COPD: op het kruispunt van infecties en auto-immuniteit · COPD: op het kruispunt van infecties en...
Transcript of COPD: op het kruispunt van infecties en auto-immuniteit · COPD: op het kruispunt van infecties en...
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.
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____________________________________________
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.