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1、哮喘免疫表型,哮喘免疫表型哮喘免疫表型AsthmaAsthma is clinically defined as a syndrome with episodic wheezing,shortness of breath,cough and sputum productionThe constant features are airway irritability(hyperresponsiveness)and inflammation2020/11/142,2020/11/14,2,Asthma,Asthma is clinically defined as a syndrome with
2、episodic wheezing,shortness of breath,cough and sputum productionThe constant features are airway irritability(hyperresponsiveness)and inflammation,2020/11/14,3,Asthma:Epidemiology,Between 150-300 million patients worldwide15-25 million in the U.S.Most common chronic disease of childhoodOver 500,000
3、 E.R.visits per year25,000 ICU admissions5-6,000 deaths in U.S.On the increase,2020/11/14,4,Allergic Asthma:Pathways,2020/11/14,5,IgE,IL,-,13,Eosinophils,IL-5,IL,-,13,Th2,Th1,Mast Cell,B-cell,IL-4,TCR,MHC II,T Lymphocyte,CD80,CD86,CD28,Generation of Allergic Adaptive Immune Responses,2020/11/14,6,Se
4、vere Asthma,Definition Phenotypes-Pathologic/Clinical Therapeutic Options,2020/11/14,7,Inflammation and Remodeling in Asthma,Courtesy of Marllyn Glassberg,MD,2020/11/14,8,Approach to Management/Contributing Factors/Co-Morbid Conditions,Examine for concomitant medical disorders,i.e.sinusitis,OSA,VCDG
5、ERD-acid and non-acid refluxEnvironmental controlAlternative diagnosesIncorporate objective measures into managementWritten action planReview medication technique,2020/11/14,9,Severe Asthma Clusters,Moore et al.AJRCCM 2010;181:315-323,2020/11/14,10,Asthma Clusters,Cluster 1:early onset,atopic,nl lun
6、g fxn 2 controllers,nl lung fxn,significant health care utilizationCluster 3:adult onset,obese woman with low lung fxn,high medication requirement and healthcare utilizationCluster 4:early onset,atopic,severe obstruction with some reversibility(FEV1:57%to 76%pred),high healthcare utilizationCluster
7、5:early onset,severe obstruction,66%atopic;less reversibility(FEV1:43%to 58%),high health care utilization,Moore et al.AJRCCM 2010;181:315-323,2020/11/14,11,Asthma Phenotypes:Heterogeneous Disease,Clinical:Pathologic:Fixed obstructionEosinophilicObeseNon-eosinophilicAdult onsetPauci-granulocyticExac
8、erbation proneTreatment resistantTriggers:OccupationalAspirinExerciseMenses,2020/11/14,12,Pathological Phenotypes,Eosinophilic/TH2(IL-4,IL-5 and IL-13)Non-eosinophilic(sputum eos 2%,or peripheral blood eos 200/l),2020/11/14,13,Clinical Features of Asthmatics with“High”and“Low”IL-13 Gene Signatures,W
9、oodruff,et al.AJRCCM 2009;180:388-395,2020/11/14,14,Woodruff et al Am J Respir Crit Care Med 180:3888-95,2009,Th2“high”vs.“low”signature results in different clinical characteristics and response to ICS,2020/11/14,15,Interleukin-13 and Non-Interleukin-13 Inflammatory Pathways in Asthma,Kraft M.N Eng
10、l J Med 2011;365:1141,2020/11/14,16,Biomarkers to identify the Th2 phenotype,Sputum eosinophilsExhaled nitric oxideCirculating eosinophilsPeriostin IgEAllergen skin testing,2020/11/14,17,Severe Asthma:Periostin correlates with sputum and tissue eosinophils,Jia et al.JACI 2012;130:647,2020/11/14,18,E
11、osinophilic Phenotype:Some Treatment Options,2020/11/14,19,Eosinophilic Phenotype:Rationale for Zileuton(Leukotriene Inhibitor),Anti-eosinophil and anti-mast cell effectsDecreased BAL eos in nocturnal asthma(Wenzel ARRD 1995)Decreased mast cell tryptase following ASA challenge(Israel,ARRD 1993)Broad
12、er effect than montelukastInhibits activation of multiple cysLT receptorsBlocks LTB4Blocks other 5 LO metabolites,2020/11/14,20,Eosinophils Phenotype:Omalizumab(anti-IgE)reduces submucosal Eosinophils,Eosinophils(cells/mm2),Baseline,Posttreatment,0,20,60,80,80,60,20,0,40,40,Baseline,Posttreatment,8.
13、0,1.5,6.3,6.4,Placebo(n=14),Omalizumab(n=14),P0.001,P=0.81,P=0.033,Djukanovic et al.AJRCCM 2004,2020/11/14,21,Lung Function:Inhibition of IL-13,Corren et al.NEJM 2011;365:1088,2020/11/14,22,Non-eosinophilic Asthma,2020/11/14,23,Eosinophilic and non-eosinophilic asthma:pathologic comparison,Berry et
14、al.Thorax 2007;62:1043,2020/11/14,24,Inhaled Corticosteroids:Airways Hyperresponsiveness,Berry et al.Thorax 2007;62:1043,2020/11/14,25,Inhaled Corticosteroids:Quality of Life,Berry et al.Thorax 2007;62:1043,2020/11/14,26,Non-eosinophilic asthma:other mediators?,2020/11/14,27,Wang,Curr Opin Immun 200
15、8;20:697-702,2020/11/14,28,Increased Membrane Bound TNF-in Refractory Asthma,Berry,et al.NEJM 2006;354:697-708,2020/11/14,29,BAL TNF-Levels are Increased in The Lungs of Obese Asthmatics,*p0.001,*p0.01,#p0.05,Lugogo et al.AJRCCM 2012;864:404,2020/11/14,30,Non-eosinophilic phenotype:treatment options
16、?,2020/11/14,31,Asthma Phenotypes and Macrolides,Brusselle et al.recruited 109 subjects with asthma,on combination 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 prev
17、ious 12 monthsAzithromycin vs.placebo added to combination therapy for 6 months in a double-blind fashionPrimary outcome was the rate of exacerbations and LTRI requiring antibiotics,2020/11/14,32,Asthma Phenotypes and Macrolides-Results in the Entire Cohort,Brusselle et al.Thorax 2013;177:148,2020/1
18、1/14,33,Nonoesinophilic Asthma:Only(defined as blood eos 200/l),Brusselle et al.Thorax 2013;177:148,2020/11/14,34,Severe Asthma:Tiotropium,Kerstjens et al.NEJM 2012,2020/11/14,35,Environment and immunity:impact on asthma pathogenesis?,2020/11/14,36,NEJM 347:911,2002,Epidemiological trends in infecti
19、ons and chronic diseases,2020/11/14,37,Innate and Adaptive Immunity,InnateAntigen independentPattern-Recognition ReceptorsToll-like receptors(TLRs)NOD-like receptors(NLRs)Collectins(SP-A/D),AdaptiveAntigen dependentT and B cellsAntigen Specific Receptors TCR,2020/11/14,38,Toll-like Receptor Family,I
20、g,Ig-like,Leucine-richdomain,LeucineRich,LRRCT,Leucine-richrepeat C-terminaldomain,Toll Interleukin 1resistance,TLR1 762 aa,TLR2 766 aa,TLR3 881 aa,TLR4 816 aa,LeucineRich,LeucineRich,LRRCT,TLR7 1023 aa,LeucineRich,LeucineRich,TLR8 1015 aa,LeucineRich,TLR10 792 aa,LeucineRich,LRRCT,LeucineRich,Leuci
21、neRich,LRRCT,LRRCT,LRRCT,TLR5 838 aa,LeucineRich,LRRCT,TLR9 1007 aa,LeucineRich,LRRCT,TLR6 796 aa,LeucineRich,LRRCT,LeucineRich,LeucineRich,LRRCT,LeucineRich,LeucineRich,LeucineRich,LeucineRich,LeucineRich,LeucineRich,LeucineRich,LpA,Ppg,2020/11/14,39,TLR4,APC,T cell,CD28,costimulation,CD86,CD80,MHC
22、,TCR,transcription,IkB,P,P,PPG,NF-B activation,TLR2,CD14,MyD88,Innate and Adaptive Immunity,2020/11/14,40,2020/11/14,41,Lancet 358:1129,2001,Early life exposure to farm animals reduces asthma and hay fever,2020/11/14,42,NY,2020/11/14,43,Asthma Rates:NYC Children,15%Bronx 1996,AECOM21-23%Hunts Point,
23、2006,NYC Bronx Heath Dept38%Homeless2007,Children Children Health Dept,Percentage of asthma Location Data Source,2020/11/14,44,T Cell,Proliferation and differentiation,TH1 cell,TH2 cell,IFN-TNF-IL-15 IL-18 IL-12,APC,IL-10IL-13IL-4 IL-5 IL-6,COSTIMULATION,Th1/Th2 Cytokine Expression,2020/11/14,45,Wha
24、t T Cell Subsets(in Addition to Th1,Th2)Are Involved in Allergic Responses?,2020/11/14,46,T Cell,Proliferation and differentiation,TH1 cell,TH2 cell,IFN-IL-15 IL-18 IL-12,APC,IL-13IL-4 IL-5,COSTIMULATION,T Cell Subsets,Th17,Treg,IL-17,IL-10TGF-,2020/11/14,47,T Regulatory Cells(Tregs),T cell subtype
25、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.Immunol.5,14611471 1993.CD4+CD25+,GITR,LAG-3,Foxp3,CTLA4,2020/11/14,48,Maternal Atopy:Association With Decreased Foxp3,n=29 mothers without and n=21 mot
26、her with atopy,B Schaub,PW Finn et al,Respiratory Research 2006,2020/11/14,49,Summary,Severe asthma is a spectrum of disease,with different pathologic and clinical phenotypesDefining phenotypes is in its infancyTailoring treatment to phenotypes is the ultimate goalImportance of contributing factors
27、and adherence cannot be overestimatedInnate and adaptive immunity impact asthma pathogenesis,2020/11/14,50,Symbionts,Commensals,Pathobionts,Tregs,Th 17cells,Healthy microbiota,Altered microbiota,Symbionts,Commensals,Pathobionts,immune dysregulation,Infectious susceptibility,Tregs,Th 17cells,Nakajima et al.Semin Immunopathol.2011,2020/11/14,51,谢谢！,
