COPD: op het kruispunt van infecties en auto-immuniteit

Guy Brusselle, MD, PhD Universitair Ziekenhuis Gent

Gent, Belgium

Immunology of COPD: Overview Introduction

Innate immunity

Dendritic cells

Adaptive immunity

Auto-immunity in COPD?

Respiratory infections in COPD

Conclusion

Definition of COPD Chronic obstructive pulmonary disease (COPD) is a disease state that is – characterized by airflow limitation:

not fully reversible usually progressive

– associated with an abnormal inflammatory response of the lungs to noxious particles or gases.

COPD is a preventable and treatable disease with some significant extrapulmonary effects. Comorbidities and exacerbations contribute to the severity in individual patients.

COPD: epidemiology

Bousquet J. et al, Eur Respir J 2010; 36: 995-1001.

Bronchiolitis Emphysema

SYMPTOMS cough sputum dyspnea

EXPOSURE TO RISK FACTORS

tobacco occupation

indoor/outdoor pollution

SPIROMETRY

Diagnosis of COPD

: FEV1/FVC < 70% Post bronchodilatation!

COPD: accelerated decline in lung function

Fletcher & Peto, 1977

Never smoked

Stopped at 65

Stopped at 45 Smoked regularly and susceptible

to its effects

100

75

50

0

25

25 50 75

Age (years)

FEV1 (% of value at age 25)

Disability

Death

COPD: impaired lung growth and/or accelerated decline in lung function

Guy Brusselle, New Engl J Med 2009.

Local and systemic effects of COPD

SYSTEMIC INFLAMMATION

ATHEROSCLEROSIS

MUSCLE WEAKNESS

OSTEOPOROSIS

BAL / LUNG INFLAMMATION

LYMPHOID FOLLICLES

EMPHYSEMA

AIRWAY WALL REMODELING

INNATE ADAPTIVE

BLOOD SERUM

TNFCRP

Leukocytosis

LOCAL (PULMONARY)

EFFECTS

SYSTEMIC EFFECTS

Innate and adaptive immunity in COPD

Brusselle G. et al, Lancet 2011; 378: 1015-26.

Immunology of COPD: Overview Introduction

Innate immunity Dendritic cells

Adaptive immunity

Auto-immunity in COPD?

Respiratory infections in COPD

Conclusion

Chronic CS-exposure in mice is a relevant model of human COPD

COPD patients Smoking mice

Etiology Cigarette smoke

Cigarette smoke

Duration chronic chronic

Genetic predisposition

20% of smokers straindependent

Pulmonary inflammation

innate adaptive immune cells

innate adaptive immune cells

Time course of cigarette smoke-induced BAL inflammation in mice

D’Hulst A et al, Eur Resp J 2005; 26: 204-213.

D’Hulst A et al, Resp Research 2005.

CS-induced increase in innate inflammatory cells in BAL of wild type Balb/c and scid mice

CS-induced increase in adaptive immune cells in lungs of wild type Balb/c and scid mice

D’Hulst A et al, Resp Research 2005.

CS-induced emphysema in Balb/c and scid mice

WT

scid

D’Hulst A et al, Resp Research 2005.

Air CS (Cigarette Smoke)

TLRs

IL-1β secretion

P2X7

NLRPs

pro caspase-1

mature IL-1β

NF-KB

caspase-1

pro IL-1β

PAMPs DAMPs

ROS Proteolytic enzymes (NE, MMP-9, MMP-12,…)

Pro-inflammatory cytokines and chemokines (TNF-α, IL-1β, CXCL8,…)

I) sensing cigarette smoke and danger signals

II) effector phase

INFLAMMASOME

P2Y2

TLRs

RAGE

P2X7

IL-1R

TNF-α CXCL8

ROS

cell death (apoptotic, necrotic)

bacteria viruses

Innate immune responses in COPD

Sensing of cigarette smoke components and Damage Associated Molecular Patterns (DAMPs) in COPD

Brusselle G. et al, Lancet 2011.

Immunology of COPD: Overview Introduction

Innate immunity

Dendritic cells Adaptive immunity

Auto-immunity in COPD?

Respiratory infections in COPD

Conclusion

Function of dendritic cells (DC)

Vermaelen K et al, AJRCCM 2005.

Time course of the effect of cigarette smoke exposure on dendritic cell number in BAL

D’Hulst A et al, Eur Resp J 2005; 26: 204-213.

Accumulation of Langerin+ dendritic cells in small airways of COPD patients

Demedts I. et al, Am J Respir Crit Care Med. 2007.

Never smoker “Healthy” Smoker COPD GOLD I

COPD GOLD II COPD GOLD III COPD GOLD IV

Air Smoke

MHC II

CD86

CD80

CD40

Dendritic cells in BAL fluid of CS-exposed mice show increased expression of MHC class II and costimulatory molecules.

D’Hulst A et al, Eur Resp J 2005; 26: 204-213.

Pulmonary dendritic cells express MMP-12 mRNA

Bracke K. et al, Int Arch Allergy Immunol 2005.

Dendritic cells drive CD4+ T helper cell differentiation

Brusselle G. et al, Lancet 2011; 378: 1015-26.

Immunology of COPD: Overview Introduction

Innate immunity

Dendritic cells

Adaptive immunity Auto-immunity in COPD?

Respiratory infections in COPD

Conclusion

Adaptive immune responses in COPD

Brusselle G. et al, Lancet 2011; 378: 1015-26.

Lymphoid follicles in patients with severe COPD

Hogg J et al, NEJM 2.004; 350:2645-53.

Lymphoid (B-cell) follicles in murine lung tissue after 2-6 months smoke exposure

Van der Strate B. et al, AJRCCM 2006; 751-758.

The development of B-cell follicles is progressive with time and correlates with the increase in airspace enlargement. Correlation causal association?

CS-induced increase in lymphoid follicles

WT

Scid

D’Hulst A et al, Eur Resp J 2005; 26: 204-213.

Air

Air

CS

CS

Lm: wild type: Air: 38.1 µm CS: 41.6 µm p<0.01 Lm: scid: Air: 38.3 µm CS: 41.4 µm p<0.05

ERJ 2009; 34:219-30.

______________________________________ ______

____________________________________________

Drivers of adaptive immune responses in COPD?

Cigarette smoke components (eg tobacco glycoprotein)? Bacterial colonization (eg H. influenzae) Viral infections (eg adenovirus) Breakdown products of extracellular matrix

(eg elastin fragments) Autoimmunity? Self (neo)antigens?

+ + - -

Immunology of COPD: Overview Introduction

Innate immunity

Dendritic cells

Adaptive immunity

Auto-immunity in COPD? Respiratory infections in COPD

Conclusion

Autoimmune disease: definition A chronic inflammatory process leading to progressive tissue damage Induced by an interaction of a genetic predisposition and exogenic factors Persistent even when the initial inciting agent has disappeared (eg smoking cessation) Mediated by adaptive immune mechanisms (auto-antibodies, autoreactive T cells) Sequence of events!

Pathogenesis of rheumatoid arthritis

I. Mcinnes and G. Schett, Nature Reviews Immunology 2007.

Autoantibodies before SLE

Arbuckle M. et al, NEJM 2003.

Nat Med 2007; 13: 567-69.

_____________________________________________ _________________________________

Innate and adaptive immune responses in COPD

Lee S. et al, Nature medicine 2007.

C. Greene et al, AJRCCM 2010; 181: 31-35.

_____________

AntiNuclear Antibodies (ANA) in COPD

Nunez B. et al, AJRCCM 2011; 183: 1025-31.

AntiTissue Antibodies (AT) in COPD

Nunez B. et al, AJRCCM 2011; 183: 1025-31.

The paradigm of autoimmune disease

Gene environment

autoantibody

Disease

The paradigm of autoimmune disease

Gene environment

Specific autoantibody

Disease

Non-specific autoantibody

What constitutes a specific autoantibody?

Specific Antigen-specific Disease or subset specific High titre (>10x normal) Used in clinical diagnosis Likely to be involved in pathogenesis. Family of biologically related proteins

Non-Specific Cross-reactive Present in other autoimmune diseases Low titre (2-3 x normal) Of little clinical use Results from tissue injury or polyclonal activation Heterogeneous antigens

Immunology of COPD: Overview Introduction

Innate immunity

Dendritic cells

Adaptive immunity

Auto-immunity in COPD?

Respiratory infections in COPD Conclusion

M. Hilty et al, Plos One 2010; 5: e8578.

Distribution of common bacterial phyla and genera in normal and diseased bronchi

M. Hilty et al, Plos One 2010; 5: e8578.

Pathogen Associated Molecular Patterns (PAMPs) and Pattern Recognition Receptors (PRR) in COPD

Defective macrophage phagocytosis of bacteria in COPD

A. Taylor et al, ERJ 2010; 35: 1039-47.

Macrolides stimulate phagocytosis of bacteria by macrophages

A. Taylor et al, ERJ 2010; 35: 1039-47.

Mucosal IgA switching and secretory IgA (sIgA) epithelial transcytosis via pIgR

Cerutti A. Nat Rev Immunol 2008; 8: 421-34.

Bronchial secretory IgA deficiency in COPD

Polosukhin V. et al, AJRCCM 2011; 184: 317-27.

Deficiency of secretory IgA (SIgA) in BAL fluid of COPD

Polosukhin V. et al, AJRCCM 2011; 184: 317-27.

Vicious-circle hypothesis of infection and inflammation in COPD

S. Sethi and T. Murphy, NEJM 2008; 359: 2355-65.

PAMPs DAMPs

Azithromycine ter preventie van exacerbaties bij COPD

Albert R. et al, NEJM 2011; 689-98.

Experimental rhinovirus infection in subjects with COPD causes exacerbations

Mallia P. et al, AJRCCM 2011; 183: 734-42.

Experimental rhinovirus infection in subjects with COPD causes exacerbations

Mallia P. et al, AJRCCM 2011; 183: 734-42.

Immunology of COPD: Overview Introduction

Innate immunity

Dendritic cells

Adaptive immunity

Auto-immunity in COPD?

Respiratory infections in COPD

Conclusion

Immunology of COPD: conclusions (1)

Cigarette smoke activates innate immune cells (macrophages, neutrophils and epithelial cells) by triggering Pathogen Recognition Receptors: – directly (e.g. LPS, oxidative stress) or – indirectly (via DAMPs).

Defective macrophage phagocytosis of bacteria and apoptotic cells in COPD.

Immunology of COPD: conclusions (2)

Dendritic cells accumulate in the lungs of CS-exposed mice and in the small airways of patients with (severe) COPD.

Chronic adaptive immune responses (Th1 and Th17 CD4+ cells, cytotoxic CD8+ cells and B cells) lead to the development of lymphoid follicles.

Immunology of COPD: conclusions (3)

Autoantibodies are present in a subgroup of patients with severe COPD (emphysema): pathogenic?

The sequence of events in the pathogenesis of RA (rheumatoid arthritis) and COPD is different: – RA: auto-antibodies articular inflammation

and destruction

– COPD: pulmonary inflammation and destruction auto-antibodies?

Immunology of COPD: conclusions (4)

Viral and bacterial infections of the respiratory tract: – cause acute exacerbations of COPD

(proof of concept: Rhinovirus) – amplify and perpetuate chronic

inflammation in stable COPD (via PAMPs). Deficiency of bronchial secretory IgA in COPD.

ACKNOWLEDGMENTS: Lab for Translational Research of Obstructive Pulmonary Disease

Guy Brusselle

Guy Joos

Karim Vermaelen

Ken Bracke

Tania Maes Sharen Provoost

Lies Lahousse

Ingel Demedts

Geert Van Pottelberge

Yannick van Durme

Eliane Castrique

Ann Neesen

Indra De Borle

Philippe De Gryze

Katleen De Saedeleer

Marie-Rose Mouton

Greet Barbier

Anouck Goethals

Christelle Snauwaert

Department of Respiratory Medicine

Ghent University, Ghent, Belgium

Leen Seys Griet Conickx Fien Verhamme Lisa Dupont Ellen Lanckacker Tine Demoor

Nele Pauwels

An D’Hulst

Chris Van Hove

Katrien Moerloose

Prof Dr B Stricker Prof Dr A Hofman Prof A Uitterlinden Prof C Van Duijn Prof H Hoogsteden Dr A Ikram Dr M Vernooij Dr J Heeringa

Dr L Lahousse Dr Y van Durme Dr D Loth Dr J Aerts Dr K Verhamme Dr M Eijgelsheim Lic F van Rooij Mevr J verkroost And all other colleagues and researchers at

the Erasmus University / Ommoord research centre (ERGO); the CHARGE consortium: ARIC, CHS, FHS and RS.

Acknowledgments

Immunopathology of COPD

P. Barnes, Nat Rev Immunol 2008.