Innate (Native) Immunity in COPD Sanjay Sethi MD Professor Pulmonary, Critical Care and Sleep...

Innate (Native) Immunity in COPD Innate (Native) Immunity in COPD

Sanjay Sethi MDSanjay Sethi MD

ProfessorProfessor

Pulmonary, Critical Care and Sleep Pulmonary, Critical Care and Sleep MedicineMedicine

University at Buffalo, SUNYUniversity at Buffalo, SUNY

[email protected]@buffalo.edu

COPD: EtiologyCOPD: Etiology

Pathogenesis of COPDPathogenesis of COPD

NOXIOUS AGENT(tobacco smoke, pollutants, occupational

agent)

Airflow Obstruction

Genetic factors

Respiratory infection

Airway Hyper-reactivity

Nutritional factors

Infections in COPDInfections in COPD

Acute or ChronicAcute or Chronic PathogensPathogens

Typical bacteria Typical bacteria Nontypeable Nontypeable Haemophilus Haemophilus

influenzaeinfluenzae Streptococcus Streptococcus

pneumoniaepneumoniae Moraxella catarrhalisMoraxella catarrhalis Pseudomonas aeruginosaPseudomonas aeruginosa

Atypical bacteriaAtypical bacteria Chlamydia pneumoniaeChlamydia pneumoniae Mycoplasma pneumoniaeMycoplasma pneumoniae

Viruses Viruses InfluenzaInfluenza ParainfluenzaParainfluenza RhinovirusRhinovirus AdenovirusAdenovirus RSVRSV

FungiFungi Pneumocystis jirvoceiPneumocystis jirvocei

Patient 14Time Line 1 month

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI HI

A A A A B B B B B B C D D D D D D D D D D

Buffalo VA COPD Study Clinic

ex

25 30 35 40 45 50

Clinic visit

Hi Hi Hi Hi Hi Hi

Haemophilusinfluenzae

SDS-PAGE

PFGE

38 39 40 42 43 44 45

PCR-P2 gene, sputum pelletsMurphy et al AJRCCM 2004

Impaired lung defense

Impaired host defenses: respiratory viruses new strains of bacteria environmental irritants

Progressive loss of lung function and deteriorating quality of life

Smoking/irritants

Chronic cycle

Acute cycle

COPD Pathogenesis: InfectionCOPD Pathogenesis: Infection

Acute on chronic inflammation

(pathogen + host- mediated inflammatory factors)

Chronic inflammation

(bacterial + host- mediated inflammatory factors)

Chronic bacterial colonization

Definition of ‘Colonization’Definition of ‘Colonization’

Absence of immune responseAbsence of immune response Absence of damaging effects to the hostAbsence of damaging effects to the host Not defined by absence of symptomsNot defined by absence of symptoms

Mandell et al, Principles and Practice of Infectious Diseases

Small Airways in COPDSmall Airways in COPDInflammatory mucus exudatesInflammatory mucus exudates

Hogg et al, NEJM, June 2004

Small Airways in COPDSmall Airways in COPDLymphocytesLymphocytes

Hogg et al, NEJM, June 2004

Sputum Inflammation and Bacterial Sputum Inflammation and Bacterial ColonizationColonization

Banerjee D et al Eur Respir J. 2004 ;23:685-91. n=27 n=40 n=27 n=40

Bronchial Inflammation and Bronchial Inflammation and Bacterial colonizationBacterial colonization

Bronchoscopy with BALBronchoscopy with BAL Stable COPD (n = 52)Stable COPD (n = 52) Healthy Smokers (n = 18)Healthy Smokers (n = 18) Non-smokers (n = 8)Non-smokers (n = 8)

PPM colonizationPPM colonization 32% Stable COPD32% Stable COPD 42% Smokers42% Smokers 0% Non-smokers0% Non-smokers

Increased airway Increased airway inflammation with inflammation with bacterial colonizationbacterial colonization

0

10

20

30

40

50

60

70

PMN TNF IL-8

PPM

No PPM

Soler et al ERJ 1999;14:1015-22

* *

Bacterial Colonization Bacterial Colonization in Ex-smokers with COPDin Ex-smokers with COPD

GroupGroup % positive for % positive for PPM >/=10PPM >/=1022/ml /ml

Pathogens Pathogens isolated isolated

Titer Titer

1 (ex-smokers 1 (ex-smokers with COPD)with COPD)

34.6 % 34.6 % (9/26)(9/26)

1) NTHI and HP1) NTHI and HP

2) NTHI and SP2) NTHI and SP

3) HP3) HP

4) PA4) PA

5) SA5) SA

6) NTHI6) NTHI

7) NTHI7) NTHI

8) HP8) HP

9) HP9) HP

3 x 103 x 1022 2 x 10 2 x 1022

7 x 107 x 1044 2 x 10 2 x 1044

1 x 101 x 1022

6 x 106 x 1022

1 x 101 x 1022

1.5 x 101.5 x 1044

5 x 105 x 1055

6.5 x 106.5 x 1055

3 x 103 x 1055

2 (ex-smokers 2 (ex-smokers without without COPD)COPD)

0% (0/20)0% (0/20)

3 (healthy 3 (healthy non-smokers)non-smokers)

6.7% (1/15)6.7% (1/15) 1) HP1) HP 2 x 102 x 1022

Sethi et al AJRCCM 2006, 173:991-8

0

10

20

30

40

50

60

70

80

90

COPD PPB+

COPDPPB-

Ex-smokers Non-smokers

%

PMN

Groups

p<0.001

p<0.001

p=0.03

p=0.02

p=0.004

0

50000

100000

150000

200000

250000

300000

350000

400000

450000

PMN

/ml

p=0.02

p=0.007

p<0.001

COPD PPB+

COPDPPB-



Groups


1

10

100

1000IL-8 pg/ml

Groups

p=0.006

p<0.001

p<0.001

p=0.02

Ex-smokers Non-smokersCOPD PPB+

COPDPPB-

1

10

100

1000

10000

100000

1000000

Active MMP-9 units/ml

Groups

p=0.04

p<0.001

p=0.01

p=0.002

p=0.007

COPD PPB+

COPDPPB-







Smoking/irritants

Chronic cycle

Acute cycle







Cause or EffectCause or Effect

Discovery of specific pathways of innate Discovery of specific pathways of innate immunityimmunity

Very small clinically relevant quantities of Very small clinically relevant quantities of bacterial molecules are pro-inflammatorybacterial molecules are pro-inflammatory

Persistence mechanisms of NTHI not dependent Persistence mechanisms of NTHI not dependent on airway inflammationon airway inflammation

Impaired ability of innate defense to clear NTHIImpaired ability of innate defense to clear NTHI What is the evidence that inflammation induces What is the evidence that inflammation induces

‘colonization’ in the lower respiratory tract? ‘colonization’ in the lower respiratory tract?

TLR activation and signaling

Clin. Sci. (2005) 109, 125-133

NTHI Components are Potent NTHI Components are Potent Stimulants of Macrophages Stimulants of Macrophages

Purified components of Purified components of NTHINTHI OMP P6OMP P6 OMP P2OMP P2 LOSLOS Total OMPTotal OMP

Biologically relevant Biologically relevant concentrations concentrations

Sputum levels with 10Sputum levels with 1077 bacteria/mlbacteria/ml P6: 4 P6: 4 µµg/mlg/ml P2: 95 P2: 95 µµg/mlg/ml

Berenson et al Infect Immun 2005;73: 2728-35

http://iai.asm.org/content/vol73/issue5/images/large/zii0050548240007.jpeg

H. influenzaeH. influenzae in Bronchial in Bronchial TissueTissue

NTHI in tissueNTHI in tissue 13 of 15 critically ill 13 of 15 critically ill

patients with acute patients with acute exacerbation exacerbation

8 of 24 stable COPD8 of 24 stable COPD 0 of 7 healthy controls0 of 7 healthy controls

Bandi et al AJRCCM 2001;164:2114-19

Biofilm Formation by NTHIBiofilm Formation by NTHI

Jursicek J et al , Infect Immun 2005;73: 3210-8

http://iai.asm.org/content/vol73/issue6/images/large/zii0060548800002.jpeg




Smoking/irritants

Chronic cycle

Acute cycle







Innate Lung Defense Innate Lung Defense Mechanisms Mechanisms

Mucociliary clearanceMucociliary clearance Airway antimicrobial Airway antimicrobial

peptidespeptides Cationic polypeptidesCationic polypeptides

LysozymeLysozyme LactoferrinLactoferrin SLPI SLPI CathelicidinCathelicidin

Collectins Collectins Surfactant protein ASurfactant protein A Surfactant protein DSurfactant protein D DefensinsDefensins

Airway epitheliumAirway epithelium AdherenceAdherence Cytokine/ChemokineCytokine/Chemokine

Lung macrophagesLung macrophages OpsonophagocytosisOpsonophagocytosis Cytokine/ChemokineCytokine/Chemokine

Inflammatory cellsInflammatory cells ImmunoglobulinsImmunoglobulins

IgAIgA

Surfactant proteins in COPDSurfactant proteins in COPD

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

COPD Ex-smokers Non-smokers COPD Ex-smokers Non-smokers-500

0

500

1000

1500

2000

2500

3000

SpA SpD

Cytokine Response of Macrophages Cytokine Response of Macrophages to NTHI antigensto NTHI antigens

Berenson C et al AJRCCM 2006

Phagocytosis of NTHI by Lung and Blood Phagocytosis of NTHI by Lung and Blood MacrophagesMacrophages

0

.5

1

1.5

2

2.5

COPDn = 10

Non-COPDn = 17

Non-smokersn = 9

NTHI Strain14P13H5

Pha

gocy

tosi

s In

dex

*

*

**

**

Alveolar Macrophages

0

.5

1

1.5

2

2.5

3

3.5

COPDn = 12

Non-COPDn = 17

Non-smokersn = 9

NTHI Strain14P13H5

Pha

gocy

tosi

s In

dex

Blood Macrophages

Berenson C et al JID 2006

ConclusionsConclusions

Further elucidation of Further elucidation of Mechanisms of colonization and inflammationMechanisms of colonization and inflammation Impact of colonization on disease progressionImpact of colonization on disease progression

Treatments to interrupt the vicious cycle Treatments to interrupt the vicious cycle Antibiotics (PULSE study)Antibiotics (PULSE study) Alternative treatments that interrupt the Alternative treatments that interrupt the

inflammatory or infectious processinflammatory or infectious process The British may have been right all the The British may have been right all the

time!!time!!

AcknowledgmentsAcknowledgments

Innate (Native) Immunity in COPD Sanjay Sethi MD Professor Pulmonary, Critical Care and Sleep...

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