哮喘免疫表型课件.ppt

1、Asthma:Immune PhenotypesAsthma Asthma is clinically defined as a syndrome with episodic wheezing,shortness of breath,cough and sputum production The constant features are airway irritability(hyperresponsiveness)and inflammationAsthma:Epidemiology Between 150-300 million patients worldwide 15-25 mill

2、ion in the U.S.Most common chronic disease of childhood Over 500,000 E.R.visits per year 25,000 ICU admissions 5-6,000 deaths in U.S.On the increaseAllergic Asthma:PathwaysIL-13Eosinophils-Mast CellB-cellTCRMHC IIT Lymphocyte APCCD80CD86CD28Generation of Allergic Adaptive Immune ResponsesSevere Asth

3、ma Definition Phenotypes-Pathologic/Clinical Therapeutic OptionsInflammation and Remodeling in AsthmaCourtesy of Marllyn Glassberg,MDApproach to Management/Contributing Factors/Co-Morbid ConditionsExamine for concomitant medical disorders,i.e.sinusitis,OSA,VCDGERD-acid and non-acid refluxEnvironment

4、al controlAlternative diagnosesIncorporate objective measures into managementWritten action planReview medication techniqueSevere Asthma ClustersMoore et al.AJRCCM 2010;181:315-323Asthma Clusters Cluster 1:early onset,atopic,nl lung fxn 2 controllers,nl lung fxn,significant health care utilization C

5、luster 3:adult onset,obese woman with low lung fxn,high medication requirement and healthcare utilization Cluster 4:early onset,atopic,severe obstruction with some reversibility(FEV1:57%to 76%pred),high healthcare utilization Cluster 5:early onset,severe obstruction,66%atopic;less reversibility(FEV1

6、:43%to 58%),high health care utilizationMoore et al.AJRCCM 2010;181:315-323Asthma Phenotypes:Heterogeneous DiseaseClinical:Pathologic:Fixed obstructionEosinophilicObeseNon-eosinophilicAdult onsetPauci-granulocyticExacerbation proneTreatment resistantTriggers:OccupationalAspirinExerciseMensesPatholog

7、ical Phenotypes Eosinophilic/TH2(IL-4,IL-5 and IL-13)Non-eosinophilic(sputum eos 2%,or peripheral blood eos 200/l)Clinical Features of Asthmatics with“High”and“Low”IL-13 Gene SignaturesWoodruff,et al.AJRCCM 2009;180:388-395Woodruff et al Am J Respir Crit Care Med 180:3888-95,2009Th2“high”vs.“low”sig

8、nature results in different clinical characteristics and response to ICSInterleukin-13 and Non-Interleukin-13 Inflammatory Pathways in AsthmaKraft M.N Engl J Med 2011;365:1141Biomarkers to identify the Th2 phenotype Sputum eosinophils Exhaled nitric oxide Circulating eosinophils Periostin IgE Allerg

9、en skin testingSevere Asthma:Periostin correlates with sputum and tissue eosinophilsJia et al.JACI 2012;130:647Eosinophilic Phenotype:Some Treatment OptionsEosinophilic Phenotype:Rationale for Zileuton(Leukotriene Inhibitor)Anti-eosinophil and anti-mast cell effects Decreased BAL eos in nocturnal as

10、thma (Wenzel ARRD 1995)Decreased mast cell tryptase following ASA challenge(Israel,ARRD 1993)Broader effect than montelukast Inhibits activation of multiple cysLT receptors Blocks LTB4 Blocks other 5 LO metabolites Eosinophils Phenotype:Omalizumab(anti-IgE)reduces submucosal EosinophilsEosinophils(c

11、ells/mm2)BaselinePosttreatment020608080602004040BaselinePosttreatment8.01.56.36.4Placebo(n=14)Omalizumab(n=14)P0.001P=0.81P=0.033Djukanovic et al.AJRCCM 2004Lung Function:Inhibition of IL-13Corren et al.NEJM 2011;365:1088Non-eosinophilic AsthmaEosinophilic and non-eosinophilic asthma:pathologic comp

12、arisonBerry et al.Thorax 2007;62:1043Inhaled Corticosteroids:Airways HyperresponsivenessBerry et al.Thorax 2007;62:1043Inhaled Corticosteroids:Quality of Life Berry et al.Thorax 2007;62:1043Non-eosinophilic asthma:other mediators?Wang,Curr Opin Immun 2008;20:697-702Increased Membrane Bound TNF-in Re

13、fractory AsthmaBerry,et al.NEJM 2006;354:697-708BAL TNF-Levels are Increased in The Lungs of Obese Asthmatics*p0.001,*p0.01,#p0.05 Lugogo et al.AJRCCM 2012;864:404Non-eosinophilic phenotype:treatment options?Asthma Phenotypes and Macrolides Brusselle et al.recruited 109 subjects with asthma,on combi

14、nation therapy(Thorax 2013;177:148)Subjects were“exacerbation prone”as they were required to have had two exacerbations requiring oral corticosteroids or LTRI requiring antibiotics in the previous 12 monthsAzithromycin vs.placebo added to combination therapy for 6 months in a double-blind fashionPri

15、mary outcome was the rate of exacerbations and LTRI requiring antibioticsAsthma Phenotypes and Macrolides-Results in the Entire CohortBrusselle et al.Thorax 2013;177:148Nonoesinophilic Asthma:Only(defined as blood eos 200/l)Brusselle et al.Thorax 2013;177:148Severe Asthma:Tiotropium Kerstjens et al.

16、NEJM 2012Environment and immunity:impact on asthma pathogenesis?NEJM 347:911,2002Epidemiological trends in infections and chronic diseasesInnate and Adaptive Immunity Innate Antigen independent Pattern-Recognition Receptors Toll-like receptors(TLRs)NOD-like receptors(NLRs)Collectins(SP-A/D)Adaptive

17、Antigen dependent T and B cells Antigen Specific Receptors TCRToll-like Receptor FamilyIgIg-likeLeucine-richdomainLeucineRichLRRCTLeucine-richrepeat C-terminaldomainTIRToll Interleukin 1resistanceTIRTLR1 762 aaTIRTLR2 766 aaTIRTLR3 881 aaTIRTLR4 816 aaLeucineRichLeucineRichLRRCTTIRTLR7 1023 aaLeucin

18、eRichLeucineRichTIRTLR8 1015 aaLeucineRichTIRTLR10 792 aaLeucineRichLRRCTLeucineRichLeucineRichLRRCTLRRCTLRRCTTIRTLR5 838 aaLeucineRichLRRCTTIRTLR9 1007 aaLeucineRichLRRCTTIRTLR6 796 aaLeucineRichLRRCTLeucineRichLeucineRichLRRCTLeucineRichLeucineRichLeucineRichLeucineRichLeucineRichLeucineRichLeucin

19、eRichLpAPpg TLR4APCT celltranscriptionIkBPPPPG LPSNF-B activation TLR2CD14MyD88Innate and Adaptive ImmunityLancet 358:1129,2001Early life exposure to farm animals reduces asthma and hay feverNY Asthma Rates:NYC Children15%Bronx 1996,AECOM21-23%Hunts Point,2006,NYC Bronx Heath Dept38%Homeless2007,Chi

20、ldren Children Health Dept Percentage of asthma Location Data SourceT CellProliferation and differentiationIFN-TNF-IL-15 IL-18 IL-12APCIL-10IL-13IL-4 IL-5 IL-6MHCTCRCOSTIMULATIONTh1/Th2 Cytokine ExpressionWhat T Cell Subsets(in Addition to Th1,Th2)Are Involved in Allergic Responses?T CellProliferati

21、on and differentiationIFN-IL-15 IL-18 IL-12APCIL-13IL-4 IL-5COSTIMULATIONT Cell SubsetsTh17TregIL-17IL-10TGF-T Regulatory Cells(Tregs)T cell subtype known as T regulatory(Treg)cells.Suppresses T Cells.Distinct subsets of CD4+T cells protect from chronic intestinal inflammation.Powrie,F et al Int.Imm

22、unol.5,14611471 1993.CD4+CD25+,GITR,LAG-3,Foxp3,CTLA4 Maternal Atopy:Association With Decreased Foxp3 n=29 mothers without and n=21 mother with atopy 0.05-0.61.59Foxp3P ValueMaternal AtopyNo Maternal AtopyParameterB Schaub,PW Finn et al,Respiratory Research 2006Summary Severe asthma is a spectrum of

23、 disease,with different pathologic and clinical phenotypes Defining phenotypes is in its infancy Tailoring treatment to phenotypes is the ultimate goal Importance of contributing factors and adherence cannot be overestimated Innate and adaptive immunity impact asthma pathogenesisSymbiontsCommensalsPathobiontsTregsTh 17cells Healthy microbiota Altered microbiotaSymbiontsCommensalsPathobiontsimmune dysregulationInfectious susceptibility TregsTh 17cellsNakajima et al.Semin Immunopathol.2011