%) 50 40 30 20 10 Asthmatic Children without Atopy Asthmatic Children with Atopy Control Children Unpublished data

  29. The innate immune response to viral infections is impaired early in life in children with asthma, either atopic or non-atopic Susceptibility to exacerbations Functional impairment

  30. The observation of impaired immune response even in the absence of atopy Reconsider the classical view of the immune response in asthma as triggered only by allergic stimulus IL-4 even in the absence of atopy IL-5 even in the absence of eosinophilia

  31. We should be cautious to force our view in strict categories, by assigning too much importance to a single cell type or cytokine

  32. “ we all have our favorite hypothesis focused on a specific cell type, and we even assign personalities to these cells: altruism in the case of T-helper or even homicidal intent for the natural killer cells” Our hypothesis is not a law! Lawrence Steinman, Nature Medicine 2007; 13: 139

  33. Complex phenotypes are just that - complicated - and attempts at reductionism are useful only when they lead to new insights. No single cytokine can regulate a vital process like tissue damage. It is a constellation of cytokines, tuned in concert, that ultimately produce a complex event like tissue damage and recovery from it. Steinman, Nature Medicine 2007; 13: 139

  34. In asthma(as in many in other fields…)

  35. Work together with harmony to build up a team to get the best results

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