1、Asthma:Immune PhenotypesAsthma:Immune PhenotypesAsthmaAsthma is clinically defined as a syndrome with episodic wheezing, shortness of breath, cough and sputum productionThe constant features are airway irritability (hyperresponsiveness) and inflammationAsthmaAsthma is clinically defAsthma: Epidemiol

2、ogyBetween 150-300 million patients worldwide15-25 million in the U.S.Most common chronic disease of childhoodOver 500,000 E.R. visits per year25,000 ICU admissions5-6,000 deaths in U.S.On the increaseAsthma: EpidemiologyBetween 1Allergic Asthma: PathwaysAllergic Asthma: PathwaysIgEIL-13EosinophilsI

3、L-5IL-13Th2Th1Mast CellB-cellIL-4TCRMHC IIT Lymphocyte APCCD80CD86CD28Generation of Allergic Adaptive Immune ResponsesIgEIL-13EosinophilsIL-5IL-13ThSevere Asthma Definition Phenotypes - Pathologic/Clinical Therapeutic OptionsSevere Asthma DefinitionInflammation and Remodeling in AsthmaCourtesy of Ma

4、rllyn Glassberg, MDInflammation and Remodeling CoApproach to Management/Contributing Factors/Co-Morbid ConditionsExamine for concomitant medical disorders, i.e. sinusitis, OSA, VCDGERD - acid and non-acid refluxEnvironmental controlAlternative diagnosesIncorporate objective measures into managementW

5、ritten action planReview medication techniqueApproach to Management/ContribSevere Asthma ClustersMoore et al. AJRCCM 2010;181:315-323Severe Asthma ClustersMoore etAsthma ClustersCluster 1: early onset, atopic, nl lung fxn 2 controllers, nl lung fxn, significant health care utilizationCluster 3: adul

6、t 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 5: early onset, severe obstruction, 66% atopic; less reversibility ( FE

7、V1: 43% to 58%), high health care utilizationMoore et al. AJRCCM 2010;181:315-323Asthma ClustersCluster 1: earlAsthma Phenotypes: Heterogeneous DiseaseClinical:Pathologic:Fixed obstructionEosinophilicObeseNon-eosinophilicAdult onsetPauci-granulocyticExacerbation proneTreatment resistantTriggers:Occu

8、pationalAspirinExerciseMensesAsthma Phenotypes: HeterogenePathological PhenotypesEosinophilic/TH2 (IL-4, IL-5 and IL-13)Non-eosinophilic (sputum eos 2%, or peripheral blood eos 200/l)Pathological PhenotypesEosinopClinical Features of Asthmatics with “High” and “Low” IL-13 Gene SignaturesWoodruff, et

9、 al. AJRCCM 2009; 180:388-395Clinical Features of AsthmaticWoodruff et al Am J Respir Crit Care Med 180:3888-95, 2009Th2 “high” vs. “low” signature results in different clinical characteristics and response to ICSWoodruff et al Am J Respir CriInterleukin-13 and Non-Interleukin-13 Inflammatory Pathwa

10、ys in AsthmaKraft M. N Engl J Med 2011;365:1141Interleukin-13 and Non-InterleBiomarkers to identify the Th2 phenotypeSputum eosinophilsExhaled nitric oxideCirculating eosinophilsPeriostin IgEAllergen skin testingBiomarkers to identify the Th2Severe Asthma: Periostin correlates with sputum and tissue

11、 eosinophilsJia et al. JACI 2012;130:647Severe Asthma: Periostin correEosinophilic Phenotype: Some Treatment OptionsEosinophilic Phenotype: Some Eosinophilic Phenotype: Rationale for Zileuton (Leukotriene Inhibitor)Anti-eosinophil and anti-mast cell effectsDecreased BAL eos in nocturnal asthma (Wenz

12、el ARRD 1995)Decreased mast cell tryptase following ASA challenge (Israel, ARRD 1993)Broader effect than montelukastInhibits activation of multiple cysLT receptorsBlocks LTB4Blocks other 5 LO metabolites Eosinophilic Phenotype: RationEosinophils Phenotype: Omalizumab (anti-IgE) reduces submucosal Eo

13、sinophilsEosinophils(cells/mm2)BaselinePosttreatment020608080602004040BaselinePosttreatment8.01.56.36.4Placebo (n=14)Omalizumab (n=14)P0.001P=0.81P=0.033Djukanovic et al. AJRCCM 2004Eosinophils Phenotype: OmalizuLung Function: Inhibition of IL-13Corren et al. NEJM 2011; 365:1088Lung Function: Inhibi

14、tion of Non-eosinophilic AsthmaNon-eosinophilic AsthmaEosinophilic and non-eosinophilic asthma: pathologic comparisonBerry et al. Thorax 2007;62:1043Eosinophilic and non-eosinophiInhaled Corticosteroids: Airways HyperresponsivenessBerry et al. Thorax 2007;62:1043Inhaled Corticosteroids: AirwInhaled

15、Corticosteroids:Quality of Life Berry et al. Thorax 2007;62:1043Inhaled Corticosteroids:QualiNon-eosinophilic asthma: other mediators?Non-eosinophilic asthma: othWang, Curr Opin Immun 2008; 20:697-702Wang, Curr Opin Immun 2008; 20Increased Membrane Bound TNF- in Refractory AsthmaBerry, et al. NEJM 2

16、006; 354:697-708Increased Membrane Bound TNF-BAL TNF- Levels are Increased in The Lungs of Obese Asthmatics*p0.001, *p0.01, #p0.05 Lugogo et al. AJRCCM 2012; 864:404BAL TNF- Levels are IncreasedNon-eosinophilic phenotype: treatment options?Non-eosinophilic phenotype: trAsthma Phenotypes and Macrolid

17、es 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 previous 12 monthsAzithromycin vs. placebo ad

18、ded to combination therapy for 6 months in a double-blind fashionPrimary outcome was the rate of exacerbations and LTRI requiring antibioticsAsthma Phenotypes and MacrolidAsthma Phenotypes and Macrolides- Results in the Entire CohortBrusselle et al. Thorax 2013;177:148Asthma Phenotypes and MacrolidN

19、onoesinophilic Asthma: Only (defined as blood eos 200/l)Brusselle et al. Thorax 2013;177:148Nonoesinophilic Asthma: Only Severe Asthma: Tiotropium Kerstjens et al. NEJM 2012Severe Asthma: Tiotropium KersEnvironment and immunity: impact on asthma pathogenesis?Environment and immunity: impaNEJM 347:91

20、1, 2002Epidemiological trends in infections and chronic diseasesNEJM 347:911, 2002EpidemiologiInnate and Adaptive ImmunityInnateAntigen independentPattern-Recognition ReceptorsToll-like receptors (TLRs)NOD-like receptors (NLRs)Collectins (SP-A/D)AdaptiveAntigen dependentT and B cellsAntigen Specific

21、 Receptors TCRInnate and Adaptive ImmunityInToll-like Receptor FamilyIgIg - likeLeucine-richdomainLeucineRichLRRCTLeucine-richrepeat C-terminaldomainTIRToll Interleukin 1resistanceTIRTLR1 762 aaTIRTLR2 766 aaTIRTLR3 881 aaTIRTLR4 816 aaLeucineRichLeucineRichLRRCTTIRTLR7 1023 aaLeucineRichLeucineRich

22、TIRTLR8 1015 aaLeucineRichTIRTLR10 792 aaLeucineRichLRRCTLeucineRichLeucineRichLRRCTLRRCTLRRCTTIRTLR5 838 aaLeucineRichLRRCTTIRTLR9 1007 aaLeucineRichLRRCTTIRTLR6 796 aaLeucineRichLRRCTLeucineRichLeucineRichLRRCTLeucineRichLeucineRichLeucineRichLeucineRichLeucineRichLeucineRichLeucineRichLpAPpgToll-

23、like Receptor FamilyIgIg TLR4APCT cellCD28costimulationCD86CD80MHCTCRtranscriptionIkBPPPPG LPSNF-B activation TLR2CD14MyD88Innate and Adaptive Immunity TLR4APCT cellCD28costimulatio哮喘免疫表型課件Lancet 358:1129, 2001Early life exposure to farm animals reduces asthma and hay feverLancet 358:1129, 2001Early

24、 lifNY NY Asthma Rates: NYC Children15 %Bronx 1996, AECOM21-23%Hunts Point, 2006, NYC Bronx Heath Dept38%Homeless2007, Children Children Health Dept Percentage of asthma Location Data SourceAsthma Rates: NYC Children15 %T CellProliferation and differentiationTH1 cellTH2 cellIFN- TNF- IL-15 IL-18 IL-

25、12APCIL-10IL-13IL-4 IL-5 IL-6MHCTCRCOSTIMULATIONTh1/Th2 Cytokine ExpressionProliferation and differentiatWhat T Cell Subsets (in Addition to Th1, Th2) Are Involved in Allergic Responses?What T Cell Subsets (in AdditT CellProliferation and differentiationTH1 cellTH2 cellIFN-IL-15 IL-18 IL-12APCIL-13I

26、L-4 IL-5COSTIMULATIONT Cell SubsetsTh17TregIL-17IL-10TGF-Proliferation and differentiatT 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.Immunol. 5, 14611471 1993.CD4+CD25+, GITR, LAG-3, Foxp3, C